National Health and Medical Research Council (NHMRC)

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This is a collection of NHMRC-funded research publications authored by Flinders academics.

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Secreted human Ro52 autoantibody proteomes express a restricted set of public clonotypes
(Elsevier, Dec-12) Arentz, Georgia; Thurgood, Lauren Alexandra; Lindop, Rhianna; Chataway, Timothy Kennion; Gordon, Thomas Paul
Long-lived secreted autoantibody responses in systemic autoimmunity are generally regarded to be polyclonal and to express a diverse B-cell repertoire. Here, we have used a proteomic approach based on de novo sequencing to determine the clonality and V region structures of human autoantibodies directed against a prototypic systemic autoantigen, Ro52 (TRIM21). Remarkably, anti-Ro52 autoantibodies from patients with primary Sjögren’s syndrome, systemic lupus erythematosus, systemic sclerosis or polymyositis were restricted to two IgG1 kappa clonotypes that migrated as a single species on isoelectric focusing; shared a common light chain paired with one of two closely-related heavy chains; and were public in unrelated patients. Targeted mass spectrometry using these uniquely mutated V region peptides as surrogates detected anti-Ro52 autoantibodies in human sera with high sensitivity and specificity compared with traditional ELISA. Mass spectrometry-based detection of specific autoantibody motifs provides a powerful new tool for analysis of humoral autoimmunity.
Effects of amino acid substitutions at positions 33 and 37 on UDP-glucuronosyltransferase 1A9 (UGT1A9) activity and substrate selectivity
(Elsevier, Dec-12) Korprasertthaworn, Porntipa; Rowland, Andrew; Lewis, Benjamin Cavell; Mackenzie, Peter Ian; Yoovathaworn, Krontong; Miners, John Oliver
UGT1A9 contributes to the glucuronidation of numerous drugs and xenobiotics. There is evidence to suggest that the Met33Thr substitution, as occurs in the polymorphic variant UGT1A9*3, variably affects xenobiotic glucuronidation. The equivalent position in UGT1A4 is also known to influence enzyme activity, whilst an N-terminal domain histidine (His37 in UGT1A9) is believed to function as the catalytic base in most UGT enzymes. To elucidate the roles of key amino acids and characterise structure–function relationships, we determined the effects of amino acid substitutions at positions 33 and 37 of UGT1A9 on the kinetics of 4-methylumbelliferone (4-MU), mycophenolic acid (MPA), propofol (PRO), sulfinpyrazone (SFZ), frusemide (FSM), (S)-naproxen (NAP) and retigabine (RTB) glucuronidation, compounds that undergo glucuronidation at either a phenolic (4-MU, MPA, PRO), carboxylate (FSM, NAP), acidic carbon (SFZ) or amine (RTB) function. Substitution of Met33 with Val, Ile, Thr, and Gln, as occur in UGT1A1, UGT1A3, UGT1A4 and UGT1A6 respectively, variably affected kinetics and catalytic efficiency. Whilst Km values were generally higher and Vmax and CLint values were generally lower than for wild-type UGT1A9 with most substrate-mutant pairs, the pattern and the magnitude of the changes in each parameter differed substantially. Moreover, exceptions occurred; CLint values for MPA and FSM glucuronidation by the position-33 mutants were the same as or higher than that of UGT1A9. Mutation of His37 abolished activity towards all substrates, except RTB N-glucuronidation. The data confirm the importance of single amino acids for UGT enzyme activity and substrate selectivity, and support a pivotal role for residue-33 in facilitating substrate binding to UGT1A9.
Preproglucagon neurons innervate neurochemically identified autonomic neurons in the mouse brainstem
(Elsevier, Jan-13) Llewellyn-Smith, Ida Jonassen; Gnanamanickam, Greta J E; Reimann, Frank; Gribble, Fiona M; Trapp, Stefan
Preproglucagon (PPG) neurons produce glucagon-like peptide-1 (GLP-1) and occur primarily in the nucleus tractus solitarius (NTS). GLP-1 affects a variety of central autonomic circuits, including those controlling the cardiovascular system, thermogenesis, and most notably energy balance. Our immunohistochemical studies in transgenic mice expressing YFP under the control of the PPG promoter showed that PPG neurons project widely to central autonomic regions, including brainstem nuclei. Functional studies have highlighted the importance of hindbrain receptors for the anorexic effects of GLP-1.
