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1.  An Acquired Factor VIII Inhibitor in a Patient with HIV and HCV: A Case Presentation and Literature Review 
Case Reports in Hematology  2013;2013:628513.
Introduction. Despite its low incidence, acquired factor VIII inhibitor is the most common autoantibody affecting the clotting cascade. The exact mechanism of acquisition remains unclear, but postpartum patients, those with autoimmune conditions or malignancies, and those with exposure to particular drugs appear most susceptible. There have been several case reports describing acquired FVIII inhibitors in patients receiving interferon alpha for HCV treatment and in patients being treated for HIV. To our knowledge, this is the first case of a patient with HCV and HIV who was not actively receiving treatment for either condition. Case Presentation. A 57-year-old Caucasian male with a history of HIV and HCV was admitted to our hospital for a several day history of progressively worsening right thigh bruising and generalized weakness. CTA of the abdominal arteries revealed large bilateral retroperitoneal hematomas. Laboratory studies revealed the presence of a high titer FVIII inhibitor. Conclusion. Our case of a very rare condition highlights the importance of recognizing and understanding the diagnosis of acquired FVIII inhibitor. Laboratory research and clinical data on the role of newer agents are needed in order to better characterize disease pathogenesis, disease associations, genetic markers, and optimal disease management.
PMCID: PMC3806160  PMID: 24198984
2.  Pascal panretinal laser ablation and regression analysis in proliferative diabetic retinopathy: Manchester Pascal Study Report 4 
Eye  2011;25(11):1447-1456.
To quantify the 20-ms Pattern Scan Laser (Pascal) panretinal laser photocoagulation (PRP) ablation dosage required for regression of proliferative diabetic retinopathy (PDR), and to explore factors related to long-term regression.
We retrospectively studied a cohort of patients who participated in a randomised clinical trial, the Manchester Pascal Study. In all, 36 eyes of 22 patients were investigated over a follow-up period of 18 months. Primary outcome measures included visual acuity (VA) and complete PDR regression. Secondary outcomes included laser burn dosimetry, calculation of retinal PRP ablation areas, and effect of patient-related factors on disease regression. A PDR subgroup analysis was undertaken to assess all factors related to PDR regression according to disease severity.
There were no significant changes in logMAR VA for any group over time. In total, 10 eyes (28%) regressed after a single PRP. Following top-up PRP treatment, regression rates varied according to severity: 75% for mild PDR (n=6), 67% for moderate PDR (n=14), and 43% in severe PDR (n=3). To achieve complete disease regression, mild PDR required a mean of 2187 PRP burns and 264 mm2 ablation area, moderate PDR required 3998 PRP burns and area 456 mm2, and severe PDR needed 6924 PRP laser burns (836 mm2; P<0.05).
Multiple 20-ms PRP treatments applied over time does not adversely affect visual outcomes, with favourable PDR regression rates and minimal laser burn expansion over 18 months. The average laser dosimetry and retinal ablation areas to achieve complete regression increased significantly with worsening PDR.
PMCID: PMC3213651  PMID: 21818132
Pascal panretinal photocoagulation; laser dosimetry; proliferative diabetic retinopathy
3.  Polyoma virus infection and urothelial carcinoma of the bladder following renal transplantation 
British Journal of Cancer  2008;99(9):1383-1386.
Renal transplant recipients are at increased risk of bladder carcinoma. The aetiology is unknown but a polyoma virus (PV), BK virus (BKV), may play a role; urinary reactivation of this virus is common post-renal transplantation and PV large T-antigen (T-Ag) has transforming activity. In this study, we investigate the potential role of BKV in post-transplant urothelial carcinoma by immunostaining tumour tissue for PV T-Ag. There was no positivity for PV T-Ag in urothelial carcinomas from 20 non-transplant patients. Since 1990, 10 transplant recipients in our unit have developed urothelial carcinoma, and tumour tissue was available in eight recipients. Two patients were transplanted since the first case of PV nephropathy (PVN) was diagnosed in our unit in 2000 and both showed PV reactivation post-transplantation. In one of these patients, there was strong nuclear staining for PV T-Ag in tumour cells, with no staining of non-neoplastic urothelium. We conclude that PV infection is not associated with urothelial carcinoma in non-transplant patients, and is uncommon in transplant-associated tumours. Its presence in all tumour cells in one patient transplanted in the PVN era might suggest a possible role in tumorigenesis in that case.
