Call number: LD2668 .R4 1967 C33

Purpose: We evaluate solutions for an applanating surface modification to the Goldmann tonometer prism, which substantially negates the errors due to patient variability in biomechanics. Methods: A modified Goldmann or correcting applanation tonometry surface (CATS) prism is presented which was optimized to minimize the intraocular pressure (lOP) error due to corneal thickness, stiffness, curvature, and tear film. Mathematical modeling with finite element analysis (FEA) and manometric lOP referenced cadaver eyes were used to optimize and validate the design. Results: Mathematical modeling of the optimized CATS prism indicates an approximate 50% reduction in each of the corneal biomechanical and tear film errors. Manometric lOP referenced pressure in cadaveric eyes demonstrates substantial equivalence to GAT in nominal eyes with the CATS prism as predicted by modeling theory. Conclusion: A CATS modified Goldmann prism is theoretically able to significantly improve the accuracy of lOP measurement without changing Goldmann measurement technique or interpretation. Clinical validation is needed but the analysis indicates a reduction in CCT error alone to less than +/- 2 mm Hg using the CATS prism in 100% of a standard population compared to only 54% less than +/- 2 mm Hg error with the present Goldmann prism. Translational Relevance: This article presents an easily adopted novel approach and critical design parameters to improve the accuracy of a Goldmann applanating tonometer.

Purpose: To compare the effect of topical prednisolone acetate 1% (PA) used after routine cataract surgery to the effect of difluprednate 0.05% (DFBA) used for the same indication on intraocular pressure (IOP). Methods: An electronic query was created to gather information from all cataract surgeries between January 2010 and January 2015 within the electronic health record database at Barnet Dulaney Perkins, a multicenter, multiphysician private practice in Phoenix, Arizona. Information collected included age, sex, diabetes status, glaucoma history, medication regimen (use of PA or DFBA), and IOP before surgery, 5-10 days postoperatively (TP1) and 3-6 weeks postoperatively (TP2). Postoperative IOP measurements were compared to baseline IOP measurement in each patient. Results: Regardless of steroid used, all patients in this study experienced an increase in IOP within TP1 and returned to baseline IOP (+/- 2.0 mmHg) by TP2. Patients who received DFBA showed a statistically significant increase in IOP at TP1 compared to those on PA (P<0.001) with the mean IOP an average 0.60 mmHg higher (95% CI = 0.3, 0.9). The odds ratio of a clinically significantly increased IOP at TP1 (defined as overall IOP >= 21 mmHg and an increase of >= 10 mmHg) in DFBA-treated patients was 1.84 (95% CI = 1.4, 2.6). In patients treated with PA, 3% reached a significantly increased IOP, compared to 4.4% of patients in the DFBA group (P<0.05). Risk factors for increased IOP were identified, and include advanced age (>75) (P<0.005) and a history of glaucoma (P<0.001). Conclusion: In postoperative cataract patients, use of DFBA increased the risk of a clinically significant IOP increase.