Long-term Ro60 humoral autoimmunity in primary Sjogren's syndrome is maintained by rapid clonal turnover
(Elsevier, Jul-13) Lindop, Rhianna; Arentz, Georgia; Bastian, Isabell; Whyte, Andrew F; Thurgood, Lauren Alexandra; Chataway, Timothy Kennion; Jackson, Michael W; Gordon, Thomas Paul
Long-term humoral autoimmunity to RNA–protein autoantigens is considered a hallmark of systemic autoimmune diseases. We use high resolution Orbitrap mass spectrometric autoantibody sequencing to track the evolution of a Ro60-specific public clonotypic autoantibody in 4 patients with primary Sjögren's syndrome. This clonotype is specified by a VH3–23/VK3–20 heavy and light chain pairing. Despite apparent stability by conventional immunoassay, analysis of V-region molecular signatures of clonotypes purified from serum samples collected retrospectively over 7 years revealed sequential clonal replacement. Prospective longitudinal studies confirmed clonotype loss and replacement at approximately three-monthly intervals. Levels of secreted anti-Ro60 clonotypes fluctuated markedly over time, despite minimal changes in clonal affinity. Our novel findings indicate a relentless turnover of short-lived clonotypic variants, masquerading as long-lived Ro60 humoral autoimmunity.
Whose values in health? An empirical comparison of the application of adolescent and adult values for the CHU9D and AQOL-6D in the Australian adolescent general population
(Elsevier, 11/06/2012) Ratcliffe, Julie; Stevens, Katherine; Flynn, Terry; Brazier, John; Sawyer, Michael G
The Child Health Utility-9D (CHU-9D) and the Assessment of Quality of Life-6D (AQOL-6D) presently represent the only two generic preference-based instruments developed for application with young people with both adult- and adolescent-specific scoring algorithms. The main objective of this study was to compare and contrast the application of adult and adolescent scoring algorithms for the CHU-9D and AQOL-6D in valuing the health of a community-based sample of adolescents.
Work organisation, job insecurity and occupational health disparities
(Wiley-Blackwell, 16/10/2012) Landsbergis, PA; Grzywacz, JG; LaMontagne, Anthony D
Changes in employment conditions in the global economy over the past 30 years have led to increased job insecurity and other work organization hazards. These hazards may play a role in creating and sustaining occupational health disparities by socioeconomic position, gender, race, ethnicity, and immigration status.
Selective expression of α-synuclein-immunoreactivity in vesicular acetylcholine transporter-immunoreactive axons in the guinea-pig rectum and human colon
(Wiley-Blackwell, 17/12/2012) Sharrad, DF; de Vries, E; Brookes, Simon Jonathan
Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α-synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α-synuclein have not been identified. We used multiple-labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed α-synuclein in their axons. α-Synuclein-immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)-immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)-IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)-IR varicosities in guinea pig rectal myenteric ganglia. However, α-synuclein-immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)-IR varicosities (88 ± 3%, P < 0.001). Of SOM-IR, SP-IR, and VIP-IR varicosities that lacked VAChT-immunoreactivity, only 1 ± 0.3%, 0 ± 0.3%, and 0% contained α-synuclein-immunoreactivity, respectively. 71 ± 0.8% of VAChT-IR varicosities in myenteric ganglia of human colon were α-synuclein-IR. In guinea pig rectal myenteric ganglia, α-synuclein- and VAChT-immunoreactivity coexisted in 15 ± 1.4% of biotinamide-labeled extrinsic varicosities; only 1 ± 0.3% of biotinamide-labeled extrinsic varicosities contained α-synuclein-immunoreactivity without VAChT-immunoreactivity. α-Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell-selective α-synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease.
