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Biomedical subjects

S Dhillon

Publications and source records attributed to S Dhillon.

At least 19 recordsLinked to original sources
PubMed2001

An efficient procedure for genotyping single nucleotide polymorphisms.

Analysis of single nucleotide polymorphisms (SNPs) has been and will be increasingly utilized in various genetic disciplines, particularly in studying genetic determinants of complex diseases. Such studies will be facilitated by rapid, simple, low cost and high throughput methodologies for SNP genotyping. One such method is reported here, named tetra-primer ARMS-PCR, which employs two primer pairs to amplify, respectively, the two different alleles of a SNP in a single PCR reaction. A computer program for designing primers was developed. Tetra-primer ARMS-PCR was combined with microplate array diagonal gel electrophoresis, gaining the advantage of high throughput for gel-based resolution of tetra-primer ARMS-PCR products. The technique was applied to analyse a number of SNPs and the results were completely consistent with those from an independent method, restriction fragment length polymorphism analysis.

DNA↗
PubMed2001

Invasiveness of cutaneous malignant melanoma is influenced by matrix metalloproteinase 1 gene polymorphism.

The matrix metalloproteinases (MMPs) are implicated in connective tissue destruction during cancer invasion and metastasis. A naturally occurring variant arising from the insertion or deletion of a guanine in the promoter of the MMP-1 gene has recently been reported and shown to influence its transcriptional activity in melanoma cells. In this study, MMP-1 genotype was determined in 139 Caucasian patients with cutaneous malignant melanoma. The insertion allele was associated with deep invasive, and therefore poorer-prognosis, primary tumors [(34% of patients with vertical growth phase tumor were homozygous for the insertion allele compared with 17% of patients with horizontal growth phase tumor (P = 0.0333; odds ratio = 2.51)]. These data suggest that the invasiveness of cutaneous malignant melanoma is influenced by variation in the MMP-1 gene promoter that affects MMP-1 expression.

Cell Division↗
PubMed2001

Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Intracranial aneurysm, which underlies the vast majority of subarachnoid hemorrhage incidences, has a multifactorial etiology, and the importance of genetic factors is increasingly recognized. Development and rupture of intracranial aneurysms involve degradation and remodeling of the vascular wall matrix in which the matrix metalloproteinases (MMPs) play an important role. The possible impact of MMP gene polymorphisms on susceptibility to intracranial aneurysms is still controversial, with conflicting data from different reported studies. METHODS: In this study we analyzed 5 different functional promoter polymorphisms in the MMP-1, MMP-3, MMP-9, and MMP-12 genes in a sample of 92 patients with aneurysmal subarachnoid hemorrhage and 158 healthy control subjects, all from southern England. RESULTS: No significant difference was detected between the patient and control groups in genotype distribution of any of the polymorphisms studied. CONCLUSIONS: The data do not support the hypothesis that MMP gene variations influence the development of intracranial aneurysms in the population studied.

Adult↗
PubMed2001

Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary.

