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1.  Lumbosacral actinomycosis in an immunocompetent individual: An extremely rare case 
Actinomycosis is a gram positive commensal bacteria. In predisposed individuals like immunocompromised patients, it can cause myriad lesions involving virtually any organ of the body. Involvement of spinal cord with its compression is rare though. We are reporting here a case of 30-year-old immunocompetent male who presented with weakness of left lower limb. Radiologically differential diagnosis was tuberculosis or lymphoma of spinal cord. Histopathology showed actinomycotic colonies that were periodic Schiff (PAS) positive and revealed gram positive filamentous bacteria.
PMCID: PMC4279282  PMID: 25558150
Actinomycosis; immunocompetent; lumbosacral spine
2.  Comment on Gitelman's syndrome: Rare presentation with growth retardation 
PMCID: PMC4165070  PMID: 25249735
3.  Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress 
British Journal of Cancer  2013;109(4):983-993.
We have previously identified peroxiredoxin-3 (PRDX-3) as a cell-surface protein that is androgen regulated in the LNCaP prostate cancer (PCa) cell line. PRDX-3 is a member of the peroxiredoxin family that are responsible for neutralising reactive oxygen species.
Experimental design:
PRDX-3 expression was examined in tissue from 32 patients using immunohistochemistry. Subcellular distribution was determined using confocal microscopy. PRDX-3 expression was determined in antiandrogen-resistant cell lines by western blotting and quantitative RT–PCR. The pathways of PRDX-3 overexpression and knockdown on apoptosis and response to oxidative stress were investigated using protein arrays.
PRDX-3 is upregulated in a number of endocrine-regulated tumours; in particular in PCa and prostatic intraepithelial neoplasia. Although the majority of PRDX-3 is localised to the mitochondria, we have confirmed that PRDX-3 at the cell membrane is androgen regulated. In antiandrogen-resistant LNCaP cell lines, PRDX-3 is upregulated at the protein but not RNA level. Resistant cells also possess an upregulation of the tricarboxylic acid (TCA) pathway and resistance to H2O2-induced apoptosis through a failure to activate pro-apoptotic pathways. Knockdown of PRDX-3 restored H2O2 sensitivity.
Our results suggest that PRDX-3 has an essential role in regulating oxidation-induced apoptosis in antiandrogen-resistant cells. PRDX-3 may have potential as a therapeutic target in castrate-independent PCa.
PMCID: PMC3749568  PMID: 23880827
prostate cancer; anti-androgen; oxidation
6.  Investigation of erectile dysfunction 
The British Journal of Radiology  2012;85(Spec Iss 1):S69-S78.
Erectile dysfunction (ED) represents a common and debilitating condition with a wide range of organic and non-organic causes. Physical aetiologies can be divided into disorders affecting arterial inflow, the venous occlusion mechanism or the penile structure itself. Various imaging modalities can be utilised to investigate the physical causes of ED, but penile Doppler sonography (PDS) is the most informative technique, indicated in those patients with ED who do not respond to oral pharmacological agents (e.g. phosphodiesterase type 5 inhibitors). This review will examine the anatomical and physiological basis of penile erection, the method for performing PDS and features of specific causes of ED, and will also consider the alternative imaging modalities available.
PMCID: PMC3746402  PMID: 23118101
7.  Priapism: pathophysiology and the role of the radiologist 
The British Journal of Radiology  2012;85(Spec Iss 1):S79-S85.
Priapism is defined as a penile erection that persists for 4 h or longer and is unrelated to sexual activity. Its identification is important as lack of timely treatment (particularly of the low flow/ischaemic subgroup) can result in persisting erectile dysfunction as a consequence of irreversible corporal fibrosis. This review describes the physiology and anatomy of the normal erection, the aetiology and pathophysiology of the different types of priapism, and the role of the radiologist in the management of the condition. The treatment of iatrogenic priapism following intracavernosal injection of pharmacostimulant is discussed.
PMCID: PMC3746404  PMID: 22960245
8.  In vivo confocal microscopy of the cornea in Morquio syndrome 
Eye  2012;26(10):1394-1395.
PMCID: PMC3470058  PMID: 22863816
9.  Twice-Daily Subcutaneous Injection of Kisspeptin-54 Does Not Abolish Menstrual Cyclicity in Healthy Female Volunteers 
Kisspeptin is a critical hypothalamic regulator of reproductive function. Chronic kisspeptin administration causes profound tachyphylaxis in male monkeys and in women with functional hypothalamic amenorrhea. The pharmacological effects of chronic kisspeptin exposure in healthy women with normal menstrual cycles have not been studied previously.
Our aim was to determine the effects of follicular-phase kisspeptin-54 treatment on menstrual cyclicity in healthy women.
