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Biomedical subjects

O Khan

Publications and source records attributed to O Khan.

At least 19 recordsLinked to original sources
PubMed2006

Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells.

Hormones acting through G protein-coupled receptors (GPCRs) can cause androgen-independent activation of androgen receptor (AR) in prostate cancer cells. Regulators of G-protein signaling (RGS) proteins, through their GTPase activating protein (GAP) activities, inhibit GPCR-mediated signaling by inactivating G proteins. Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells. Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgen-independent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G(q)-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G(q)Q209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G(q)Q209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G(q)Q209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgen-sensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.

Adenocarcinoma↗
PubMed2006

Renal ENaC subunit, Na-K-2Cl and Na-Cl cotransporter abundances in aged, water-restricted F344 x Brown Norway rats.

Renal sodium reabsorption is a key determinant of final urine concentration. Our aim was to determine whether differences existed between aged and young rats in their response to water restriction with regard to the regulation of abundance of any of the major distal renal sodium transporter proteins. Male Fisher 344 x Brown Norway (F344 x BN) rats of 3-, 10-, 24-, or 31 months of age (3M, 10M, 24M, or 31M) were either water restricted (WR) for 5 days or control (ad libitum water). Major renal sodium transporters and channel subunits were evaluated by immunoblotting and immunohistochemistry. Age did not significantly affect plasma arginine vasopressin or aldosterone levels, but renin activity was only 8% in 31M-WR rats relative to 3M-WR (P<0.05). Extreme aging (31M) led to decreased outer medullary abundance of the bumetanide-sensitive Na-K-2Cl cotransporter and decreased cortical abundance of the beta- and gamma-subunits (70-kDa band) of the epithelial sodium channel (ENaC) (P<0.05). Water restriction significantly (P<0.05) increased the abundance of Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC) across ages. However, these increases were significantly blunted as rats aged. Mean band densities were increased in WR rats (relative to age controls) by 54 and 106% at 3M, but only 25 and 29% at 24M and 0 and 6% at 31M for NKCC2 and NCC, respectively. Aged F344 x BN rats have reduced basal distal tubular renal sodium transporter abundances and blunted upregulation during water restriction, which may contribute to decreased urinary concentrating capacity.

Aging↗
PubMed2006

Clinical course after change of immunomodulating therapy in relapsing-remitting multiple sclerosis.

We examined the clinical course after switching disease-modifying therapy (DMT) in patients with relapsing-remitting multiple sclerosis (RRMS). Eighty-five consecutive RRMS patients who received weekly interferon beta-1a (IFN beta-1a) 6 MU i.m. for at least 18 months were enrolled. Baseline annualized relapse rate (ARR) for the 2 years prior to initiating therapy with IFN beta-1a was obtained from charts. All 85 patients received treatment with IFN beta-1a at 6 MU i.m. weekly for 18-24 months (mean 19.7 months). Treatment with IFN beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005). All 85 patients were then switched to glatiramer acetate (GA) 20 mg s.c. daily and prospectively followed up for 36-42 months (mean 37.5 months). Patients were switched because of persistent clinical disease activity (n=62) or persistently unacceptable toxicity (n=23) as determined by the treating neurologist. Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001). Subgroup analysis showed that in patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001). In contrast, in patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN beta-1a to 0.47 on GA (P, non-significant). Our observations suggest that clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice. More definitive consensus criteria incorporating magnetic resonance imaging and clinical observations for defining optimal response and tolerability need to be developed for the routine clinical management of RRMS patients receiving DMT.

Adjuvants, Immunologic↗
PubMed2004

Identifying and treating patients with suboptimal responses.