Hypertension is the major cause of cardio-vascular diseases and contributes to 13.5% of premature deaths worldwide. With a 10–year risk to develop organ damages estimated at 30%, severe hypertension exposes even more patients to premature death. Severe hypertension is a type of hypertension with systolic blood pressure ≥ 180mmHg and/or diastolic blood pressure ≥ 110 mmHg that may present with or without symptoms/signs or target organ damages, and may be classified accordingly as asymptomatic (without symptoms/signs) severe hypertension, hypertension urgency (with symptoms/signs, no target organ damage) or hypertension emergency (with target organ damage). Hypertension urgency and hypertension emergency are considered hypertension crisis. This study aimed to establish the socio-demographic and clinical characteristics of the patients who presented with severe hypertension at the Emergency Departments of two private hospitals of the Netcare Management (Pty) Limited in Johannesburg during the period from the 1st of January 2010 to 30th April 2011. These patients presumably receive quality health care and may not be expected to develop severe hypertension. Therefore, this study would contribute to efforts to identify patients at risk and those who may benefit from preventive measures. The methodology of this study was a retrospective, transversal and comparative study. One thousand and forty-two patients were included in the study. All of these participants had a medical aid cover or were able to pay for medical consultation at a private hospital. Data were collected from an electronic database, the Medibank™, and from manual patients’ registers kept in each hospital’s Emergency Department. Severe hypertension was found among 1.7% of all patients who presented to the studied emergency departments. Only 817 patients were classified in the different subtypes of SH. Asymptomatic severe hypertension was the most common (83.4%) type of severe hypertension and hypertension emergency was the least common (4.8%). At Mulbarton Hospital, 50.2% of severe hypertension patients were male and at Linksfield Hospital, 60.3% were female. Male patients were younger than female patients. White patients and elderly were mostly affected by severe hypertension in the studied population. Systolic blood pressures were similar among the different races and genders. Black patients had higher diastolic blood pressure compared to white patients. White patients were older and may have had a tendency of isolated systolic hypertension. Overall, the most common symptoms/signs in hypertension urgency were chest pains (46.4%), headache (34.0%) and epistaxis (11.3%). The most common target organ damages in hypertension emergency were stroke (58.9%), left ventricular failure/congestive cardiac failure (28.2%) and seizures (12.8%). None of the studied characteristics could be claimed predictors of hypertension crisis. Also, there was no association between seasons and days of presentation and onset of severe hypertension in each hospitals. Further studies are required to include other factors that are known to affect the occurrence of severe hypertension, such as co-morbidities, smoking, alcohol intake and poor adherence to medication by known hypertensive patients. Also, risk factors contributing to the occurrence of SH among younger black patients need to be analysed.

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / In groups of African ancestry, who have a high prevalence of “salt-sensitive, low-renin” hypertension, there is considerable uncertainty as to relevance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of primary hypertension. In the present thesis I explored the possibility that the RAAS, through interactions with environmental effects, contributes to blood pressure (BP) in this ethnic group. After excluding participants with aldosterone-to-renin ratios (ARR) above the threshold for primary aldosteronism, in 575 participants of African ancestry, I demonstrated that with adjustments for confounders, an interaction between ARR and urinary Na+/K+ (and index of salt intake obtained from 24-hour urine samples) was independently associated with BP (p<0.0001). This effect was accounted for by interactions between serum aldosterone concentrations and urinary Na+/K+ (p<0.0001), but not between plasma renin concentrations and urinary Na+/K+ (p=0.52). The interaction between ARR and urinary Na+/K+ translated into a marked difference in the relationship between urinary Na+/K+ and BP in participants above and below the median for ARR (p<0.0001 for a comparison of the relationships). Having demonstrated that circulating aldosterone concentrations may account for a substantial proportion of the relationship between salt intake and BP in this community sample, I subsequently assessed whether genetic factors contribute toward serum aldosterone concentrations. In 153 randomly selected nuclear families of African ancestry consisting of 448 participants without primary aldosteronism, with, but not without adjustments for plasma renin concentrations, independent correlations were noted for iii serum aldosterone concentrations between parents and children (p<0.05), with parent-child partial correlation coefficients being greater than those for father-mother relationships (p<0.05). Furthermore, after, but not before adjustments for plasma renin concentrations, serum aldosterone concentrations showed significant heritability (h2=0.25±0.12, p<0.02). No independent relationships between RAAS gene polymorphisms and serum aldosterone concentrations were observed. I also aimed to assess whether RAAS genes modify the relationship between cigarette smoking and BP in groups of African descent. However, as the impact of mild smoking on BP is uncertain, and in the community studied only 14.5% smoked and the majority of smokers were mild smokers (mean=7.4±4.6 cigarettes per day) in 689 randomly participants I initially assessed the relationship between smoking habits and out-of-office BP. In this regard, current smokers had higher unadjusted and multivariate adjusted 24-hour systolic/diastolic BP (SBP/DBP in mm Hg) (p<0.005-p<0.0005) than non-smokers, effects that were replicated in sex-specific groups, non-drinkers, and in the overweight and obese. Current smoking was second only to age and at least equivalent to body mass index in the quantitative impact on out-of-office BP and the risk of uncontrolled out-of-office BP was increased in smokers as compared to non-smokers. Thus, despite minimal effects on in-office BP, predominantly mild current smoking was independently associated with an appreciable proportion of out-of-office BP in a community of African ancestry. In 652 participants I subsequently assessed whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism accounts for the strong relationships between predominantly mild smoking and out-of-office BP. After iv appropriate adjustments, an interaction between ACE DD genotype and current cigarette smoking, or the number of cigarettes smoked per day was independently associated with 24-hour and day diastolic BP (DBP) (p<0.05-0.005). This effect translated into a relationship between smoking and out-of-office BP or the risk for uncontrolled out-of-office BP only in participants with the DD as compared to the ID + II genotypes. In conclusion therefore, I afford evidence to suggest that in groups of African ancestry, aldosterone, within ranges that cannot be accounted for by the presence of primary aldosteronism, modifies the relationship between salt intake and BP, and that genetic factors account for the variation in serum aldosterone concentrations in this group. Furthermore, I show that the ACE gene modifies the relationship between smoking and out-of-office BP and hence accounts for even predominantly mild smoking producing a marked and clinically important effect on out-of-office BP. The present thesis therefore provides further evidence in favour of an important pathophysiological role for the RAAS in contributing toward BP in groups of African ancestry.