We performed a prospective, single-blinded, 1-way crossover study. Healthy women received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline during menstrual days 7–14 (n = 5 per treatment arm). Serial assessments of basal reproductive hormones, ultrasound parameters, LH pulsatility, and acute sensitivity to GnRH and kisspeptin-54 injection were performed.
Menstrual cyclicity persisted in all women after follicular-phase kisspeptin-54 treatment. Chronic exposure to kisspeptin-54 did not abolish acute stimulation of LH after injection of kisspeptin-54 or GnRH. In addition, kisspeptin-54 treatment was associated with a shorter mean length of the menstrual cycle (mean length of menstrual cycle was 28.6 ± 1.4 days with saline vs 26.8 ± 3.1 days with kisspeptin, P < .01), earlier onset of highest recorded serum LH (mean menstrual day of highest LH was 15.2 ± 1.3 with saline vs 13.0 ± 1.9 with kisspeptin, P < .05), and earlier onset of the luteal phase (mean menstrual day of progesterone increase was 18.0 ± 2.1 with saline vs 15.8 ± 0.9 with kisspeptin, P < .05).
Our data suggest that 1 week of exogenous kisspeptin-54 does not abolish menstrual cyclicity in healthy women. Further work is needed to determine whether kisspeptin could be used to treat certain anovulatory disorders.
PMCID: PMC4111853  PMID: 24030945
10.  Provincial screening rates for chronic diseases of lifestyle, cancers and HIV in a health-insured population 
Screening for asymptomatic diseases can reduce the burden of morbidity and mortality in all population groups. There is widespread geographical variation in the quality of care. Few data are available on national screening rates in South Africa and how these vary across the provinces.
To examine screening rates for chronic diseases of lifestyle (CDL), HIV and cancer in a privately insured population for a single insurer across all nine provinces in South Africa, and to determine whether or not there are any differences between the provinces.
Screening rates were calculated as the proportion of eligible members who had received screening tests during 2011 in each province. Mean screening rates were compared between Gauteng and the other eight provinces.
Nationwide screening rates were 20.5% for CDL, 8.2% for HIV and 31.9% for cancer. Despite similar insurance coverage, screening rates ranged from 0.3% to 0.95% lower in other provinces compared with Gauteng. Of all the provinces, Gauteng had the highest annual screening rates for CDL, breast cancer, prostate cancer and HIV (p<0.001), while the Western Cape had the highest rate for cervical cancer (p<0.001).
There is much variation in preventive care utilisation across the provinces within this health-insured population. Provinces with more abundant healthcare resources have higher screening rates. Further research is required to understand the reasons for the variation, given equal payment access.
PMCID: PMC3752603  PMID: 23971120
11.  Uterine artery pulsatility index: a predictor of methotrexate resistance in gestational trophoblastic neoplasia 
British Journal of Cancer  2012;106(6):1089-1094.
Neo-angiogenesis is a hallmark of cancer. The aim of this study was to test the hypothesis, in a prospective patient cohort, that in low-risk gestational trophoblastic neoplasia (LR-GTN) the uterine artery pulsatility index (UAPI), a measure of tumour vascularity, can predict resistance to methotrexate chemotherapy (MTX-R).
286 LR-GTN patients (Charing Cross Hospital (CXH) score 0–8, or FIGO score 0–6) were treated with methotrexate between January 2008 and June 2011 at CXH. During staging investigations, patients underwent a Doppler ultrasound to assess the UAPI.
239 patients were assessable for both UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R compared with MTX-sensitive patients (0.8 vs 1.4, P<0.0001). In multivariate logistic regression, UAPI⩽1 predicted MTX-R, independent of both CXH and FIGO scores. The risk of MTX-R in patients with a FIGO score of 6 and UAPI⩽1 was 100% vs 20% in patients with UAPI>1 (χ2 P<0.0001).
UAPI represents an independently validated clinically useful predictor of MTX-R in LR-GTN. Further, consideration of whether to incorporate UAPI into the FIGO scoring system is now warranted so that patients with a score of 6 and a UAPI ⩽1 might be upstaged and offered combination chemotherapy rather than MTX.
PMCID: PMC3304432  PMID: 22374461
low-risk GTN; UAPI; drug resistance; angiogenesis
12.  A novel approach to the management of a ruptured Type II endoleak following endovascular repair of an internal iliac artery aneurysm 
The British Journal of Radiology  2011;84(1008):e240-e242.
Endovascular repair of isolated iliac artery aneurysms is an established safe and effective management option. Type II endoleak is a potential complication, but rarely results in significant morbidity or mortality. We report a case of a patient who presented with a ruptured internal iliac artery aneurysm secondary to a Type II endoleak. To our knowledge this and the following method of managing this have not been previously reported. Established methods of managing endoleaks, such as intravascular transfemoral embolisation and open or laparoscopic ligation, were not possible. Therefore, we resorted to a novel approach to this type of aneurysm and successfully performed a transcutaneous direct puncture and embolisation of the superior gluteal artery.
