Whole document restricted, see Access Instructions file below for details of how to access the print copy. / Antenatal glucocorticoids are widely used in perinatal medicine, and are one of the key treatments responsible for improving survival of preterm infants since the 1960s. A systematic review reported in this thesis concludes that antenatal glucocorticoids reduce the risk of neonatal death, respiratory distress syndrome (RDS), intraventricular haemorrhage, necrotising enterocolitis, infectious morbidity and need for respiratory support. Several areas of uncertainty have been clarified, including the effectiveness of treatment in the current era of neonatal practice, and in women with hypertension syndromes and premature rupture of membranes. However there is a paucity of data on long-term outcomes after exposure to antenatal glucocorticoids. This is particularly important given recent proposals that fetal exposure to excess glucocorticoids may be a core mechanism explaining the epidemiological evidence that those born small are at increased risk of later adult disease. Furthermore, the relative contributions of fetal growth and prematurity to small size at birth, and hence later disease risk, has not been well elucidated. This thesis reports the follow-up of 534 thirty year olds whose mothers participated in the first, and largest, randomised trial of antenatal betamethasone for prevention of neonatal RDS. Two-thirds of participants were born preterm. Follow-up assessments included cardiovascular risk factors, spirometry, psychological assessment and bone densitometry. Exposure to antenatal betamethasone did not affect mortality, body size, blood pressure, lung function, fasting plasma levels of lipids, cortisol or IgE, socio-economic status, psychological functioning, health related quality of life or bone mass. However betamethasone-exposed participants showed increased insulin resistance. This is the first experimental evidence in man to demonstrate long-term metabolic effects of fetal glucocorticoid exposure. However, as all other outcomes are reassuring, and treatment significantly reduces neonatal mortality and morbidity, obstetricians should continue to use a single course of glucocorticoids for the prevention of neonatal RDS. Adults who were born preterm had increased blood pressure, insulin resistance, reduced lung function and reduced adult height at age thirty. This is the largest reported follow-up of ex-preterm infants into adulthood. Although the associations are relatively small, their potential implications for the prevalence of later chronic obstructive pulmonary and cardiovascular disease are of concern.

New Zealand society assumes that the medical complaints process enhances the delivery of medical care, although the literature suggests that complaints may impact negatively on doctors, and their ability to practice. This thesis examines the impact of the complaints process on doctors in New Zealand. It considers the practice of medicine from the viewpoints of the epistemology of medicine; the doctor-patient relationship; and the notion of professionalism. It presents the results of research methods investigating New Zealand doctors using focus groups; a cross sectional questionnaire based survey; and in-depth semi-structured interviews. Findings include: One in three doctors has received a complaint. The annual rate of complaint is 5.70%, 15% of complaints are upheld. Complaints impact negatively on the person of the doctor, the doctor-patient relationship, and doctors’ ability to practice. The purposes of a complaints system include: the maintenance of trust and professional standards; being a voice for patients; and learning from mistakes and errors. Doctors’ attitudes are consistent with notions of professionalism. Defensive medicine is an adverse outcome of the complaints process. Doctors suggest a Complaints Tribunal as a single point of entry into the complaints process. The current complaints process is not improving the delivery of medical care to New Zealand society. New Zealand doctors are aware of both the biomedical and bio-psychosocial paradigms underlying modern medicine, and the results confirm the importance of the self of the doctor and the doctor-patient relationship in medical practice. The emergence of defensive medicine indicates that doctors may respond to complaints by practicing in a way that is not in their patients’ best interests, but which serves to protect doctors themselves. Defensive medicine risks being unrecognised and becoming normalised into mainstream medical practice. The negative impact of complaints on doctors’ values and beliefs indicate an erosion of values based professionalism. This thesis suggests that an appropriate model for considering medical professionalism is as a state of relationship between doctors and society. Appropriate change to the complaints process may enhance the doctor-society relationship and ultimately enhance the delivery of medical care in New Zealand.