Multiple sclerosis (MS) is an immune-mediated neurologic disease in which acute inflammatory events early in the disease course contribute to subsequent neurologic disability. The early relapsing inflammatory phase is followed by a progressive degenerative phase in which the frequency of acute inflammatory attacks diminishes but progressive loss of neurologic function continues. Current immune therapies are most effective in suppressing the acute inflammatory events that characterize the earlier stages of disease. Optimal suppression of these inflammatory events is likely to have the best potential for delaying or preventing loss of axons and decline in neurologic function. In view of these considerations, and because MS is a heterogeneous disease and response to disease-modifying agents (DMA) varies across individuals, it is important to identify suboptimal responders as early as possible to allow therapeutic modification while the opportunity to avert future loss of function remains. At present, no criteria for identifying suboptimal responders have been validated. In January 2004, a group of neurologists from 16 MS centers in the United States met to develop a consensus on criteria for defining suboptimal response for use in compelling clinical situations and to prompt clinical studies to validate the efficacy of these criteria. Consensus criteria included relapse rates of either 1/year or unchanged from pretreatment rates, incomplete recovery from multiple attacks, evolution of polyregional neurologic involvement, recurrent brainstem or spinal cord lesions, and cumulative loss of neurologic function sufficient to disrupt daily activities. The panel then considered the use of mitoxantrone for patients with worsening MS and a suboptimal response to DMA therapy.

Clinical Trials as Topic↗
PubMed2004

Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis.

BACKGROUND: African American (AA) individuals are thought to develop multiple sclerosis (MS) less frequently than Caucasian American (CA) individuals. OBJECTIVE: To compare the clinical characteristics of AA and CA patients with MS. METHODS: The clinical features of MS were compared in a large retrospective cohort of AA (n = 375) and CA (n = 427) subjects. RESULTS: The proportion of women to men was similar in AA and CA subjects (81% [AA] vs 77% [CA]; p = 0.122). There were no differences in the proportions of subjects with relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. The median time to diagnosis was 1 year after symptom onset in AA subjects and 2 years after symptom onset in CA subjects (p = 0.0013). The age at onset was approximately 2.5 years later in AA than CA subjects (33.7 vs 31.1 years; p = 0.0001). AA subjects presented with multisite signs and symptoms at disease onset more often than CA subjects (p = 0.018). Clinical involvement restricted to the optic nerves and spinal cord (opticospinal MS) occurred in 16.8% of AA patients compared with 7.9% of CA patients (p < 0.001). Transverse myelitis also occurred more frequently in AA subjects (28 vs 18%; p = 0.001). Survival analysis revealed that AA subjects were at higher risk for development of ambulatory disability than CA subjects. After adjusting for baseline variations and differences in therapeutic interventions, AAs were at 1.67-fold greater risk for requiring a cane to ambulate than CA patients (p < 0.001). There was a trend suggesting that AAs were also at greater risk for development of wheelchair dependency (p = 0.099). Adjusted Cox proportional hazard models showed that this effect was in part attributable to the older age at onset in AAs (p < 0.001). CONCLUSIONS: Compared with multiple sclerosis (MS) in Caucasian Americans, African American patients with MS have a greater likelihood of developing opticospinal MS and transverse myelitis and have a more aggressive disease course.

Adult↗
PubMed2004

Stevens Johnson syndrome in Pakistan: a ten-year survey.

OBJECTIVE: A pre-tested questionnaire-based, retrospective study to highlight the causative factors, mode of presentation, complications and outcome of patients with Stevens Johnson syndrome. SETTING: Aga Khan University Hospital over a 10 year period. METHODS: All case records with a diagnosis of Steven Johnson Syndrome in the period 1990 to 2000 were retrospectively reviewed. Data was retrieved on a comprehensive questionnaire. The demographic variatbles and drugs taken within the previous 21 days were noted. Date analysis was done by Epi-Info Version 6.0. RESULTS: Of the 101 studied patient files, the most common offender was found to be the Penicillins as a group and Sulfadoxine-Pyrimethamine (Fansidar) when considering all drugs individually. Most common complications included electrolyte disturbances (13.9%) and congestive heart failure (6.9%). Mortality rate was high at 10.1%. CONCLUSION: SJS was found to be a rare condition but having a mortality rate of 10.1%. As it can be induced by a large number of drugs, caution should be practiced while prescribing.

Adult↗
PubMed2003

Lymphoscintigraphic evaluation of chronic lower limb oedema.

Ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), venography, lymphoscinti-graphy (LS) and contrast lymphography are frequently utilized in the evaluation of lower limb oedema but no clinical data from the Caribbean have been published on the role of LS despite its well-recognized clinical application. The successful clinical application of CT, colour doppler sonography and MRI in differentiating the various causes of lower limb oedema is well understood. Lymphoscintigraphy has found less acceptability especially in the Caribbean where nuclear imaging techniques are only now currently being developed. This paper describes the initial experience with this technique in 15 patients over a five-year period and discusses its value when lower limb lymphoedema is suspected. Scintigrams were analyzed for visualization of lymph vessels and lymph nodes, dilatation of lymphatic vessels, collaterals and dermal back flow. Lymphoscintigrams were classified as normal (n = 5) or consistent with lymphoedema (n = 10). Failure to visualize lymphatic vessels occurred in two cases of suspected primary lymphoedema. In the remaining eight cases of secondary lymphoedema, a positive study based on altered lymphatic flow and anatomy was recorded. An alternative explanation was offered in three out of five cases in which a normal lymphoscintigram was obtained.

Adult↗
PubMed2002

Value of routine long bone radiographs in management of babies with a positive VDRL at the Mount Hope Women's Hospital.

This retrospective study examined the records of 44 mothers and 44 babies with a positive blood VDRL test and/or who showed symptoms of congenital syphilis at the Mount Hope Women's Hospital (MHWH), Trinidad, between June 1, 1996 and September 30, 1998. Long bone radiographs of 40/44 (91%) babies were assessed independently by two radiologists for signs of congenital syphilis and the data were analysed using frequency tables. Of the 44 mothers in the study, 34 (77%) were VDRL positive and the rest were either negative or unknown. Maternal age ranged from 14 to 39 years and most (92%) had antenatal care. Fourteen of the 34 (41%) VDRL positive mothers received treatment antenatally. All mothers were asymptomatic and none had any clinical features of syphilis. In 35/44 babies, the VDRL test was positive and in nine, the test was either negative or unknown. Twenty-six of the babies had signs suggestive of congenital syphilis and in 12, (46%) long bone radiographs revealed changes compatible with the diagnosis of congenital syphilis. Radiographic abnormalities were present only in infants with VDRL titres > 1:8.

Adolescent↗
PubMed2001

HIV/AIDS in Pakistan.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.

Animals↗
PubMed2001

Organophosphate poisoning in a group of replacement heifers and dry cows.

Terbufos ingestion caused acute organophosphate poisoning in 67 Holstein heifers and dry cows, 7 months to 5 years old. Overall mortality was 31%, with attack rates of 4% and 48% for the dry cows and heifers, respectively. Less severely affected animals were treated with atropine sulfate for 7 days.

Animals↗
PubMed2000

The role of quantitative single photon emission computerized tomography (SPECT) in the osseous integration process of dental implants.

OBJECTIVE: To evaluate the integration process of endosseous dental implants by using quantitative bone single photon emission computerized tomography (SPECT). METHODS: Five consecutive patients receiving titanium implants (Astra Tech, Mölndal, Sweden) in the normal edentulous jaw were evaluated by bone SPECT before loading and at regular intervals up to 5 months after loading. Osteoblastic activity at the implant site was compared with activity within the skull (reference) to calculate an osteoblastic activity index (AI). RESULTS: A time activity curve obtained by plotting AI against time over 5 months showed 3 distinct phases of osteoblastic activity: (1) a rise in osteoblastic activity, part of which may reflect postoperative changes, (2) maximum activity about 1 month after implant, and (3) a gradual falloff in the AI, which returned to pre-implant levels at about 4 months. CONCLUSIONS: We conclude that this method offers a simple, reproducible, objective, and physiologic approach to studying the osseous integration process that occurs after endosseous dental implants. In this small series of patients, this osseous integrative process appears to have become established approximately 4 months after loading. This method also has the capability of quantitating bone activity in absolute terms of microCi/gram (microcuries per gram) and can be useful when bone grafting and other surgical procedures are involved.

Dental Implantation, Endosseous↗
PubMed2000

The role of labelled red blood cell scintigraphy in the detection of acute gastrointestinal bleeding.