PMCID: PMC3473829  PMID: 22101591
13.  Inferring subjective states through the observation of actions 
Estimating another person's subjective confidence is crucial for social interaction, but how this inference is achieved is unknown. Previous research has demonstrated that the speed at which people make decisions is correlated with their confidence in their decision. Here, we show that (i) subjects are able to infer the subjective confidence of another person simply through the observation of their actions and (ii) this inference is dependent upon the performance of each subject when executing the action. Crucially, the latter result supports a model in which motor simulation of an observed action mediates the successful understanding of other minds. We conclude that kinematic understanding allows access to the higher-order cognitive processes of others, and that this access plays a central role in social interactions.
PMCID: PMC3497093  PMID: 23034708
inference; kinematics; action observation
14.  Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction 
Molecular Psychiatry  2012;17(9):887-905.
We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein–coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
PMCID: PMC3427857  PMID: 22584867
biomarkers; convergent functional genomics; genetic risk prediction; pathways; schizophrenia
16.  Childhood blindness and severe visual impairment in Malaysia: a nationwide study 
Eye  2011;25(4):436-442.
To determine the causes of childhood blindness and severe visual impairment (BL/SVI) in schools for the blind in Malaysia.
All children ≤15years attending 24 schools for the blind throughout the country were examined using the WHO Prevention of Blindness Programme (WHO/PBL) eye examination record for children, and visual loss was classified according to the International Classification of Disease (ICD).
In all, 469 children were examined, of whom 448 (95.6%) had BL/SVI. The major causes of visual loss were retinal disorders (n=148, 33% mainly retinopathy of prematurity (n=78, 17.4%)), cataract/pseudophakia/aphakia (n=77, 17.2%), and anomalies affecting the whole globe. (n=86, 19.2%). The major underlying etiology was undetermined (n=193, 43.1%), followed by hereditary factors, 21.7% (mainly retinal dystrophies), and perinatal factors, 20.5%. More than 34 (7.6%) cases were considered potentially preventable and 192 (42.9%) potentially treatable.
Diseases of the retina are the major cause of visual impairment, with retinopathy of prematurity being an important avoidable cause. This reflects expansion of neonatal services in Malaysia, and improved survival of very low birth weight and preterm babies. Lens-related causes of visual impairment reflect the need to further improve pediatric ophthalmology services in Malaysia.
PMCID: PMC3171242  PMID: 21350565
childhood blindness; severe visual impairment; Malaysia; retinopathy of prematurity; WHO prevention of blindness programme
18.  Stroke volume variation guided fluid therapy in septic shock with ARDS 
Critical Care  2012;16(Suppl 1):P233.
PMCID: PMC3363651
20.  Preparation and evaluation of Levosalbutamol sulphate chitosan microsphere for the treatment of asthma 
Journal of Pharmacy & Bioallied Sciences  2012;4(Suppl 1):S46-S47.
Mucoadhesive drug delivery systems are those that provide intimate contact of the drug with the mucosa for an extended period of time. In present work, mucoadhesive chitosan microspheres of Levosalbutamol sulphate were prepared by Spray drying method. Formulations were characterized for various physicochemical attributes size, encapsulation efficiency, swelling ability, in vitro release study and mucoadhesion study by rat ileum. Through these parameters we conclude that the batch B2 was found to be best mainly by mucoadhesion study and in vitro drug release. Mucoadhesion was found to be increased with incresed concentration of polymer and visa versa in case of drug release. Batch B3 had also similar results with that of Batch B2. That's why here Batch B2 was said to be the best batch with less polymeric content as compare to Batch B3.
PMCID: PMC3467846  PMID: 23066203
Chitosan microspheres; spray drying; in vitro release study
21.  Granular and Lattice Deposits in Corneal Dystrophy Caused by R124C Mutation of TGFBI 
Cornea  2010;29(11):1215-1222.
Both granular and lattice deposits are present in Avellino corneal dystrophy (ACD), primarily associated with R124H mutation of transforming growth factor β-induced protein (TGFBI). We investigated the presence of these deposits in other TGFBI mutations and the use of Thioflavin-T (ThT), a fluorescent amyloid stain for characterizing corneal amyloid deposits.
Surgical corneal specimens of three unrelated patients clinically diagnosed with ACD were studied. Corneal sections from normal and prior patients with lattice corneal dystrophy (LCD) were used as controls. Histochemical studies were performed with Congo red and Masson trichrome, and fluorescent imaging with scanning laser confocal microscopy was performed for ThT and an anti-TGFBI antibody staining.