Background Considerable uncertainty exists about the strength and shape of associations of blood pressure and cholesterol with the risks of stroke, coronary heart disease and total cardiovascular death in eastern Asian populations. Therefore, uncertainty also exists about the size of the likely effects on cardiovascular mortality and morbidity of prolonged exposure changes in these populations. The Eastern Stroke and Coronary Heart Disease Collaborative Project was initiated to determine the associations of usual diastolic blood pressure (DBP) and usual cholesterol with the risks of stroke, coronary heart disease (CHD) and total cardiovascular death in cohort studies from eastern Asia. Methods A collaborative overview of cohort studies included data from 13 cohorts from the People’s Republic of China (PRC) and five cohorts from Japan, involving a total of 124,774 participants among whom 837,214 person-years were observed. The overall mean age of participants was 47 years, 43% were current smokers and 39% were female. Both parametric and non-parametric analyses were performed, with adjustments made for several potential confounding factors. Efforts were made to correct for the bias introduced by estimation of "usual" DBP and cholesterol from measurements made at baseline (the "regression dilution" bias). The resulting estimates of associations of blood pressure and cholesterol with cardiovascular diseases were combined with data from surveys of blood pressure and cholesterol levels in Asian and other populations, estimates of the incidence of cardiovascular disease, and results from randomised trials of blood pressure and cholesterol lowering treatments to estimate the possible effects of blood pressure and cholesterol lowering. Findings The overall mean DBP at baseline was 78 mmHg. A total of 1,798 strokes were observed, of which about 45% were confirmed by computed tomography (CT) or autopsy. Each 5 mmHg lower usual DBP was associated with about two-fifths lower non-haemorrhagic stroke risk and about one-half lower haemorrhagic stroke risk(-5 mmHg: odds ratio 0.56, 95% Cl: 0.53-0.59 and 0.69, 0.65-0.73, respectively). The risks were continuous throughout the range of DBP studied (baseline DBP 70-114 mmHg, usual DBP 76-97 mmHg). Each 5 mmHg lower usual DBP was associated with almost a halving of total stroke risk (-5 mmHg: 0.56, 0.53-0.59). The risk of CHD was also strongly and positively related to usual DBP (-5 mmHg: 0.73, 0.66-0.80). Since about half of all cardiovascular deaths were due to stroke, they were strongly related to blood pressure with, on average, each 5 mmHg lower usual DBP associated with about one-third fewer such deaths (-5 mmHg: 0.69, 0.65-0.73). The mean cholesterol at baseline was 4.5 mmol/l (174 mg/dl) and disease risks were assessed across a range of cholesterol levels that correspond approximately to the lower two thirds of the distribution in most Western populations (baseline cholesterol 3.4-6.7mmol/l and estimated usual cholesterol 4.15.8mmol/l). There was a trend toward a negative association of usual cholesterol with strokes classified as haemorrhagic (0.6 mmol/l lower usual cholesterol associated with odds ratio of 1.27, 95% confidence limits 0.84-1.91) and a trend toward a positive association with strokes classified as non-haemorrhagic (-0.6 mmol/l: 0.77, 0.57-1.06). The consequence of these two apparently different (P=0.06) associations, was a weak positive association of usual cholesterol with total stroke (-0.6 mmol/l: O.92, 0.72-1.17). in contrast, there was clear evidence of strong positive associations of usual cholesterol with the risks of CHD (_0.6 mmol/l: 0.47,0.31, 0.71) and of total cardiovascular death (_0.6 mmol/l: 0.58, 0.44-0.76).Overall, there was no clear indication of an interaction between the effects of cholesterol and DBP, when assessed on a multiplicative scale. The estimates of the potential effects of blood pressure lowering indicated that a 3 mmHg lower usual DBP should eventually result in about one-third fewer strokes and one-sixth fewer CHD events. If accompanied by a 0.3 mmol/l lower usual cholesterol, then eventually one-third fewer stroke and CHD events should occur. In the PRC alone, such reductions would be expected to avert over half a million deaths annually. Most events would be prevented in those without hypertension or hypercholesterolaemia. World-wide, a 2% reduction in cholesterol levels would avert about 0'5 million (4%) of CHD deaths in 2020. A 2% reduction in DBP would avert an estimated 1.2 million (16%) stroke deaths and 0.6 million (6%) CHD deaths in 2020. Interpretation Blood pressure is a profoundly important determinant of cardiovascular disease in eastern Asian populations. The relationship observed here between blood pressure and total cardiovascular deaths is steeper than that typically observed in Western populations. This difference appears to be largely due to the different composition of cardiovascular deaths in Eastern populations, with a larger proportion of deaths due to conditions that are strongly related to blood pressure, such as haemorrhagic stroke. In these populations with comparatively low cholesterol from eastern Asia, there was no clear evidence of a cholesterol level below which risks of CHD or total cardiovascular death did not continue to decrease. The strength of the association of cholesterol with CHD was similar to that observed in other populations. The results suggest that modest population-wide reductions in these exposures, particularly blood pressure, could avert a large proportion of the substantial and increasing burden of cardiovascular disease in eastern Asian and other populations.