Hypertension is a major risk factor for cardiovascular disease in both developed and developing countries. Blood pressure normally decreases at night and a number of studies have indicated that a reduced nocturnal decline in blood pressure (BP) increases the risk for cardiovascular disease. Nocturnal decreases in BP are attenuated in subjects of African as compared to European descent, but the mechanisms of this effect require clarity. In the present study I attempted to identify potentially modifiable factors that contribute toward nocturnal decreases in BP in a random sample of 171 nuclear families comprising 438 black South Africans living in Soweto. Prior studies have suggested that adiposity and salt intake may determine nocturnal decreases in BP. Adiposity and salt intake were considered to be potentially important factors to consider in the present study as 67% of the group studied were either overweight or obese and in 291 subjects that had complete 24-hour urine collections (used to assess salt intake) and BP measurements, Na+ and K+ intake was noted to be considerably higher and lower respectively than the recommended daily allowance in the majority of people. Moreover, a lack of relationship between either hypertension awareness and treatment and Na+ and K+ intake suggested that current recommendations for a reduced Na+ intake and increased K+ intake in hypertensives do not translate into clinical practice in this community. In order to assess whether adiposity or salt intake are associated with nocturnal decreases in BP in this community, ambulatory BP monitoring was performed using Spacelabs model 90207 oscillometric monitors. Of the 438 subjects recruited, 314 had ambulatory BP measurements that met pre-specified quality criteria (more than 20 hours of recordings and more than 10 and 5 readings for the computation of daytime and nighttime means respectively). To identify whether adiposity or salt intake are associated with a reduced nocturnal decline in BP, non-linear regression analysis was employed with indices of adiposity and urinary Na+ and K+ excretion rates and urine Na+: K+ ratios included in the regression model with adjustments for potential confounders. Neither body mass index, skin-fold thickness, waist circumference, waist-to hip ratio, urinary Na+ and K+ excretion rates, nor urine Na+: K+ ratios were associated with nocturnal decreases in systolic and diastolic BP. Indices of adiposity were however associated with 24 hour ambulatory systolic and diastolic BP. Unexpectedly, female gender was associated with an attenuated nocturnal decrease in BP. In conclusion, in the first random, community-based sample with large sample sizes conducted with ambulatory BP monitoring in Africa, I found that neither adiposity nor salt intake are associated with a reduced nocturnal decline in BP. The lack of association between either salt intake or adiposity and nocturnal decreases in BP was despite a high prevalence of excessive adiposity in the community, as well as clear evidence that current recommendations for a reduced Na+ intake and increased K+ intake do not translate into clinical practice in this community. Thus, based on this study, the question arises as to whether primordial prevention programs targeting excess adiposity or inappropriate salt intake are likely to modify nocturnal decreases in BP, in urban, developing communities of African ancestry in South Africa. However, unexpectedly I noted that females were more likely to have an attenuated nocturnal decrease in BP. Thus further work is required to explain this finding.