Hyperandrogenism observed in women with a variety of insulin-resistant states is thought to be due to a stimulatory effect of insulin on ovarian steroid hormone production. However, it is not known what mechanisms could allow the ovary to remain sensitive to insulin while classical target organs for insulin action (liver, fat, and muscle) exhibit insulin resistance. One hypothesis proposed to explain this paradox suggests that a postbinding divergence of insulin receptor signaling occurs in the ovary and that signaling pathways for steroid hormone synthesis and other ovarian effects of insulin may be distinct from classical glucose signaling pathways. We now report that activation of phosphatidyl-inositol-3 (PI-3) kinase, which is crucial for glucose transport, is not necessary for the insulin-induced stimulation of progesterone production or for the insulin-induced inhibition of insulin-like growth factor binding protein 1 (IGFBP-1) production in cultured human ovarian cells. Human granulosa cells obtained during in vitro fertilization procedures were cultured with 10, 10(2), 10(3), or 10(4) ng/mL insulin with or without preincubation with 100 nM wortmannin, a specific irreversible inhibitor of PI-3 kinase. IGFBP-1 concentration in the conditioned medium was measured using immunoradiometric assay or by Western blot analysis. Progesterone concentration was measured using RIA. Additional studies were carried out in cultures of human ovarian cells prepared from homogenized whole ovarian tissue of a woman with a family history of breast cancer and a mutation of BRCA-1 gene who underwent bilateral oophorectomy. These cells were cultured with 10(3) ng/mL insulin with or without preincubation with 100 nM wortmannin. Two-way ANOVA was used to compare mean values of IGFBP-1 and progesterone according to insulin dose and the use of wortmannin. In cultured granulosa cell medium, progesterone production was stimulated by insulin in a dose-related manner up to 175% of control (P < 0.0001). In tissue culture medium from ovarian cells obtained from a patient with BRCA-gene mutation, concentration of progesterone in the tissue culture medium increased from 2.5 +/- 0.2 ng/mL for control to 5.4 +/- 0.3 ng/mL for cells incubated with insulin (P < 0.001). IGFBP-1 production in tissue culture medium from human granulosa cells was inhibited by insulin to the nadir of 45% of control (P < 0.0001). Preincubation with wortmannin, despite complete inhibition of PI-3 kinase in both cell systems confirmed by Western blot analysis, failed to significantly alter these results. We conclude that inhibition of PI-3 kinase by wortmannin fails to abolish stimulatory effect of insulin on progesterone production or inhibitory effect of insulin on IGFBP-1 production in cultured human ovarian cells. These findings suggest that activation of PI-3 kinase, an enzyme crucial for insulin-stimulated glucose transport, is not necessary for the above effects of insulin in the ovary. These data provide evidence for the presence of PI-3 kinase-independent insulin signaling pathway(s) in human ovarian cells.

Androstadienes↗
PubMed2000

MK801 increases retinotectal arbor size in developing zebrafish without affecting kinetics of branch elimination and addition.

Visual activity refines the retinotopic map formed on tectum during regeneration and development in goldfish through an N-methyl-D-aspartate (NMDA) receptor-mediated mechanism. Retinal arbors are enlarged in fish with unrefined maps. Here, we examined the effect of NMDA receptor blockers on the development of retinotectal arbors in zebrafish. Since visual behaviors begin 68-79 h postfertilization, we blocked NMDA receptors by immersion of larvae in MK801, AP5, or CPP starting at either 48 or 72 h. We then labeled axons with DiI at 72 or 96 h and examined them 5-9 h later. Arbors at 101-105 h (31 cases) were larger than at 77-79 h (11 cases): The average number of branches increased from 4.0 to 7.6 and the area (convex polygon method) increased by 42%. Blocking NMDA receptors with MK801 from 72 to 101-105 h significantly enlarged arbor size, but the number of branches remained roughly the same. The length and area of the arbors were both significantly increased (21% and 36%), whereas the width increased by a smaller amount (6%). This increase was reflected in longer distances between branches within the arbor (interbranch segments, +13%) as well as in the summed length of all branches (+28%). This selective effect on the extent but not number of branches is in agreement with our previous report of strobe effects in both developing and regenerating projections in goldfish, and supports the role of NMDA receptors in the first 24 h of synaptic transmission. We also used DiO to label arbors in time-lapse images taken at hourly intervals from 77 to 112 h. These sequences confirmed that individual arbors grew during this time, but showed that rates of branch addition and deletion and branch lifetimes were unaltered by the MK801 treatment. This is consistent with a simple model of random insertion of new branches and selective activity-driven elimination of those at the periphery to keep the normal arbor focused. Blocking NMDA receptors is postulated to randomize the elimination allowing the periphery to expand, thus accounting for the enlarged areas, without change in branch numbers or branch dynamics.

2-Amino-5-phosphonovalerate↗
PubMed2000

Prospective assessment of accuracy of endoanal MR imaging and endosonography in patients with fecal incontinence.