PMCID: PMC2579688  PMID: 18971934
BK virus; bladder cancer; transplant recipients
4.  Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours 
Gut  2006;55(11):1586-1591.
Background and aims
Midgut carcinoid tumours are uncommon tumours with an unpredictable clinical behaviour and few useful prognostic markers. Somatostatin analogues are widely used in treatment but a survival advantage has not been proven. We analysed features associated with poor prognosis and assessed the clinical implications of the biochemical response to therapy.
Clinical and biochemical data were collected for patients with midgut carcinoid tumours attending a tertiary referral neuroendocrine clinic from 1978 to 2000. Using death as the end point, univariate and multivariate survival analyses were performed to identify prognostic indicators. The significance of altering biomarkers with therapy was also studied by including repeated measurements of the most prognostic biochemical parameter in a time dependent covariate survival analysis.
We identified 139 patients with sufficient data for our analyses. Factors associated with a poor outcome on univariate analysis included: plasma neurokinin A (NKA), urinary 5‐hydroxyindolacetic acid output, age, and ⩾5 liver metastases. Plasma NKA was the strongest and only independent predictor of outcome on multivariate analysis. Patients in whom NKA continued to rise despite somatostatin analogues had a significantly worse survival than those in whom NKA stabilised or fell (one year survival rate 40% v 87%). Time dependent covariate analysis concluded that survival was better predicted by the most recent plasma NKA value rather than by the initial value.
Plasma NKA is an accurate marker of prognosis for midgut carcinoid tumours. This is the first paper to support a survival advantage in patients in whom plasma NKA is altered by somatostatin analogues.
PMCID: PMC1860112  PMID: 16556667
neuroendocrine tumours; prognosis; carcinoid tumours; somatostatin; neurokinin A
5.  Mutations in the RSK2(RPS6KA3) gene cause Coffin–Lowry syndrome and nonsyndromic X-linked mental retardation 
Clinical genetics  2006;70(6):509-515.
We describe three families with X-linked mental retardation, two with a deletion of a single amino acid and one with a missense mutation in the proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90 kDa, polypeptide 3) protein similar to mutations found in Coffin–Lowry syndrome (CLS). In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation. In the third family, although CLS had been suspected, the clinical features were atypical and the degree of intellectual disability much less than expected. These families show that strict reliance on classical clinical criteria for mutation testing may result in a missed diagnosis. A less targeted screening approach to mutation testing is advocated.
PMCID: PMC2714973  PMID: 17100996
Coffin–Lowry syndrome; nonsyndromic mental retardation; RSK2 mutation
6.  Chromosomal copy number changes in patients with non‐syndromic X linked mental retardation detected by array CGH 
Journal of Medical Genetics  2005;43(4):362-370.
Several studies have shown that array based comparative genomic hybridisation (CGH) is a powerful tool for the detection of copy number changes in the genome of individuals with a congenital disorder. In this study, 40 patients with non‐specific X linked mental retardation were analysed with full coverage, X chromosomal, bacterial artificial chromosome arrays. Copy number changes were validated by multiplex ligation dependent probe amplification as a fast method to detect duplications and deletions in patient and control DNA. This approach has the capacity to detect copy number changes as small as 100 kb. We identified three causative duplications: one family with a 7 Mb duplication in Xp22.2 and two families with a 500 kb duplication in Xq28 encompassing the MECP2 gene. In addition, we detected four regions with copy number changes that were frequently identified in our group of patients and therefore most likely represent genomic polymorphisms. These results confirm the power of array CGH as a diagnostic tool, but also emphasise the necessity to perform proper validation experiments by an independent technique.
PMCID: PMC2563232  PMID: 16169931
Array CGH; XLMR; duplications; copy number polymorphisms (CNPs); MLPA
7.  Mutation screening in Börjeson‐Forssman‐Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient 
Journal of Medical Genetics  2005;43(3):238-243.