Faculty of Health Sciencs School of physiology 0010633J bnkeh@uycdc.uninet.m / Blood pressure (BP) is a heritable trait. However, the loci responsible and the mechanisms by which these genes determine BP are uncertain. Based on widely published data regarding frequent phenotypic characteristics that exemplify essential hypertension (EHT) in persons of African ancestry, in the present thesis I explored the role of gene candidates most likely to contribute to BP in this group. In this regard a high frequency of persons of African descent experience increases in BP in response to an enhanced salt intake (salt-sensitive hypertension). In addition, many patients of African origin with EHT fail to respond to inhibition of angiotensin-converting enzyme (ACE) with an appropriate decrease in BP, a factor that cannot be explained entirely on the basis of reduced plasma renin levels in this group. Thus, I evaluated the role of several gene variants that could influence either renal salt handling or the activity and effects of the renin-angiotensin system on BP in subjects of African ancestry. Although the angiotensinogen (AGT) gene has at least 3 variants in the promoter region that influence angiotensinogen expression and which occur with a remarkably high frequency in populations of African ancestry, their role in this group is still controversial. To-date, interactions between these variants have not been considered. Using a casecontrol study design in a sample of 1325 subjects, as well as association analysis with 24 hour ambulatory BP (ABP) values in 626 hypertensives, I confirmed that an independent effect of functional AGT gene variants on the risk for EHT or 24 hour ABP was weak at best. Importantly, however, interactions between the -20A C and -217G A variants were noted to strongly impact on the risk for EHT as well as ABP. Furthermore, interactions between the -20A C and -217G A variants played a major role in iii contributing toward the variability of ABP responses to ACE inhibitors, but not calcium channel blockers in this population group, with genotype determining whether or not ACE inhibitor responses occurred. Although the 825C T polymorphism of the guanosine triphosphate (G) protein 3 subunit (GNB3) gene influences the activity of a substance that modifies renal salt handling, namely the Na+/H+ exchanger, its impact in hypertensives of African descent is controversial. In the present thesis I confirmed in a large sample that the GNB3 variant was not associated with the risk for EHT or ABP values in subjects of African ancestry. However, because the activity of the exchanger is enhanced in obesity I hypothesised that the GNB3 gene variant could mediate a clinically relevant BP effect by modifying the impact of body size on BP (type I or II genetic effect). Indeed, GNB3 genotype proved to be a strong determinant of the impact of body size on systolic BP values, with genotype determining whether or not the effect occurred. The epithelial sodium channel (ENaC) and atrial natriuretic peptide (ANP) have an important influence on renal salt handling. The T594M polymorphism of the -subunit of the ENaC gene only exists with a relatively high frequency in subjects of African ancestry. Previous studies conducted in this population group in relatively small samples have indicated that the ENaC and ANP gene variants determine BP in subjects of African descent. In a larger sample of subjects of African descent I demonstrated that the T594M polymorphism of the ENaC gene has no impact on BP in this population group. However, my results suggest that the ANP gene may be a candidate worthy of further study. In conclusion, the results described in this thesis provide evidence that lends some clarity to the role of likely gene candidates for BP control in people of African descent. iv Importantly, data from this thesis suggest that interactions between functional variants of specific loci (e.g the AGT gene), and clinically relevant type I or II genetic effects (no independent actions, but modifier gene effects, e.g, GNB3) should be considered before excluding loci as playing an important role in BP control. Moreover, this thesis provides the first substantial data to indicate that gene variants determine the variability of BP responses to pharmacological agents in hypertension in this population group.