OBJECTIVE: Endoanal MR imaging was prospectively compared with anal endosonography to determine any superiority in the characterization of sphincter morphology in fecal incontinence. SUBJECTS AND METHODS: Fifty-two consecutive patients with fecal incontinence were examined with anal endosonography and endoanal MR imaging after a detailed bowel history, clinical examination, and complete anorectal physiologic testing. External and internal anal sphincter integrity was noted on both endosonograms and MR images by two radiologists in consensus, who read individual scans in a random order to avoid recall bias. Imaging findings were subsequently compared, and arbitration of any disagreement between endosonography and MR imaging was made in consensus by a surgeon and a gastroenterologist who also had access to the patient's history, clinical examination, and anorectal physiologic testing results. RESULTS: Complete agreement was found between anal endosonographic and MR imaging interpretations in 32 patients (62%): 10 with combined external and internal sphincter injuries, two with isolated internal sphincter injury, and 20 with intact sphincters. Of 20 patients in whom results of the scans were disparate, incorrect interpretation was found on endosonography in six patients, on MR imaging in 15. Overall, one error relating to the internal sphincter was made on endosonography versus 12 on MR imaging (p = 0.002), and five errors relating to the external sphincter were made on endosonography versus six on MR imaging (p = 1.0). CONCLUSION: This study suggests that endoanal sonography and endoanal MR imaging are equivalent in diagnosing external anal sphincter injury, but MR imaging is inferior in diagnosing internal anal sphincter injury.

Adolescent↗
PubMed1999

Upregulation of KIR expression on murine bone marrow cells by paraformaldehyde fixed tumor cells.

We have previously shown that the activation of mouse spleen NK cells by IL2 is markedly boosted if paraformaldehyde fixed tumor target cells are added during the activation phase. In the present study, we have shown that such a boosting effect is not seen if mouse bone marrow (BM) cells are used instead of spleen cells. Addition of fixed tumor cells (1:100 ratio of tumor cells to BM cells) however resulted in a marked increase in the expression of Ly49 molecules on BM cells. The enhancement of Ly49 expression was not seen if fixed allogeneic BM cells were added, suggesting that Ly49 upregulation was tumor specific. Expression of Ly49A as well as Ly49C isotypes were augmented by fixed tumor cells. Moreover, increased Ly49 expression was seen on cell populations expressing TCRbeta as well as NK1.1 markers. These results indicate that exposure to tumor cells may be an important factor regulating KIR expression on NK and T cells. Implications of these results are discussed.

Animals↗
PubMed1998

Tumor specific boosting of IL-2 induced NK activation by paraformaldehyde fixed tumor cells.

NK activation in C57B1/6 mouse spleen cells was carried out with IL-2 in the presence or absence of paraformaldehyde fixed YAC tumor cells. Generation of anti-YAC cytolytic activity was markedly higher when activation was carried out in the presence of fixed tumor cells. In addition the cytotoxic effector cells generated were resistant to anti-Thy-1 + C treatment, indicating that the effector cells were not T lymphocytes. IL-2 activation of NK cells was compared When fixed YAC or EL4 tumor cells were added during the IL-2 activation phase, it was found that the addition of either of these tumor cells significantly boosted the levels of cytotoxic activity generated against both targets. Significantly higher anti-YAC cytotoxic activity was however generated when fixed YAC cells instead of EL4 cells were present during the activation phase. Similarly, significantly greater cytolytic activity was generated against EL4 cells, when fixed EL4 rather than YAC cells were present during the activation phase. Addition of paraformaldehyde fixed syngeneic or allogenic spleen cells instead of tumor cells, did not boost NK activation in response to IL-2, indicating that the boosting of NK activation did not result from exposure to alloantigens during the activation phase. These results indicate that an exposure to tumor cells during IL-2 activation phase, may boost the activation of NK cells in a tumor specific manner.

Animals↗
PubMed1998

Drug-associated facial dyskinesias--a study of 238 patients.