Börjeson‐Forssman‐Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function.
To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X‐inactivation testing in the mothers of these individuals.
25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, two of which (c.940A→G and c.27_28insA) were novel. One of these new mutations, c.27_28insA, was identified in a female BFLS patient. This was shown to be a de novo mutation arising on the paternal chromosome. This is the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. In addition, the X‐inactivation status of the mothers of 19 males with suggested clinical diagnosis of BFLS was determined. Skewed (⩾70%) X‐inactivation was present in five mothers, three of whom had sons in whom a PHF6 mutation was detected. The mutation positive female also showed skewing.
The results indicate that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X‐inactivation is found in the mother.
PMCID: PMC2563250  PMID: 15994862
BFLS; PHF6; mutation summary; skewed X‐inactivation
8.  Exaggerated relative nasal-temporal asymmetry of macular capillary blood flow in patients with clinically significant diabetic macular oedema 
Aims: To compare the macular capillary blood flow of patients with clinically significant diabetic macular oedema (DMO) with that of non-diabetic subjects and to determine the relation between blood flow and capillary leakage in patients with DMO.
Methods: The sample comprised 45 non-diabetic subjects (mean age 59 years) and 18 type 2 patients with clinically significant DMO (mean age 60 years). Macular capillary blood flow measurements were acquired using the Heidelberg retina flowmeter (HRF) and a 10°×2.5° scan field centred on the fovea. Fluorescein angiography was undertaken on each of the diabetic patients after the completion of HRF measurements.
Results: Temporal macular capillary blood flow was significantly lower for the patients with clinically significant DMO compared with age matched non-diabetic subjects (ANCOVA, p = 0.0011) while relative nasal-temporal asymmetry of macular capillary blood flow was significantly higher (p = 0.0125). Nasal-temporal asymmetry of macular capillary blood flow was significantly higher for the patients with DMO and capillary leakage within the scan area (two tailed t test, p = 0.0071). Macular capillary blood flow was always lower in areas of DMO and capillary leakage.
Conclusion: Capillary blood flow was reduced in areas of DMO and capillary leakage, suggesting the presence of a localised perturbation of capillary blood flow regulation.
PMCID: PMC1772510  PMID: 15665341
diabetic macular oedema; retinal thickening; capillary blood flow
9.  Resolution of chronic severe refractory thrombocytopenia after treatment of hypothyroidism 
Journal of Clinical Pathology  2004;57(9):995-996.
The case of a 52 year old woman with chronic severe refractory thrombocytopenia is presented. Over a three year period, her platelet count was persistently less than 20 × 109/litre (normal range, 150–400). She required repeated hospital admission for management of bleeding and received multiple blood transfusions. She was given repeated courses of steroids, immunosuppression, immunoglobulin, and splenectomy, without success, in an attempt to stop the chronic blood loss. Eventually, she was found to be profoundly hypothyroid. On correction of her thyroid deficiency the platelet count returned to the normal range and all bleeding stopped. The platelet count remains in the normal range three years later.
PMCID: PMC1770415  PMID: 15333667
hypothyroidism; thrombocytopenia; thyroxine
10.  Correlation of a scanning laser derived oedema index and visual function following grid laser treatment for diabetic macular oedema 
Aim: To correlate change of an oedema index derived by scanning laser tomography with change of visual function in patients undergoing grid laser photocoagulation for clinically significant diabetic macular oedema (DMO).
Methods: The sample comprised 24 diabetic patients with retinal thickening within 500 μm of the fovea. Inclusion criteria included a logMAR visual acuity of 0.25, or better. Patients were assessed twice before a single session of grid laser treatment and within 1 week of, and at 1, 2, 4, and 12 weeks after, treatment. At each visit, patients underwent logMAR visual acuity, conventional and short wavelength automated perimetry (SWAP), and scanning laser tomography. Each visual function parameter was correlated with the mean oedema index. The mean oedema index represented the z-profile signal width divided by the maximum reflectance intensity (arbitrary units). A Pearson correlation coefficient (Bonferroni corrected) was undertaken on the data set of each patient.