Thesis advisor: Stephen Wilson / The work performed within this thesis is divided into two parts, each focusing primarily on the study of magnetic phase behavior using neutron scattering techniques. In first part, I present transport, magnetization, and neutron scattering studies of materials within the iridium oxide-based Ruddelsden-Popper series [Srn+1IrnO3n+1] compounds Sr3Ir2O7 (n=2) and Sr2IrO4 (n=1). This includes a comprehensive study of the doped bilayer system Sr3(Ir1-xRux )2O7. In second part, I present my studies of the effect of uniaxial pressure on magnetic and structural phase behavior of the iron-based high temperature superconductor Ba(Fe1-xCox)2As2. Iridium-based 5d transition metal oxides host rather unusual electronic/magnetic ground states due to strong interplay between electronic correlation, lattice structure and spin-orbit effects. Out of the many oxides containing iridium, the Ruddelsden-Popper series [Srn+1IrnO3n+1] oxides are some of the most interesting systems to study both from the point of view of physics as well as from potential applications. My work is focused on two members of this series Sr3Ir2O7 (n=2) and Sr2IrO4 (n=1). In particular, our combined transport, magnetization and neutron scattering studies of Sr3Ir2O7 (n=2) showed that this system exhibits a complex coupling between charge transport and magnetism. The spin magnetic moments form a G-type antiferromagnetic structure with moments oriented along the c-axis, with an ordered moment of 0.35±0.06 µB/Ir. I also performed experiments doping holes in this bilayer Sr3(Ir1-xRux)2O7 system in order to study the role of electronic correlation in these materials. Our results show that the ruthenium-doped holes remain localized within the Jeff=1/2 Mott insulating background of Sr3Ir2O7, suggestive of `Mott blocking' and the presence of strong electronic correlation in these materials. Antiferromagnetic order however survives deep into the metallic regime with the same ordering q-vector, suggesting an intricate interplay between residual AF correlations in the Jeff=1/2 state and metallic nanoscale hole regions. Our results lead us to propose an electronic/magnetic phase diagram for Sr3(Ir1-xRux)2O7 system showing how the system moves from Jeff=1/2 antiferromagnetic Mott insulator (Sr3Ir2O7) to paramagnetic Fermi liquid metal (Sr3Ru2O7). On the other hand, our neutron scattering measurements on Sr2IrO4 (n=1), a prototypical Jeff=1/2 Mott insulator, showed that the spins arranged antiferromagnetically in ab-plane with an ordered moment comparable to that of Sr3Ir2O7. The second part of my work is comprised of a neutron scattering-based study of the Ba(Fe1-xCox)2As2 system, a bilayer family of iron-based high temperature superconductors. Undoped, this system exhibits either simultaneous or nearly simultaneous magnetic and structural phase transitions from a high temperature paramagnetic tetragonal phase to low temperature orthorhombic antiferromagnetic phase. With the gradual suppression of these two temperatures, the superconducting phase appears with the highest TC obtained just beyond their complete suppression. It has been proposed that these coupled magnetostructural transitions are secondary manifestations which arise as a consequence of electronic nematic ordering that occurs at a temperature higher than either of them. My work is mainly focused on probing the spin behaviors coupling to this electronic nematic phase. I devised a small device to apply uniaxial pressure along an in-plane high symmetry axis and studied the magnetic and structural behavior in series of Ba(Fe1-xCox)2As2 compounds via neutron scattering in presence of uniaxial pressure. There is an upward thermal shift in the onset of structural and magnetic transition temperature caused by this uniaxial pressure which is surprisingly insensitive to cobalt concentration in the absolute scale. Furthermore, on the first order side of the phase diagram (below the tricritical point), the structural and magnetic transitions are decoupled with magnetic transition following structural distortion. This study suggests the importance of both spin-lattice and orbital-lattice interactions in these families of compounds. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Physics.

Trace elements are highly fractionated during large-scale melting associated with planetary differentiation events. The resulting partition coefficients are used to constrain a range of geological processes and are known to be influenced by pressure, temperature, and compositional changes in crystalline structures. Although recent studies have shown that melt compositional changes affect the partitioning of trace elements, the degree to which these ratios are influenced by alterations in the melt structure, especially with increasing pressure, is poorly constrained due to the difficulty of collecting structural information on bonding environments in situ. A basic understanding of how these elements are incorporated in silicate melts is critical to interpreting early planetary differentiation and crust forming events. This thesis presents results from both x-ray diffraction and absorption techniques on trace element (Y, Zr, Lu and Nd) incorporation in silicate melt structures. The structure of two rare Earth element doped model end member silicate liquids, a highly polymerised haplogranite (Si- Al-Na-K-O) and a less polymerised