Viscerofugal neurons recorded from guinea-pig colonic nerves after organ culture
(Wiley-Blackwell, 19/07/2012) Hibberd, TJ; Zagorodnyuk, Vladimir Petrovich; Spencer, Nicholas John; Brookes, Simon Jonathan
Background Enteric viscerofugal neurons provide cholinergic synaptic inputs to prevertebral sympathetic neurons, forming reflex circuits that control motility and secretion. Extracellular recordings of identified viscerofugal neurons have not been reported. Methods Preparations of guinea pig distal colon were maintained in organotypic culture for 4-6 days (n = 12), before biotinamide tracing, immunohistochemistry, or extracellular electrophysiological recordings from colonic nerves. Key Results After 4-6 days in organ culture, calcitonin gene-related peptide and tyrosine hydroxylase immunoreactivity in enteric ganglia was depleted, and capsaicin-induced firing (0.4 micromol L-1) was not detected, indicating that extrinsic sympathetic and sensory axons degenerate in organ culture. Neuroanatomical tracing of colonic nerves revealed that viscerofugal neurons persist and increase as a proportion of surviving axons. Extracellular recordings of colonic nerves revealed ongoing action potentials. Interestingly, synchronous bursts of action potentials were seen in 10 of 12 preparations; bursts were abolished by hexamethonium, which also reduced firing rate (400 micromol L-1, P < 0.01, n = 7). DMPP (1,1-dimethyl-4-phenylpiperazinium; 10-4 mol L-1) evoked prolonged action potential discharge. Increased firing preceded both spontaneous and stretch-evoked contractions (X2 = 11.8, df = 1, P < 0.001). Firing was also modestly increased during distensions that did not evoke reflex contractions. All single units (11/11) responded to von Frey hairs (100-300 mg) in hexamethonium or Ca2+-free solution. Conclusions & Inferences Action potentials recorded from colonic nerves in organ cultured preparations originated from viscerofugal neurons. They receive nicotinic input, which coordinates ongoing burst firing. Large bursts preceded spontaneous and reflex-evoked contractions, suggesting their synaptic inputs may arise from enteric circuitry that also drives motility. Viscerofugal neurons were directly mechanosensitive to focal compression by von Frey hairs.
Socio-demographic and work setting correlates of poor mental health in a population sample of working Victorians: application in evidence-based intervention priority setting
(Taylor and Francis, 2/07/2012) LaMontagne, Anthony D; D'Souza, Rennie M; Shann, Clare B
Interventions to promote mental health in the workplace are rapidly gaining acceptability as a means to prevent, screen, treat and effectively manage the growing disease burden of depression and anxiety among working people. The objective of this study was to identify socio-demographic and work setting correlates of poor mental health to consider alongside other evidence in priority setting for workplace mental health promotion (MHP). Multiple logistic regression was used to model the probability of poor mental health (SF-12) in relation to socio-demographic (gender, age, education, marital status and occupational skill level) and employment factors (workplace size and type, industrial sector, employment arrangement and working hours) in a population-based cross-sectional survey of 1051 working Victorians. As a result, poor mental health was (21% prevalence overall) higher in working females than in males and decreased with increasing age. Only one employment factor was significant in demographically adjusted multivariate analyses, showing an increase in the odds of poor mental health with increasing working hours. It is concluded that based on the prevalence of poor mental health, Victorian work settings with high proportions of younger workers, and younger working women in particular, should be prioritized for workplace MHP. Thus, together with other research demonstrating particularly poor psychosocial working conditions for young working women, sectors with an over-representation of this group (e.g. service sector) could be prioritized for workplace MHP alongside young and blue-collar males (also a priority due to low mental healthcare service use).
The impact of corneal allograft rejection on the long-term outcome of corneal transplantation
(2005) Coster, Douglas John; Williams, Keryn Anne
To examine the influence of corneal allograft rejection on the survival of penetrating corneal transplantation, to review the status of conventional therapies to improve graft survival, and to consider prospects for alternative approaches to reduce the impact of rejection. Perspective, including prospective, observational cohort study. An examination of the literature on human corneal graft rejection and data from the Australian Corneal Graft Registry, reviewed in the context of clinical experience. Corneal graft outcome is not improving with era. The sequelae of inflammation, whether occurring before corneal transplantation or subsequently, exert a profound influence by predisposing the graft to rejection. Of the developments that have been instrumental in reducing rejection in vascularized organ transplantation, living-related donation is not an option for corneal transplantation. However, HLA matching may be beneficial and requires reassessment. The evidence base to support the use of systemic immunosuppressive agents in corneal transplantation is thin, and topical glucocorticosteroids remain the drugs of choice to prevent or reverse rejection episodes. Experimental approaches to local allospecific immunosuppression, including the use of antibody-based reagents and gene therapy, are being developed but may be difficult to translate from the laboratory bench to the clinic. Corneal allograft rejection remains a major cause of graft failure. High-level evidence to vindicate the use of a particular approach or treatment to prevent or treat corneal graft rejection is lacking. In the absence of extensive data from randomized, controlled clinical trials, corneal graft registers and extrapolation from experimental models provide some clinically useful information.
Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea-hypopnea
(2007) Antic, Nicholas Alexander; Catcheside, Peter G; Mercer, Jeremy; McEvoy, Ronald Douglas; Lehman, Sam; Thompson, Courtney Cie
Rejection and acceptance of corneal allografts
(Lippincott, Williams & Wilkins, 2009) Klebe, Sonja; Coster, Douglas John; Williams, Keryn Anne
PURPOSE OF REVIEW: Corneal transplantation is successful in the short-term, but the long-term prognosis has not improved over the past 20 years. Here, we review recent findings that may contribute to improved corneal allograft survival. RECENT FINDINGS: A better understanding of the molecular pathways affecting corneal graft survival has led to more targeted approaches to immune modulation. Costimulatory molecule blockade, inhibition of chemokine-chemokine receptor interactions, modulation of apoptotic pathways, and reduction of corneal neovascularization and lymphangiogenesis have been shown to prolong corneal graft survival in animal models. Conventional immunosuppressive drugs have been tested in new combinations and formulations with some success. Two randomized prospective clinical trials in clinical penetrating corneal transplantation have been reported, but there remains little evidence on the long-term outcomes of the newer lamellar corneal graft procedures. SUMMARY: New approaches to reducing the impact of rejection on corneal graft survival have focussed on topical rather than systemic therapies, and on component corneal transplantation. The most successful experimental strategies have been those in which more than one pathway has been targeted; it now seems likely that to improve clinical allograft survival, simultaneous modulation of multiple axes of the rejection process will be necessary.
Determining the repertoire of IGH gene rearrangements in order to develop molecular markers for minimal residual disease in acute lymphoblastic leukemia
(Elsevier, 2009) Brisco, Michael; Latham, Susan Elizabeth; Sutton, Rosemary; Hughes, Elizabeth; Wilczek, Vicki Jane; van Zanten, Katrina; Budgen, Bradley John; Bahar, Anita Y; Malec, Maria; Kuss, Bryone Jean; Waters, Keith; Venn, Nicola C; Giles, Jodie E; Haber, Michelle; Norris, Murray D; Marshall, Glenn M; Morley, Alexander Alan; Sykes, Pamela Joy
Molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia were identified by determining, at the time of diagnosis, the repertoire of rearrangements of the immunoglobulin heavy chain (IGH) gene using segment-specific variable (V), diversity (D), and junctional (J) primers in two different studies that involved a total study population of 75 children and 18 adults. This strategy, termed repertoire analysis, was compared with the conventional strategy of identifying markers using family-specific V, D, and J primers for a variety of antigen receptor genes. Repertoire analysis detected significantly more markers for the major leukemic clone than did the conventional strategy, and one or more IgH rearrangements that were suitable for monitoring the major clone were detected in 96% of children and 94% of adults. Repertoire analysis also detected significantly more IGH markers for minor clones. Some minor clones were quite large and a proportion of them would not be able to be detected by a minimal residual disease test directed to the marker for the major clone. IGH repertoire analysis at diagnosis has potential advantages for the identification of molecular markers for the quantification of minimal residual disease in acute lymphoblastic leukemia cases. An IGH marker enables very sensitive quantification of the major leukemic clone, and the detection of minor clones may enable early identification of additional patients who are prone to relapse.