UNLABELLED: The purpose of this study was to determine whether antidepressant, antimania, antipsychotic, antihistamine, or antiparkinsonian drugs are associated with eyelid and facial dyskinesias; whether discontinuing such drugs results in improvement in the facial dyskinesias; and whether response to botulinum toxin treatment is influenced by such medications. METHODS: A retrospective review was performed on a population of 238 patients with presumed benign essential blepharospasm and Meige syndrome. Types of drugs taken before the development of disease and clinical response to botulinum toxin injections were studied. RESULTS: Fourteen of 238 patients (5.9%) with facial dyskinesias had been prescribed a variety of antidepressants, antimania medications, antipsychotics, antihistamines, antiparkinsonian drugs, or a combination of these substances before their condition developed. The onset of blepharospasm varied from 2 months to 35 years after administration of the drug. Three of seven patients who discontinued the presumed responsible drug had improvement in their facial dyskinesias. Of the 11 patients who did not improve when their drugs were stopped or whose medication could not be stopped, all but one patient had a good response to treatment with botulinum toxin A. CONCLUSIONS: Drug-induced blepharospasm should be considered in all patients who present with facial dyskinesias, and such patients should undergo withdrawal of the medication when possible. When withdrawal of medication is not possible or does not result in improvement in the facial dyskinesia, treatment with botulinum toxin injections should be initiated. The possible role in the production of facial dyskinesias of antidepressants that block reuptake of serotonin requires further evaluation.

Adult↗
PubMed1997

The role of proliferating cell nuclear antigen (PCNA) in differentiating idiopathic orbital inflammatory disease and lymphoid proliferations.

The purpose of the present study was to determine whether proliferating cell nuclear antigen (PCNA), an immunohistochemical marker for a nuclear protein abundant in actively proliferating (dividing) cells, is useful as an aid in differentiating idiopathic orbital inflammatory syndrome (IOIS) from lymphoproliferative lesions (LLs). Records of all patients with IOIS and LLs were studied retrospectively. Tissue biopsy specimens from four patients with IOIS and nine patients with LLs were examined. The diagnosis in each case was based on presenting signs and symptoms, orbital computed tomography (CT) and/or magnetic resonance (MR) scans, histopathologic criteria, and follow-up data consistent with the entity. These findings were correlated with the percentage of B- and T-cells in the lesions as well as with the number of cells that demonstrated staining for PCNA in formalin-fixed tissue. PCNA activity was markedly increased in the higher grade (HG) lymphoma group as compared to that in the low grade (LG) lymphoma and idiopathic inflammatory group. Lymphoma cases showed a significantly increased B-/T-cell ratio compared to IOIS lesions. PCNA activity in conjunction with the ratio of B-/T-cells may be a helpful immunohistologic adjunct for differentiating purely inflammatory lesions of the orbit from lymphoid tumors. Further studies are necessary to compare PCNA activity in fresh frozen tissue with that in formalin-fixed tissue.

B-Lymphocytes↗
PubMed1997

Interstitial nephritis.

Interstitial nephritis is an inflammatory process within the renal interstitium, and was one of the first observations made in the description of renal histopathology. Many different conditions are associated with an interstitial nephritis, and as a clinical diagnosis the term has little use unless causation is defined. However, there has been recent interest in the possibility of a common mechanism causing irreversible renal damage and eventually renal failure in many different types of interstitial nephritis. Such damage could take place due to blood-borne inflammatory mediators, or could be due to renal tubular inflammation related to abnormal components of the glomerular filtrate in renal failure, such as proteins or lipids. If such research were to result in effective therapy for interstitial nephritis, the progression of many forms of renal disease to end stage renal failure could be ameliorated.

Acute Disease↗
PubMed1996

Treatment choices of 119 patients with hemifacial spasm over 11 years.