anorthite-diopside (Si-Al-Mg-Ca-O), have been studied. The results are the first to identify trace rare Earth element (REE) incorporation in silicate melts at high pressure using x-ray diffraction techniques. The local melt structure around Y and Zr in a highly polymerised haplogranite has been studied using x-ray absorption spectroscopy up to 8GPa and 1650 K. Both elements appear to adopt 8-fold coordination within the melt structure with no variation over the pressure range studied. This was also found for the Lu bonding environment in the same composition where the coordination number of Lu-O was found to be 8, with a bond distance rLu-O = 2:36A in the haplogranite melt. At low pressures, < 5GPa, the bonding environment of Lu-O was found to be dependent on composition with coordination decreasing to CNLu-O = 6 and rLu-O = 2:29A in the anorthite-diopside melt. This compositional variance in coordination number at low pressure is consistent with observations made for Y-O in glasses at ambient conditions and is coincident with a dramatic increase in the partition coefficients previously observed for rare Earth elements (REE) with increasing melt polymerisation. However, an abrupt change in both Lu-O coordination and bond distance is observed at 5GPa in the anorthite-diopside melt, with CNLu-O increasing from 6 to 8-fold and rLu-O from 2.29 to 2.39A. This occurs over a similar pressure range where a reduction in the reported heavy REE partition coefficients is observed. X-ray diffraction experiments up to 60GPa and 2000K have also been performed on the incorporation of the larger light REE, Nd, in basaltic-like melts. The results presented show that incorporation within the anorthite-diopside composition is dependent on the size of the REE. Nd-O initially shows the same 6-fold coordination as Lu-O at ambient conditions, although the change to 8-fold coordination appears to occur at considerably lower pressure between 1-2GPa. Coordination change in both cases can be attributed to collapse of the silicate network and an increase in the average number of available 'crystal like' sites in the liquid, with ionic radius of the REE controlling at which pressure the preference for these sites in the melt occurs. Published mineral-melt partition coefficients for Nd, with major mineral phases such as garnet, show very little variation with pressure, in contrast to Lu. The difference in structural incorporation of Lu and Nd in the melts presented in this thesis could explain this partitioning behaviour. Overall this thesis highlights that important structural changes of the trace element bonding environment in silicate melts occur with both compositional variation and pressure. Melt structural changes with pressure cannot be neglected in predictive models of trace element behaviour, and using a single melt term to normalise the effects of melt on trace element partitioning will not accurately predict partitioning behaviour at depth during magma formation or differentiation.

This thesis presents the utilisation of giant piezoresistance of carbon nanotubes (CNTs) for high resolution pressure sensing. The nanoscale diameter of CNTs, used as sensing elements, increases the resolution of piezoresistive sensing by three orders of magnitude to that of silicon based sensors. The design of the sensor is based on sensing the strain in CNTs induced by the flow of gas and can be adapted to benefit cross-disciplinary fields like; flow and pressure sensing, microfluidics, Lab-on-chip and NEMS (nano-electromechanical systems). CNTs were grown inside silicon micro-cavities so as to bridge the gap between two silicon substrates. The nickel catalyst coated silicon substrates act as electrodes connected to the two ends of CNTs. The CNTs grow on the nickel nanoparticles, thus self-anchoring on to the substrate. Diffusion of nickel in silicon provides low resistive NiSi contacts to CNTs. Growth of CNTs in this form have not been reported before and presents several merits including no chemical treatment or post-growth alignment of CNTs, thus keeping the process simple and robust. CNT growth parameters; temperature, time and methane flow rate, were optimised in a custom designed chemical vapour deposition (CVD) rig, to control the CNT diameter. CNT diameter directly affects its piezoresistive coefficient, πL, and Young’s modulus, E, the factors that define piezoresistance in any material. Thus, optimised growth conditions allowed the direct tuning of piezoresistance of the sensor. Piezoresistance sensing was performed by inducing strain in CNTs with an applied differential pressure across the microcavity. Pressure loadings of as low as 0.1 atm (limited only by the gauge resolution) and a piezoresistance of as high as 16% at a pressure loading of 1 atm, were achieved. This piezoresistance is at least one order higher and the resolution is three orders higher than commercially available polysilicon and GaAs membrane based sensors. Piezoresistance was modelled by applying Euler-Bernoulli beam theory, assimilating CNTs to rigid beams with special boundary conditions, accounting for self-anchoring to Ni islands. The resulting theory is found to be in good agreement with our experimental results and estimates the E, πL and the average radius of the CNTs. This modelling, to our knowledge, is an original attempt to modify Euler-Bernoulli beam theory with the assumed boundary conditions.