Sensitive and specific measurement of minimal residual disease in acute lymphoblastic leukaemia
(Elsevier, 2009-05) Morley, Alexander Alan; Latham, Susan Elizabeth; Brisco, Michael; Sykes, Pamela J; Sutton, Rosemary; Hughes, Elizabeth; Wilczek, Vicki Jane; Budgen, Bradley John; van Zanten, Katrina; Kuss, Bryone Jean; Venn, Nicola C; Norris, Murray D; Crock, Catherine; Storey, Colin; Waters, Keith; Revesz, Tamas
A sensitive and specific quantitative real-time polymerase chain reaction method, involving three rounds of amplification with two allele-specific oligonucleotide primers directed against an rearrangement, was developed to quantify minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL). For a single sample containing 10 microg of good quality DNA, MRD was quantifiable down to approximately 10(-6), which is at least 1 log more sensitive than current methods. Nonspecific amplification was rarely observed. The standard deviation of laboratory estimations was 0.32 log units at moderate or high levels of MRD, but increased markedly as the level of MRD and the number of intact marker gene rearrangements in the sample fell. In 23 children with ALL studied after induction therapy, the mean MRD level was 1.6 x 10(-5) and levels ranged from 1.5 x 10(-2) to less than 10(-7). Comparisons with the conventional one-round quantitative polymerase chain reaction method on 29 samples from another 24 children who received treatment resulted in concordant results for 22 samples and discordant results for seven samples. The sensitivity and specificity of the method are due to the use of nested polymerase chain reaction, one segment-specific and two allele-specific oligonucleotide primers, and the use of a large amount of good quality DNA. This method may improve MRD-based decisions on treatment for ALL patients, and the principles should be applicable to DNA-based MRD measurements in other disorders.
The Influence of Rejection Episodes in Recipients of Bilateral Corneal Grafts
(2010) Williams, Keryn Anne; Kelly, T L; Lowe, Marie Therese; Coster, Douglas John
We investigated whether a rejection episode in one graft was associated with rejection in the other graft, in recipients with bilateral corneal transplants. In a prospectively maintained, national register of 14 865 followed corneal grafts, 1476 patients with bilateral penetrating corneal grafts were identified. Occurrence of rejection was a risk factor for graft failure (p < 0.0001). Logistic regression was used to calculate the adjusted odds ratio for rejection in one eye following rejection in the other eye. In the subset of 1118 patients with bilateral grafts but no history of previous grafts or rejections in either eye, the adjusted odds ratio for a rejection episode in the first eye following rejection in the second was 3.27 (95% confidence interval, CI 1.85, 5.79; p < 0.001). The adjusted odds ratio was 2.04 (95% CI 1.07, 3.91; p = 0.03) for rejection in the second eye following rejection in the first. The median time between the first rejection episode in one eye and the first rejection episode in the other eye was 15 months. Patients with bilateral corneal grafts who suffer a graft rejection episode in one eye are at significantly greater odds of suffering a rejection episode in the other corneal transplant.
EEG spindles in the rat: Evidence for a synchronous network phenomenon
(Elsevier, 2010) Mackenzie, Lorraine; Pope, Kenneth; Willoughby, John Osborne
The outcome of corneal transplantation in infants, children, and adolescents
(Elsevier, 2011) Lowe, Marie Therese; Keane, Miriam Claire; Coster, Douglas John; Williams, Keryn Anne
OBJECTIVE: To examine factors affecting penetrating corneal graft survival and visual outcomes in patients aged less than 20 years. DESIGN: Large prospective, cohort study. PARTICIPANTS: Records of 14 865 followed penetrating corneal grafts in 11 929 patients were searched to identify 765 grafts in 640 patients aged younger than 20 years of age at the time of graft. METHODS: Records submitted to the Australian Corneal Graft Registry by 381 ophthalmic surgeons and 253 follow-up practitioners from May 1985 to June 2009 were analyzed using Kaplan-Meier survival plots and Cox proportional hazards regression analysis. MAIN OUTCOMES MEASURES: Probability of corneal graft survival and Snellen acuity at the time of most recent follow-up and at defined intervals post-graft. RESULTS: Infants (<5 years) exhibited poorer graft survival than children aged 5 to 12 years. Adolescents (13-19 years) exhibited better corneal graft survival than other age groups; 86% of grafts in adolescents were for keratoconus. Factors significantly affecting corneal graft survival in pediatric patients included indication for graft, graft inflammation, history of intraocular surgery, vascularization, rejection episodes, post-graft operative procedures, and refractive surgery. Fourteen percent of pediatric grafts failed, of which 65% failed within 2 years post-graft. Forty-four percent of failures were due to unknown causes (18) or irreversible rejection (30). CONCLUSIONS: Corneal grafts for keratoconus in adolescents show excellent survival. Infants exhibit poor graft survival and visual outcomes, especially those undergoing transplantation for Peters' anomaly. Corneal graft survival and visual outcomes vary more by indication for graft than recipient age. The major reason for graft failure is irreversible rejection. Corneal transplantation improves overall bilateral vision in pediatric patients.