Aims: To determine the effect of induced myopia on the in vivo scleral biomechanical properties and scleral cell populations in the guinea pig. Methods: One week old guinea pigs were monocularly deprived of form vision (MD) for 14 days. Cycloplegic refractive error was measured with an IR Optometer, and the results analysed using power vectors and linear mixed modelling. The in vivo ocular biomechanical response was investigated by raising the IOP to 50 mmHg for one hour in anaesthetised animals. A-scan ultrasound measures of axial length were taken every 10 minutes with raised IOP, and after returning IOP to 15 mmHg. The total cell population (DAPI antibody) and myofibroblast population (α-SMA antibody) was determined in transverse scleral sections from the posterior 100 degrees of each eye. Results: The average relative myopic refractive error induced was -4.06 ± 0.35 D, which was mainly the result of vitreous chamber depth (VCD) elongation. This was confirmed by a negative correlation between mean sphere and VCD (R2 = 0.4295). On increasing the IOP the deprived and control eyes showed rapid viscoelastic expansion of the VCD that normal eyes did not show. When the increased IOP was maintained the deprived and control eyes showed lower creep rates than normal eyes. Myofibroblasts were shown to be present in guinea pig sclera, as previously observed in human and tree shrew sclera. On average, approximately 64% of the scleral cells were myofibroblasts. The induction of myopia had minimal effect on the cell populations, except for a decrease in total cell numbers in the 10° region equivalent to the location of scleral crescent formation in myopic human eyes. Conclusions: Ahigh proportion of scleral cells show contractile potential in the guinea pig. Form deprivation appears to minimally affect cell numbers, except in the region equivalent to scleral crescent formation in myopic human eyes. However, the in vivo viscoelastic response of the VCD in deprived eyes differs from that in normal eyes, suggesting some factor(s) other than cell number alone has a role in axial length control.

Voltage-activated Ca2+ channels and group I metabotropic glutamate receptors (mGluRs) are important determinants of neuronal excitability and repetitive discharge behaviour. They are also implicated in perinatal developmental processes and Ca2+ -dependent excitotoxic cascades thought to contribute to neurodegeneration. To understand the role that these channels/receptor systems play in the physiology, ontogeny and pathophysiology of MNs, it is necessary to characterise them, during development, in MNs that differ functionally in the behaviours they control, the firing behaviour they produce, their rate of maturation, and their vulnerability to degeneration in ALS. Surprisingly few studies, however, have characterised these channels/receptor systems in MNs, particularly beyond early postnatal stages. I therefore compared voltage-activated Ca2+ channels and group I mGluRs in brain slices from neonate (P1-5) and juvenile (P14-19) rat, in oculomotor (III) and hypoglossal (XII) MNs using whole-cell patch-clamp recording and immunohistochemical techniques. III MNs innervate extraocular muscles, control eye movements that are not fully functional in rat until 2 weeks postnatal, fire at high frequency for sustained periods, and are resistant in ALS. In contrast, XII MNs innervate tongue muscles, control behaviours that are functional at birth, fire bursts of low frequency action potentials, and are vulnerable to degeneration in ALS. In neonates, low voltage-activated (LVA) Ca2+ current densities are similar in III and XII MNs but high voltage-activated (HVA) Ca2+ current densities are ~2-fold higher in XII MNs. While N- and P/Q-type HVA Ca2+ channels are present in both MN pools, greater expression of P/Q-type channels in XII MNs accounts for their greater HVA Ca2+ currents. Developmentally, LVA and HVA Ca2+ current densities decrease ~2-fold by P14-19 in III MNs, but remain unchanged in XII MNs. Thus, in juveniles the HVA Ca2+ current density is ~3-fold greater and the LVA ca2+ current density ~2-fold greater in XII compared to III MNs. The group I mGluR agonist, DHPG, induces inward currents in III and XII MNs of neonatal and juvenile rat, which are mediated by the reduction of a resting K+ conductance. Antagonism of these currents by the mGluR1 antagonist LY367385, but not the mGluR5 antagonist MPEP, and immunohistochemical labelling for mGluR1a but not mGluR5 protein on III and XII MNs, suggest that currents primarily result from the activation of mGluR1. In neonatal rat the current density of DHPG-induced currents is similar between III and XII MNs. However, in juvenile rat DHPG-induced current density is ~3-fold greater in XII compared with III MNs. Differential expression of LVA and HVA Ca2+ currents and varying effects of group I mGluR activation in III and XII MNs during development supports a role for these channels and receptor systems in determining the distinct firing patterns of these two different classes of MNs. The greater voltage-activated Ca2+ currents and group I mGluR-mediated effects in XII MNs, particularly in juvenile MNs, may also contribute to the greater sensitivity of XII MNs to pathophysiological processes, predisposing them to degeneration as seen in ALS.