A retrospective study of patients with hemifacial spasm (HFS) was performed in order to determine long-term treatment choices: local botulinum toxin, type A, injections, oral pharmacologic agents, and surgery (neurosurgical decompression of the seventh nerve at the brainstem level and upper eyelid blepharoplasty). Of 119 patients with diagnosed hemifacial spasm in the Oculoplastics Division of the Department of UMD-New Jersey Medical School, Newark, NJ from September, 1983, to June 1, 1994, 108 were initially treated with 735 botulinum toxin injections. Forty-seven of the 108 patients (43.5%) initially treated at our institution received 459 injections for a median treatment period of 59 months per patient. Eight patients (7.4%) continued treated elsewhere and four other patients were injected at our institution until their death from other causes. Twenty-two patients (20.4%) were lost to followup after receiving 117 injections. Five patients (4.6%) had spontaneous resolution of their condition after botulinum toxin therapy and nine patients (8.3%) chose not to receive any additional injections or other treatment. Thirteen patients (12.0%) did not respond adequately to botulinum injections and 10 such patients obtained relief from treatments other than botulinum toxin: oral pharmacologic agents (two patients), neurosurgical decompression of the seventh nerve (two patients), and upper eyelid blepharoplasty (one patient). In addition to botulinum injections, 15 patients required adjunctive minor tranquilizers and/or antiseizure medications. Botulinum A toxin is an excellent long-term treatment of hemifacial spasm. This condition may occasionally spontaneously resolve after botulinum therapy.

Age of Onset↗
PubMed1996

Adverse effect of donor vasopressor support on immediate and one-year kidney allograft function.

BACKGROUND: This purpose of this study was to determine if there was a significant difference between the rates of acute tubular necrosis (ATN) and long-term graft survival in renal allografts procured from donors requiring inotropic support (DRIS) and those from donors not requiring inotropic support. METHODS: Eighty-two consecutive cadaveric renal transplant patients were prospectively followed in our local procurement area, the Delaware Valley Transplant Program. Forty-eight patients received organs from DRIS (> 10 mcg/kg per minute of dopamine, dobutamine, epinephrine, and norepinephrine alone or in combination), and 34 did not. RESULTS: Allografts from the non-DRIS group had an immediate function rate of 82.4% and a 1-year function rate of 91.2%. In comparison, the DRIS grafts had an immediate function rate of 58.3% and a 1-year function rate of 72.9%. These differences were statistically significant. The mean serum creatinine in the non-DRIS group was 1.46 +/- 0.58 mg/dl, whereas in the DRIS cohort it was 1.89 +/- 0.93 mg/dl. CONCLUSIONS: Kidneys transplanted from DRIS had significantly (1) poorer immediate function, (2) worse 1-year survival rates, and (3) higher serum creatinine at 1 year. We conclude that recipients receiving organs from donors requiring inotropic support are at a higher risk of developing ATN after surgery and experience reduced 1-year function.

Adolescent↗
PubMed1996

Pharmacokinetics of a single dose of teicoplanin in burn patients.

Patients with severe burns are susceptible to infection with Gram-positive organisms including methicillin-resistant Staphylococcus aureus, and often require higher antibiotic dosages compared with other patients. This study examined the pharmacokinetics of a single iv dose of teicoplanin (12 mg/kg) in 15 adults and five children with severe burns. Adults were aged 21-82 years with a median total body surface area (TBSA) burn of 30% (range 15-60%). Children were aged 10 months-l0 years with median TBSA burn of 15% (10-30%). At 12 h, the median serum teicoplanin concentration was 12.8 mg/L (9.027.1 mg/L) in adults and 7.6 mg/L (6.6-l0.8 mg/L) in children, (P < 0.01); at 24 h, the corresponding values were 8.3 mg/L (4.6-l2.9 mg/L) and 5.2 mg/L (4.2-6.0 mg/L). Using a three-compartment model, the median terminal half life in adults was 114 h (47-278 h). Children fitted a two-compartment model with a terminal half-life of 38 h (2l-41 h). The median concentration of teicoplanin in fluid from the burn wound was 60% of the serum antibiotic concentration. A single iv dose of 12 mg/kg of teicoplanin was sufficient to produce therapeutic serum concentrations in burn patients for 24 h, but monitoring of antibiotic levels in serum may be advisable in those with high total clearance, especially children.