Results: 13 patients exhibited significant correlation of the mean oedema index and at least one measure of visual function for the 10° × 10° scan field while 10 patients correlated for the 20° × 20° scan field. Seven patients demonstrated correlation for both scan fields. Laser photocoagulation typically resulted in an immediate loss of perimetric sensitivity whereas the oedema index changed over a period of weeks. Localised oedema did not impact upon visual acuity or letter contrast sensitivity when situated extrafoveally.
Conclusions: Correlation of change of the oedema index and of visual function following grid laser photocoagulation was not found in all patients. An absence of correlation can be explained by the localised distribution of DMO in this sample of patients, as well as by differences in the time course of change of the oedema index and visual function. The study has objectively documented change in the magnitude and distribution of DMO following grid laser treatment and has established the relation of this change to the change in visual function.
PMCID: PMC1771618  PMID: 12642310
diabetic macular oedema; scanning laser tomography; ocular imaging; visual function; laser photocoagulation
12.  Recurrence risks in undiagnosed mental retardation 
Journal of Medical Genetics  2000;37(12):e45.
PMCID: PMC1734484  PMID: 11106363
14.  Reproductive decisions after neonatal screening identifies cystic fibrosis 
AIMS—To document the reproductive choices made by women in New South Wales, Australia, after neonatal screening has identified cystic fibrosis (CF).
METHODS—A sample of women attending cystic fibrosis clinics in New South Wales who had a child (or children) diagnosed by neonatal screening between 1981 and 1996 were interviewed.
RESULTS—Two thirds of the women chose to avoid having another child with CF. The uptake of prenatal diagnosis was 66% in women who had a subsequent pregnancy; of these 69% terminated or would have terminated an affected fetus. Fifty nine per cent of the women who decided against a further pregnancy made this decision in order to avoid having another child with CF.
CONCLUSIONS—These data show that having a child with CF influenced subsequent reproductive choices. In addition to the medical advantages of an early diagnosis offered by neonatal screening, this also allows informed future reproductive decisions.

PMCID: PMC1721063  PMID: 10685985
15.  Genetic population structure indicates sympatric speciation of Lake Malawi pelagic cichlids. 
Allopatric processes of speciation have routinely been presented to explain the extraordinary radiation of the East African Great Lakes cichlid fish species flocks. The 21 or more species of pelagic cichlids within the Lake Malawi flock appear to have lake-wide distributions that challenge such a concept. Data from six microsatellite DNA loci indicate single, panmictic populations across the lake of three Diplotaxodon species. Levels of variability at these loci suggest that populations have been large and stable. Mitochondrial DNA sequence data (872 bp of control region + 981 bp of the NADH-2) from 90 species, representing all major clades within the Lake Malawi flock, indicate reciprocal monophyly of the pelagic clade. We suggest that these data support a hypothesis that speciation in sympatry is more plausible (and widespread) within the cichlid species flocks than previously thought.
PMCID: PMC1690821  PMID: 11413643
18.  Scanning laser tomography Z profile signal width as an objective index of macular retinal thickening 
AIMS—(i) To evaluate the relation between retinal thickness and the Z profile signal width of a scanning laser tomographer in selected patients exhibiting clinically manifest and circumscribed macular retinal thickening; (ii) to compare the Z profile signal width values of a group of age similar normal subjects with those of the patients with macular retinal thickening; and (iii) to present the methodology underlying the Z profile signal width derivation.
METHODS—Three patients with the following conditions were selected: widespread diabetic macular oedema; localised diabetic macular oedema; and macular hole. The patients were selected because they exhibited clinically manifest and circumscribed macular retinal thickening. Patients underwent fundus photography and a clinical examination which included fundus biomicroscopy. Fourteen age similar normal subjects were also assessed. The Heidelberg retina tomograph (HRT) was utilised to acquire seven topographic images of each macula. Z profile signal width data were analysed using custom software. Signal width was measured at 50% of the maximum intensity.