The differentiation of preadipocytes into adipocytes is one of the most intensely studied biological processes and has led to the understanding of a number of signaling pathways involved in cell growth and differentiation. The nuclear phosphatidyl inositol (pl) signalling pathway, centred around the enzyme phospholipase C (PLC) ��I has been demonstrated to be involved in a number of cellular processes such as mitogenesis and differentiation. Recently components of another lipid signalling pathway, that involving prostaglandins, have also been shown to localise at or within the nucleus. To date, there have been no reports demonstrating the role of either of these nuclear pathways during the differentiation of adipocytes. The 3T3-L1 preadipocyte cell line was used to study the role of nuclear pI and prostaglandin lipid signalling in adipocyte differentiation. In Chapter 3 data is presented to show that two phases of nuclear PLC ��l activity occur during adipocyte differentiation. The first phase occurs within minutes of differentiation being induced, is regulated by the actions of extracellular signal-related kinase (ERK) l/2 and protein kinase c (pKC) ��, and is involved in the mitotic clonal expansion phase of differentiation. The second phase of activity occurs from day 2 of differentiation, is regulated independently of ERK 1/2 and pKC �� and is involved in the regulation of the cell cycle factors cyclin D3 and cyclin-dependent kinase (cdk) 4. In Chapter 4 I investigate the nuclear localisation of prostaglandin synthases, how their localisation is altered by differentiation, and the role of these enzymes in adipocyte differentiation is characterized through inhibitor studies. Cytosolic phospholipase A2 (cPLA2) cyclooxygenase (COX) 1 and 2, microsomal prostaglandin E2 synthase (mPGES), prostacyclin synthase (PGIS), lipocalin prostaglandin D2 synthase (L-PGDS) are localised to the nuclear membrane and their localisation changes during differentiation. The COX 1 and2 enzymes also localise within the nucleus and this COX 1 localisation appears to be cell cycle dependent. COX 2 is functionally coupled to mPGES and PGIS and plays a role in adipocyte differentiation as inhibition of COX 2 with a specific inhibitor (NS 398) completely blocks adipocyte differentiation. COX 1 is functionally coupled with L-PGDS and appears to be involved in lipid metabolism as the inhibition of COX 1 with a specific inhinitor (SC 560) partially blocks lipogenesis. In Chapter 5, I investigate the localisation of prostaglandin receptors in the differentiation process. 3T3- L1 cells express the prostaglandin E2 (EP4) receptor, prostaglandin F2�� (FP) receptor and the prostaglandin D2 (DP) receptor but these do not have a nuclear localisation. Activation of the DP receptor is involved in lipid metabolism as the DP receptor antagonist, BW A868C, partially inhibits lipogenesis. lnternalisation of prostaglandins appears to be necessary for differentiation to occur fully as treatment of differentiating 3T3-L1 preadipocytes with the anionic transport inhibitor bromocresol green (BCG) partially inhibits carbaprostacyclin (cPGI2) induced differentiation and completely inhibits that caused by cyclopentenone prostaglandins. Thus, nuclear lipid signalling pathways appear to play a role in the process of adipocyte differentiation and a proper understanding of these pathways may lead to a better understanding of fat cell development and the role it plays in obesity and its related diseases. / Whole document restricted, but available by request, use the feedback form to request access.