Adult↗
PubMed1996

Treatment selections of 239 patients with blepharospasm and Meige syndrome over 11 years.

BACKGROUND: A retrospective review of 239 patients with benign essential blepharospasm and Meige syndrome was performed in order to determine patients' long term treatment preferences. METHODS: Of 239 patients evaluated, 228 received local injections of botulinum toxin, type A, into the eyelid and facial musculature over 11 years. RESULTS: Of 228 patients, 202 (72.1%) were still treated with botulinum toxin, type A. Eighteen patients (6.9%) no longer received botulinum toxin injections and sought no other treatment. Five patients (2.2%) had apparent remission of their disease after injection. Three patients (1.3%) ultimately obtained relief from orbicularis muscle extirpative surgery and required no additional treatment. Two of the 11 patients (4.6%) who chose not to receive botulinum toxin injections were successfully treated with other modalities: psychotherapy (one patient) and oral haloperidol (one patient). CONCLUSION: While botulinum toxin is the most highly effective treatment for benign essential blepharospasm and Meige syndrome over a long period of time, adjunctive oral drug therapy, including minor tranquillisers as well as eyelid surgery, may augment its effectiveness.

Anti-Anxiety Agents↗
PubMed1996

Clinical pharmacokinetics of oral acyclovir in patients on continuous ambulatory peritoneal dialysis.

It is increasingly recognised that dose adjustment of oral acyclovir in continuous ambulatory peritoneal dialysis (CAPD) patients is necessary to avoid neurotoxicity. A single 800-mg oral dose of acyclovir was administered to 10 uninfected anuric patients who were treated by CAPD. Serial blood and CAPD bag samples were analysed for acyclovir during the 31 h after dosing. Serum acyclovir levels were measured using radioimmunoassay and the pharmacokinetic parameters were estimated by linear regression using the STRIPE computer programme. Peak plasma levels of 8.95 +/- 3.95 microM were achieved at 4.1 +/- 1.85 h with the T1/2 calculated to be 14.52 +/- 3 h. The mean predicted serum acyclovir levels at steady state after 1,600-, 800- and 600-mg daily doses were 13.76, 6.88 and 5.16 microM, respectively. The present recommended daily doses of acyclovir (1,600 mg) for end-stage renal disease patients leads to supratherapeutic levels therefore increasing the risk and incidence of neurotoxicity. Computer modelling of various dosage simulations suggests that daily doses of 800 and 600 mg will achieve therapeutic levels (4-8 microM).

Acyclovir↗
PubMed1995

Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing haemodialysis.

Acute neurotoxicity following the administration of the recommended oral dose of acyclovir (800 mg twice daily) to dialysis-dependent patients is increasingly recognised. This suggests that the recommended dose is too high. Little is known of the pharmacokinetics of oral acyclovir in dialysis patients. We studied 7 patients with oliguric end stage renal failure receiving haemodialysis. Following haemodialysis, each patient received a single 800-mg tablet of acyclovir. Plasma acyclovir levels were monitored over the next 48 h as well as before and after the next routine dialysis. Peak plasma levels were achieved at 3 h (12.54 +/- 1.76 microM, range 8.5-17.5 microM) with the half-life calculated to be 20.2 +/- 4.6 h. Mean plasma level of 6.29 +/- 0.94 microM were within the quoted range to inhibit herpes zoster virus (4-8 microM) at 18 h. Haemodialysis (4-5 h) eliminated 51 +/- 11.5% of the acyclovir which remained at 48 h. Computer modelling of various dose modifications suggests that a loading dose of 400 mg and a maintenance dose of 200 mg twice daily is sufficient to maintain a mean plasma acyclovir level of 6.4 +/- 0.8 microM. A further loading dose (400 mg) after dialysis would raise the residual acyclovir concentration by 6.1 +/- 1.0 microM. Such a dose modification should prevent neurotoxicity, whilst the rapid elimination of acyclovir by a single haemodialysis treatment provides both a diagnostic and therapeutic tool when toxicity is suspected.

Acyclovir↗