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Articles by S Khan
Total Records ( 5 ) for S Khan
  J. M Olichney , S Chan , L. M Wong , A Schneider , A Seritan , A Niese , J. C Yang , K Laird , S Teichholtz , S Khan , F Tassone and R. Hagerman

Fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder associated with premutation alleles (55–200 CGG repeats) of the FMR1 gene, affects many carriers in late-life. Patients with fragile X-associated tremor/ataxia syndrome typically have cerebellar ataxia, intranuclear inclusions in neurons and astrocytes, as well as cognitive impairment. Dementia can also be present with cognitive deficits that are as severe as in Alzheimer’s disease, however frontosubcortical type impairment is more pronounced in fragile X-associated tremor/ataxia syndrome. We sought to characterize the P600 and N400 word repetition effects in patients with fragile X-associated tremor/ataxia syndrome, using an event-related potential word repetition paradigm with demonstrated sensitivity to very early Alzheimer’s disease. We hypothesized that the fragile X-associated tremor/ataxia syndrome-affected participants with poor declarative verbal memory would have pronounced abnormalities in the P600 repetition effect. In the event-related potential experiment, subjects performed a category decision task whilst an electroencephalogram was recorded. Auditory category statements were each followed by an associated visual target word (50% ‘congruous’ category exemplars, 50% ‘incongruous’ nouns). Two-thirds of the stimuli (category statement–target word pairs) were repeated, either at short-lag (~10–40 s) or long-lag (~100–140 s). The N400 and P600 amplitude data were submitted to split-plot analyses of variance. These analyses of variance showed a highly significant reduction of the N400 repetition effect (F = 22.5, P < 0.001), but not of the P600 repetition effect, in mild fragile X-associated tremor/ataxia syndrome (n = 32, mean age = 68.7, mean Mini-Mental State Examination score = 26.8). Patients with fragile X-associated tremor/ataxia syndrome had significantly smaller late positive amplitude (550–800 ms post-stimulus onset) to congruous words (P = 0.04 for group effect). Reduced P600 repetition effect amplitude was associated with poorer recall within fragile X-associated tremor/ataxia syndrome patients (r = 0.66) and across all subjects (r = 0.52). Larger P600 amplitude to new congruous words also correlated significantly with higher free recall scores (r = 0.37, P < 0.01) across all subjects. We found a correlation between the amplitude of late positivity and CGG repeat length in those with fragile X-associated tremor/ataxia syndrome (r = 0.47, P = 0.006). Higher levels of FMR1 mRNA were associated with smaller N400s to incongruous words and larger positive amplitudes (between 300 and 500 ms) to congruous words. In conclusion, event-related potential word repetition effects appear sensitive to the cognitive dysfunction present in patients with mild fragile X-associated tremor/ataxia syndrome. Their more severe reduction in N400 repetition effect, than P600, is in contrast to the reverse pattern reported in amnestic mild cognitive impairment and incipient Alzheimer’s disease (Olichney et al., 2008).

  J Laurson , S Khan , R Chung , K Cross and K. Raj

A common feature shared between several human cancer-associated viruses, such as Epstein-Barr virus, Hepatitis B virus and Hepatitis C virus, and Human papillomavirus (HPV) is the ability to reduce the expression of cellular E-cadherin. Since E-cadherin is used by Langerhans cells to move through the stratified epithelium, its reduction may affect the efficiency by which the immune system responds to HPV infection and the length of persistent HPV infections. We observed that the E7 protein of this virus (HPV16) is most efficient at reducing E-cadherin levels. This E7 activity is independent of retinoblastoma protein or AP-2 degradation. Instead it is associated with augmentation of cellular DNA methyltransferase I (Dnmt1) activity. Significantly, inhibition of Dnmt activity re-established E-cadherin levels of the cells, presenting the possibility that similar epigenetic intervention clinically may be a way to re-establish the influx of Langerhans cells into infected epithelium to counteract HPV persistence.

  R Fish , J Pinney , P Jain , C Addison , C Jones , S Jayawardene , J Booth , A. J Howie , T Ghonemy , S Rajabali , D Roberts , L White , S Khan , M Morgan , P Cockwell and C. A. Hutchison

Background and objectives: Monoclonal gammopathies frequently cause renal disease, but they may be an incidental finding. Assessment of renal pathology in the context of renal dysfunction and a monoclonal gammopathy therefore serves as a useful diagnostic tool and, in addition, provides prognostic information. There is, however, a theoretical risk of increased hemorrhagic complications from renal biopsies in this setting. The purpose of this study was to determine the incidence of significant hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies.

Design, setting, participants, & measurements: The case notes of 1993 unselected patients from four teaching hospitals within the United Kingdom who underwent native or transplant renal biopsies between 1993 and 2008 were reviewed. Subjects were categorized as having a monoclonal gammopathy or not, and the incidence of major hemorrhagic complications between groups was compared.

Results: In total, 74 (3.7%) patients (native and transplant biopsies) had a major hemorrhagic complication. One hundred forty-eight subjects with a monoclonal gammopathy were identified. The complication rate in this group was 4.1% compared with 3.9% in the control population (native biopsies only; P = 0.88).

Conclusions: In the population studied, the rate of major hemorrhagic complications after percutaneous renal biopsy was not significantly greater in patients with a monoclonal gammopathy.

  C. J Krebs , S Khan , J. W MacDonald , M Sorenson and D. M. Robins

Krüppel-related zinc finger proteins (KRAB-zfps) comprise the largest mammalian transcription factor family, but their specific functions are largely unknown. Two KRAB-zfps, regulator of sex-limitation (Rsl) 1 and Rsl2, repress expression of the mouse sex-limited protein (Slp) gene, the hallmark of Rsl activity, as well as some other male-predominant liver genes. This phenotype suggests Rsl modifies sex-specific transcription. The scope of Rsl control was determined by expression profiling of liver RNA from wild-type (wt), rsl, and transgenic mice with hepatic overexpression of Rsl1 or Rsl2. About 7.5% of the liver transcriptome was Rsl-responsive. More genes in males than females were affected by the loss of Rsl (e.g., in rsl mice), whereas Rsl overexpression altered more transcripts in females than males. Rsl dramatically repressed some female-predominant genes, but most were modestly (1.25- to 2-fold) influenced. In males, most Rsl-responsive genes unexpectedly expressed at lower levels in rsl than wt, suggesting not all are direct targets of Rsl repression. Gene Ontology analysis showed Rsl targets enriched in pathways of cholesterol, steroid, and lipid metabolism, linking Rsl to energy balance. In accord with this, blood glucose levels were less in male rsl than wt mice, and less responsive to fasting and refeeding. rsl mice were also leaner than wt, consistent with their hepatic regulation of phosphoenolpyruvate carboxykinase 1 and stearoyl-Coenzyme A desaturase 1. Altogether, Rsl's effect on sexually dimorphic and metabolically sensitive liver gene expression suggests a role for KRAB-zfps as broad genetic modulators of individual adaptation.

  K. J Meaburn , P. R Gudla , S Khan , S. J Lockett and T. Misteli

The nuclear repositioning of specific genes may be a novel diagnostic strategy to distinguish malignant from normal tissue.

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