Aim Multiple Sclerosis (MS) is an unpredictable demyelinating disease of the central nervous system (CNS), with fatigue being one of the least understood symptoms. Based on a systematic review of the literature, a cognitive behavioural model of MS fatigue was developed and used to design a manualised eight session cognitive behaviour therapy (CBT) intervention to treat MS fatigue. The purpose of the randomized controlled trial (RCT) was to investigate the efficacy of CBT compared to relaxation training (RT) to treat fatigue in MS. Methods Seventy-two patients with MS fatigue were randomly assigned to either eight sessions of CBT or eight sessions of RT, designed to control for therapist time and attention. Participants were assessed before and after treatment, and at three and six months follow-up. Primary outcomes included the Fatigue Questionnaire (FQ) and the Clinical Global Impression Scale (CGIS). Secondary outcomes included measures of fatigue related impairment, mood, stress, sleep problems and daytime sleepiness. Seventy of the 72 participants completed all therapy sessions and 69 participants completed all assessments. Results Analyses were carried out by intention-to-heat. There was a significant group by time interaction for fatigue, indicating that the CBT group had significantly greater reductions in fatigue severity than the RT group (p<.02). A-priori contrasts showed that this significant effect was largely accounted for by changes between baseline and end of treatment (P<.00). By six month follow-up improvement in fatigue was equivalent in both groups. The key mechanism of improvement in fatigue severity during CBT was a positive change in schematic beliefs about fatigue. At the end of treatment 88.6% of the CBT group rated themselves as improved compared to 73% of the RT group, but this difference was not significant (p<.09). Both groups improved on almost all secondary outcomes, with the CBT participants improving more significantly on depression, anxiety and stress between baseline and end of treatment (p<.05). Conclusions CBT appears to be an effective treatment for MS fatigue, with CBT participants improving significantly more on fatigue than RT participants between baseline and end of treatment. Obtained effect sizes for fatigue in both CBT and RT were considerably larger than those in previous controlled trials of pharmacological and non-pharmacological interventions. Both groups improved on almost all of the secondary outcomes. Findings support the relevance of a cognitive behavioural model for MS fatigue. / Whole document restricted, but available by request, use the feedback form to request access.

Measurement of diastolic left ventricular (LV) function is vitally important in the assessment of cardiac disease. However, only limited information on tissue function can be obtained with current clinical techniques. This Thesis developed and investigated novel parameters of both global and regional myocardial function, using cardiac magnetic resonance imaging (MRI) with three-dimensional tissue tagging. Multidirectional peak myocardial shortening strains and strain rates, as well as the peak systolic displacement and velocity of the mitral valve annulus plane (MVP), were considered as parameters of LV systolic function. The corresponding peak diastolic strain relaxation rates and peak diastolic MVP velocity were used to assess diastolic function. The effects of normal ageing were studied in people with no evidence of cardiac disease, and compared with the effects of disease in patients with type 2 diabetes mellitus (DM). In normal healthy subjects, systolic strain parameters were preserved, while diastolic parameters were impaired, with age. DM patients showed impaired diastolic function on correction for age, and systolic functional parameters were also impaired, even though LV ejection fraction was normal. MVP systolic and diastolic motion were reduced both with age and in DM patients. Systolic LV torsion was increased with age and in DM, with no corresponding increase in torsional relaxation. Both systolic and diastolic function parameters were regionally heterogeneous. With normal ageing, diastolic function was impaired in a regionally non-uniform manner. Thus, a complete assessment of LV function requires measurement of LV tissue mechanics as well as chamber haemodynamics. MRI provides valuable information regarding myocardial tissue behaviour, contributing to systolic and/or diastolic dysfunction, which cannot be obtained otherwise. Systolic tissue dysfunction may develop concomitantly in patients with diastolic dysfunction, even when global ejection fraction is preserved. Regional analyses provide important information on how local changes contribute to global function. The influence of age must be taken into account in studies of disease.