This paper describes the experience with 99m Technetium labelled red blood cell (99mTc RBC) scintigraphy in twenty-two patients presenting with acute gastrointestinal (GI) tract bleeding. Studies were positive in thirteen cases--eight from the lower GI tract and five from the upper. The data from surgical intervention were available in ten cases. Scintigraphy cannot diagnose the cause of GI bleeding, as it is a nonspecific study. Its usefulness lies in its ability to accurately diagnose the bleeding site, as was shown in this study where there was good surgical correlation. The simplicity, reproducibility and reliability of the technique, particularly when bleeding rates are low and intermittent, make it, in our view, the first line of investigation in any patient with suspected bleeding from the colon or upper GI tract if endoscopic evaluation is not possible in the latter. Its current under-utilisation in the Caribbean may be a reflection of the lack of nuclear imaging facilities.

Acute Disease↗
PubMed1999

Effects of low-dose isoflurane on saccadic eye movement generation.

The effects of 0.15% quasi-steady-state end-tidal isoflurane on two saccadic eye-movement tests were examined in five volunteers using a newly devised computer-based recording system. The tests were saccadic latency and a countermanding task, the latter being an indicator of the highest levels of conscious performance. A moving light-emitting diode target was displayed on a screen and in the saccadic-latency task the latency of eye movement to the target was measured. In all five subjects the latency increased with anaesthetic by an amount which varied from 8 to 45 ms. This result was significantly different (p < 0.05) from subjects without anaesthetic. In the countermanding task, the subject had to voluntarily inhibit movement to the target. Again anaesthetic increased the latency of response, which varied from 6 to 33 ms. This result was significantly different (p < 0.05) from subjects without anaesthetic. In these studies it appeared that two tasks, one a simple latency test and the other, the countermanding task, requiring higher cortical processing were equally impaired at subanaesthetic concentrations of isoflurane.

Anesthetics, Inhalation↗
PubMed1999

Contrast material and gallbladder kinetics: implications for same day sonography after intravenous pyelography or CT scanning.

Sonographic examination of the gallbladder has allowed us to study the effects of various substances on this organ. A prospective study involving 77 patients was undertaken to evaluate the effects of intravenous or oral contrast agents on gallbladder volume changes in patients without known gallbladder disease. A mean volume after contraction of 24.8% was observed after administration of intravenous contrast agent (P < 0.01) and of 31.9% after oral administration (P < 0.01). This phenomenon of contraction of the gallbladder should therefore be recognized when sonographic or computed tomographic evaluation of the gallbladder is undertaken after imaging procedures that use radiographic contrast agents either intravenously or orally.

Administration, Oral↗
PubMed1998

Competitive binding of xenobiotic oestrogens to rat alpha-fetoprotein and to sex steroid binding proteins in human and rainbow trout (Oncorhynchus mykiss) plasma.

The ability of a variety of "environmental oestrogens" to compete with radiolabelled steroids to rat alpha-fetoprotein (AFP) and to sex steroid binding proteins was investigated in human and rainbow trout (Oncorhynchus mykiss) plasma. For [3H]oestradiol binding to AFP, diethylstilbestrol and 4-nonylphenoxyacetic acid showed significant competition at concentrations about 100-fold greater than oestradiol (relative binding affinities approximately 1% c.f. oestradiol). All other compounds (phytooestrogens: coumestrol, daidzein, genistein; others: 4-nonylphenol, 4-tert-octylphenol, 4-nonylphenoldiethoxylate, 4-tert-butylphenol, bisphenol-A (Bis-A), bis(2- ethylhexl)phthalate, dioctylphthalate, dibutyl phthalate, 2, 4'DDT (op' enantiomer), 2,4'-DDE (mixed enantiomers), kepone) showed only very weak or no competition (relative binding affinities <<0.1% c.f. oestradiol). The situation for both human and fish plasma was very similar, with only very high concentrations (>>1000 fold more than the natural ligand) of a few of the compounds showing any ability to displace the natural ligand. These results suggest that environmental oestrogenic agents are unlikely to produce biological effects by displacing endogenous steroids from plasma steroid binding proteins unless they are present in very high concentrations.

Animals↗