Early rehabilitation management after stroke: What do stroke patients prefer?
(Foundation for Rehabilitation Information, 2011) Laver, Kate; Ratcliffe, Julie; George, Stacey; Lester, Laurence Howard; Walker, Ruth Ballance; Burgess, Leonie; Crotty, Maria
Background: Stroke rehabilitation is moving towards more intense therapy models that incorporate technologies such as robotics and computer games. It is unclear how acceptable these changes will be to stroke survivors, as little is known about which aspects of rehabilitation programmes are currently valued. Discrete choice experiments are a potential approach to assessing patient preferences, as they reveal the characteristics of programmes that are most important to consumers. METHODS: A discrete choice experiment was presented as a face-to-face interview to assess the priorities and preferences of stroke survivors (n = 50, mean age 72 years) for alternative rehabilitation service configurations. The discrete choice experiment was presented to the participants while they were on the stroke rehabilitation ward (approximately 3–4 weeks following stroke). RESULTS: Participants were highly focused on recovery and expressed strong preferences for therapy delivered one-to-one, but they did not favour very high intensity programmes (6 hours per day). While the attitudinal statements indicated high levels of agreement for programmes to incorporate the latest technology, the results from the discrete choice experiment indicated that participants were averse to computer-delivered therapy. CONCLUSION: Whilst rehabilitation therapy is highly valued, stroke survivors exhibited stronger preferences for low-intensity programmes and rest periods. High-intensity therapy protocols or approaches dependent on new technologies will require careful introduction to achieve uptake and acceptability.
Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1
(Nature Publishing Group, 2011) Burdon, Kathryn Penelope; MacGregor, Stuart; Hewitt, Alex W; Sharma, Shiwani; Chidlow, Glyn; Mills, Richard Arthur; Danoy, Patrick; Casson, Robert J; Viswanathan, Ananth C; Liu, Jimmy Z; Landers, John; Henders, Anjali K; Wood, John; Souzeau, Emmanuelle; Crawford, April; Leo, Paul; Wang, Jie Jin; Nyholt, Dale R; Martin, Nicholas G; Montgomery, Grant W; Mitchell, Paul; Brown, Matthew A; Mackey, David A; Craig, Jamie E
A genome-wide association study (GWAS) for open angle glaucoma (OAG) blindness was conducted using a discovery cohort of 590 cases with severe visual field loss and 3956 controls. Genome-wide significant associations were identified at TMCO1 (rs4656461 (G) OR=1.68, p=6.1x10-10) and CDKN2B-AS1 (rs4977756 (A) OR = 1.50, p=4.7x10-9). These findings were replicated in a second cohort of advanced OAG cases (rs4656461 p=0.010; rs4977756 p=0.042) and two further cohorts of less severe OAG. The study wide odds ratios are 1.51 (1.35-1.68), p=6.00x10-14 at TMCO1, and 1.39 (1.28-1.51), p=1.35x10-14 at CDKN2B-AS1 (also known as CDKN2BAS and ANRIL). Carriers of 1 or more risk alleles at both loci concurrently are at >3-fold increased risk of glaucoma. We demonstrate retinal expression of genes at both loci, and show that CDKN2A and CDKN2B are strongly upregulated in an animal model of glaucoma.
Sacro-lumbar Intersegmental Spinal Reflex in Autonomic Pathways Mediating Female Sexual Function
(John Wiley & Sons Ltd, 2011) Yuan, S Y; Gibbins, Ian Lewis; Zagorodnyuk, Vladimir Petrovich; Morris, Judith Louise

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