Voltage-activated Ca2+ channels and group I metabotropic glutamate receptors (mGluRs) are important determinants of neuronal excitability and repetitive discharge behaviour. They are also implicated in perinatal developmental processes and Ca2+ -dependent excitotoxic cascades thought to contribute to neurodegeneration. To understand the role that these channels/receptor systems play in the physiology, ontogeny and pathophysiology of MNs, it is necessary to characterise them, during development, in MNs that differ functionally in the behaviours they control, the firing behaviour they produce, their rate of maturation, and their vulnerability to degeneration in ALS. Surprisingly few studies, however, have characterised these channels/receptor systems in MNs, particularly beyond early postnatal stages. I therefore compared voltage-activated Ca2+ channels and group I mGluRs in brain slices from neonate (P1-5) and juvenile (P14-19) rat, in oculomotor (III) and hypoglossal (XII) MNs using whole-cell patch-clamp recording and immunohistochemical techniques. III MNs innervate extraocular muscles, control eye movements that are not fully functional in rat until 2 weeks postnatal, fire at high frequency for sustained periods, and are resistant in ALS. In contrast, XII MNs innervate tongue muscles, control behaviours that are functional at birth, fire bursts of low frequency action potentials, and are vulnerable to degeneration in ALS. In neonates, low voltage-activated (LVA) Ca2+ current densities are similar in III and XII MNs but high voltage-activated (HVA) Ca2+ current densities are ~2-fold higher in XII MNs. While N- and P/Q-type HVA Ca2+ channels are present in both MN pools, greater expression of P/Q-type channels in XII MNs accounts for their greater HVA Ca2+ currents. Developmentally, LVA and HVA Ca2+ current densities decrease ~2-fold by P14-19 in III MNs, but remain unchanged in XII MNs. Thus, in juveniles the HVA Ca2+ current density is ~3-fold greater and the LVA ca2+ current density ~2-fold greater in XII compared to III MNs. The group I mGluR agonist, DHPG, induces inward currents in III and XII MNs of neonatal and juvenile rat, which are mediated by the reduction of a resting K+ conductance. Antagonism of these currents by the mGluR1 antagonist LY367385, but not the mGluR5 antagonist MPEP, and immunohistochemical labelling for mGluR1a but not mGluR5 protein on III and XII MNs, suggest that currents primarily result from the activation of mGluR1. In neonatal rat the current density of DHPG-induced currents is similar between III and XII MNs. However, in juvenile rat DHPG-induced current density is ~3-fold greater in XII compared with III MNs. Differential expression of LVA and HVA Ca2+ currents and varying effects of group I mGluR activation in III and XII MNs during development supports a role for these channels and receptor systems in determining the distinct firing patterns of these two different classes of MNs. The greater voltage-activated Ca2+ currents and group I mGluR-mediated effects in XII MNs, particularly in juvenile MNs, may also contribute to the greater sensitivity of XII MNs to pathophysiological processes, predisposing them to degeneration as seen in ALS.

Aims: To determine the effect of induced myopia on the in vivo scleral biomechanical properties and scleral cell populations in the guinea pig. Methods: One week old guinea pigs were monocularly deprived of form vision (MD) for 14 days. Cycloplegic refractive error was measured with an IR Optometer, and the results analysed using power vectors and linear mixed modelling. The in vivo ocular biomechanical response was investigated by raising the IOP to 50 mmHg for one hour in anaesthetised animals. A-scan ultrasound measures of axial length were taken every 10 minutes with raised IOP, and after returning IOP to 15 mmHg. The total cell population (DAPI antibody) and myofibroblast population (α-SMA antibody) was determined in transverse scleral sections from the posterior 100 degrees of each eye. Results: The average relative myopic refractive error induced was -4.06 ± 0.35 D, which was mainly the result of vitreous chamber depth (VCD) elongation. This was confirmed by a negative correlation between mean sphere and VCD (R2 = 0.4295). On increasing the IOP the deprived and control eyes showed rapid viscoelastic expansion of the VCD that normal eyes did not show. When the increased IOP was maintained the deprived and control eyes showed lower creep rates than normal eyes. Myofibroblasts were shown to be present in guinea pig sclera, as previously observed in human and tree shrew sclera. On average, approximately 64% of the scleral cells were myofibroblasts. The induction of myopia had minimal effect on the cell populations, except for a decrease in total cell numbers in the 10° region equivalent to the location of scleral crescent formation in myopic human eyes. Conclusions: Ahigh proportion of scleral cells show contractile potential in the guinea pig. Form deprivation appears to minimally affect cell numbers, except in the region equivalent to scleral crescent formation in myopic human eyes. However, the in vivo viscoelastic response of the VCD in deprived eyes differs from that in normal eyes, suggesting some factor(s) other than cell number alone has a role in axial length control.