RESULTS—For each patient with macular retinal thickening, Z profile signal width analysis (after normalisation to reduce the influence of variation in reflectance intensity between successive images) revealed a significant (p<0.0001) localised increase of signal width which agreed with the HRT topographic analysis of retinal height, and also the clinical assessment of retinal thickness. The mean normalised Z profile signal width for the normal subjects (assessed over the whole image) ranged from 0.278 (SD 0.039) to 0.444 (0.063); these values compared with those obtained from patients in areas of macular retinal thickening of 0.761 (0.224) to 0.953 (0.194). Z profile signal width test-retest data for the patient with localised diabetic macular oedema were plus or minus 0.159 which compared with a mean signal width value of 0.761.
CONCLUSION—The evidence of this study, based upon three selected patients with macular retinal thickening and 14 normal subjects, would suggest that Z profile signal width analysis offers a non-invasive, objective, topographic, and reproducible index of macular retinal thickening. Studies employing larger sample sizes are required to determine the true clinical worth of the technique.

 Keywords: diabetic macular oedema; retinal thickening; scanning laser tomography; Z profile
PMCID: PMC1722496  PMID: 9613376
19.  Objective morphological assessment of macular hole surgery by scanning laser tomography 
AIM—To assess the morphological change in retinal topography using a scanning laser tomographer following macular hole surgery. To compare the results of scanning laser tomography with clinical evaluation and visual function assessment.
METHODS—The sample for this pilot study comprised four eyes exhibiting different stages of macular hole formation preoperatively. Subjects were assessed preoperatively and at 1 and 3 months postoperatively. Each assessment included visual acuity, letter contrast sensitivity, clinical examination (including automated static perimetry), and scanning laser tomography. The Heidelberg retina tomograph (HRT) was used to acquire digitised scanning laser tomography images of the macula (10° and 20° fields). Surgery essentially comprised vitrectomy, peeling of the posterior hyaloid face, if still attached, and intraocular gas tamponade. The magnitude and significance of topographic change were determined postoperatively using the HRT topographic difference facility.
RESULTS—Topographic difference analysis of the right and left eyes of case 1 showed a significant reduction in the height of the retina postoperatively. Topographic difference analysis of case 2 showed no significant change in topography. Topographic difference analysis of case 3 showed a significant increase in the height of the retina postoperatively. Scanning laser tomography agreed with clinical assessment based upon fundus biomicroscopy in three of the four eyes studied; the postoperative closure of the stage 2 macular hole (as noted by clinical assessment) proved to be too small to reach statistical significance. Scanning laser tomography agreed with the assessment of visual function in two eyes; the agreement between scanning laser tomography and visual function depends, in part, on the stage of development of the macular hole.
CONCLUSION—Scanning laser tomography provides an objective evaluation of the outcome of macular hole surgery. Studies employing larger sample sizes are required to fully determine the clinical worth of the technique.

PMCID: PMC1722126  PMID: 9059243
20.  Differential Binding of Clonal Variants of Plasmodium falciparum to Allelic Forms of Intracellular Adhesion Molecule 1 Determined by Flow Adhesion Assay 
Infection and Immunity  2000;68(1):264-269.
Adhesion of Plasmodium falciparum-infected erythrocytes to the endothelial ligand intercellular adhesion molecule 1 (ICAM-1) has been implicated in the pathogenesis of cerebral malaria. Recently, a high-frequency coding polymorphism in the N-terminal domain of ICAM-1 (ICAM-1Kilifi) that is associated with susceptibility to cerebral disease in Kenya has been described. Preliminary static adhesion assays suggested that two different selected P. falciparum lines, ITO4-A4 (A4) and ItG-ICAM (ItG), have different properties of binding to the natural variant proteins ICAM-1 and ICAM-1Kilifi. Using a flow adhesion assay system, we have confirmed differences between the two lines in binding of parasitized erythrocytes to the variant ICAM-1 proteins. Total adhesion of ItG-infected erythrocytes to ICAM-1 and ICAM-1Kilifi is greater than that of A4-infected erythrocytes, and erythrocytes infected by both parasite strains show reduced binding to ICAM-1Kilifi. However, under these physiologically relevant flow conditions, we have shown differences between A4 and ItG strains in dynamic rolling behavior on ICAM-1Kilifi. The percentage of erythrocytes infected with A4 that roll on both ICAM-1 and ICAM-1Kilifi is greater than that of those infected with ItG. Also, the rolling velocity of A4-infected erythrocytes on ICAM-1Kilifi is markedly increased compared to that on ICAM-1, in contrast to the rolling velocity of ItG-infected erythrocytes, which is similar on both proteins. These findings suggest that different parasite lines can vary in their avidity for the same host ligand, which may have important consequences for the pathophysiology of P. falciparum malaria.