Clinical and histopathological findings supported the diagnoses of ACD in these three cases, in whom granular deposits stained with Masson trichrome and lattice deposits stained with ThT and Congo red showing birefringence and dichroism as expected. However, genotyping revealed a heterozygous R124C mutation in each case. In addition to classical stromal deposits, unique sub-epithelial TGFBI aggregates, that stain with neither ThT nor trichrome, were observed. In control LCD sections, stromal deposits stained with ThT but not with trichrome, confirming lack of granular deposits.
Our results demonstrate that both granular and lattice deposits can be associated with R124C mutation, other than R124H. An additional feature of non-hyaline, non-amyloid TGFBI sub-epithelial deposits might substantiate such cases be categorized as a variant form of LCD or ACD. This study further validates ThT staining for detection of amyloid TGFBI deposits.
PMCID: PMC2965268  PMID: 20697279
Avellino corneal dystrophy; keratoepithelin; TGFBI; amyloid; ThT
22.  Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms 
Translational Psychiatry  2011;1(5):e9-.
Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain.
PMCID: PMC3309477  PMID: 22832404
anxiety; biomarkers; blood; brain; genes; microarray
23.  Convergent functional genomic studies of omega-3 fatty acids in stress reactivity, bipolar disorder and alcoholism 
Translational Psychiatry  2011;1(4):e4-.
Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease-relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well-established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond.
PMCID: PMC3309466  PMID: 22832392
alcoholism; bipolar; DHA; genomics; omega-3; stress
24.  Targeting CYP450 modulation to decrease the risk of induced cataract in the experimental model 
Indian Journal of Ophthalmology  2010;58(6):471-475.
Diabetes is one of the major causes of cataract. Some drugs prescribed for the treatment of diabetes are the modulators of CYP450, which may alter the risk of cataract.
To study the effect of CYP450 modulation in galactosemic cataract.
Materials and Methods:
Male Sprague-Dawley suckling rats were allotted to four groups (n = 6), as follows: Group 1: Normal control, Group 2: Galactose control, Group 3: CYP450 inhibitor pretreated and Group 4: CYP450 inducer pretreated. Cataract was induced in animals of all groups except group 1 by feeding them galactose (50%), 21 days after parturition. From the eighteenth day of life, CYP450 inhibitor (nifedipine; 8.1 mg/kg) and CYP450 inducer (pioglitazone; 3.8 mg/kg) were given orally to groups 3 and 4, respectively. The maturation pattern of the cataract was observed by an operating microscope, every third day. Biochemical changes in the lenses of all groups, for example, CYP450 activity expressed as µM NADPH oxidized / unit time, alterations in the levels of total proteins, soluble proteins, and reduced glutathione (GSH) following the induction of cataract, were estimated.
The microscopic examination of the lenses indicated that CYP450 inhibitor pre-treatment delayed (fourteenth day) the occurrence of cataract, while CYP450 inducer pretreatment demonstrated an early (ninth day) cataract as compared to galactose control rats (twelfth day). A significant decrease and increase in CYP450 activity was observed with the CYP450 inhibitor and inducer pre-treatment, respectively. There was no alteration in the GSH level, but a significant increase in total and soluble protein was found in groups 3 and 4 as compared to group 2.
CYP450 may have a role in the initiation of cataract without any effect on the maturation pattern, as revealed by the delayed occurrence of cataract with the CYP450 inhibitor and an early onset of cataract with the CYP450 inducer.
PMCID: PMC2993975  PMID: 20952829
Cataract; CYP450; galactose; lens
25.  A prospective study of peri-diagnostic and surgical wait times for patients with presumptive colorectal, lung, or prostate cancer 
British Journal of Cancer  2008;100(1):56-62.
The objective of this study was to prospectively measure peri-diagnostic and surgical time intervals for patients with suspected colorectal, lung, or prostate cancer. Prospective eligible patients were referred to a regional hospital in Ottawa, Canada between February 2004 and February 2005 for diagnostic assessment of presumptive colorectal, lung, or prostate cancer. Chart abstractions were used to measure nine time intervals; the primary interval was the date of referral for diagnostic assessment to the date the patient was informed of the diagnosis. Health-related quality-of-life (HRQL) was assessed 5 days following the patient being informed of their diagnosis. The median (IQR) time for the primary interval was 71 (30–110), 37 (29–49), and 81 (56–100) days for colorectal, lung, and prostate patients, respectively (Kruskal–Wallis P=0.0001). This interval was significantly less for colorectal patients diagnosed with cancer than for those without cancer (median difference=59.0 days; Wilcoxon P=0.003). No differences in HRQL existed for patients with cancer and those without. Colorectal and prostate patients wait longer between referral for suspected cancer and being informed of their diagnosis than current recommendations. The shorter diagnostic intervals for colorectal patients with cancer suggest clinicians have an effective process for triaging patients referred for diagnostic assessment.
PMCID: PMC2634695  PMID: 19088720
lung cancer; colorectal cancer; prostate cancer; health services; diagnosis; surgery

Results 1-25 (65)