PMCID: PMC97130  PMID: 10603397
21.  Unusually fine-scale genetic structuring found in rapidly speciating Malawi cichlid fishes 
Mechanisms behind the explosive radiation of over 500 cichlid fish species from a single founding population in Lake Malawi during the last 700 000 years are poorly understood. Recent studies have suggested that the degree of population subdivision among the habitat patches within the lake may be responsible, but the evidence has been circumstantial: lack of a dispersal stage in haplochromine cichlids; genetic and colour variation among populations separated by large-scale geographical barriers; and fluctuating lake levels. One reason for the rapidity of speciation in these fishes may be that population subdivision is on a much finer scale than previously thought. Here we quantify the level of population subdivision and estimate migration at a scale of 700-1400 m, in order to investigate whether cichlid populations are sufficiently isolated from each other for allopatric divergence and perhaps speciation to take place. Using six microsatellite loci, we demonstrate the existence of highly significant genetic differentiation between subpopulations on adjacent headlands in each of four rock-dwelling haplochromine cichlid species. Our results suggest that these fish populations are divided into thousands of subunits among which genetic divergence is currently occurring, and that this may provide unprecedented opportunities for allopatric speciation.
PMCID: PMC1688747
Microsatellites Allopatric Speciation Malawi Cichlids Pseudotropheus
23.  Failure to block adhesion of Plasmodium falciparum-infected erythrocytes to ICAM-1 with soluble ICAM-1. 
Infection and Immunity  1997;65(11):4580-4585.
The adhesion of Plasmodium falciparum-infected erythrocytes is thought to play a central role in the pathogenesis of severe malaria. ICAM-1 has been identified as one of the host receptors for parasitized erythrocytes and has been implicated as being involved in progression to cerebral malaria. Thus, intervention strategies based on the reversal of this interaction could potentially be used to reduce morbidity and mortality. We have investigated the inhibition of the interaction between ICAM-1 and infected erythrocytes by using recombinant soluble ICAM-1 as competitor and find that we are unable to reduce adhesion to ICAM-1 in vitro.
PMCID: PMC175657  PMID: 9353036
24.  Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome. 
Journal of Medical Genetics  1997;34(9):719-728.
Three families are reported who have a translocation involving 4p16.3. Nine subjects are described with the clinical features of the Pitt-Rogers-Danks (PRD) syndrome confirming pre- and postnatal growth failure, microcephaly, severe mental retardation, seizures, and a distinctive facial appearance; a deletion of 4p16.3 was seen in all eight patients studied with fluorescence in situ hybridisation (FISH). Eleven subjects had a new syndrome with physical overgrowth, heavy facial features, and mild to moderate mental handicap; a duplication of the chromosome region 4p16.3 was found in the four subjects studied. It is suggested that the growth abnormalities in these two families may be explained by a dosage effect of the fibroblast growth factor receptor gene 3 (FGFR3), which is located at 4p16.3, that is, a single dose leads to growth failure and a triple dose to physical overgrowth. We describe the molecular mapping of the translocation breakpoint and define it to within locus D4S43.
PMCID: PMC1051054  PMID: 9321756
25.  A nucleic acid sequence-based amplification system for detection of Listeria monocytogenes hlyA sequences. 
A nucleic acid sequence-based amplification system primarily targeting mRNA from the Listeria monocytogenes hlyA gene was developed. This system enabled the detection of low numbers (< 10 CFU/g) of L. monocytogenes cells inoculated into a variety of dairy and egg products after 48 h of enrichment in modified listeria enrichment broth.
PMCID: PMC168321  PMID: 8979357

Results 1-25 (190)