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1.  Risk of cervical cancer is not increased in Chinese carrying homozygous arginine at codon 72 of p53 
British Journal of Cancer  1999;80(11):1828-1829.
Homozygous arginine at codon 72 (HA72) of p53 was found in 22% of normal cervices and 30.0% of cervical cancers and no significant difference was detected between normal and cervical cancer with or without HPV 16/18. There was no correlation between HA72 and risk of cervical cancer in Chinese. © 1999 Cancer Research Campaign
PMCID: PMC2374271  PMID: 10468305
p53 codon 72 polymorphism; cervical cancer; Chinese
2.  Efficacies of High-Dose Fluconazole plus Amphotericin B and High-Dose Fluconazole plus 5-Fluorocytosine versus Amphotericin B, Fluconazole, and 5-Fluorocytosine Monotherapies in Treatment of Experimental Endocarditis, Endophthalmitis, and Pyelonephritis Due to Candida albicans 
Antimicrobial Agents and Chemotherapy  1999;43(12):2831-2840.
We compared the efficacies of fluconazole (Flu), amphotericin B (AmB), and 5-fluorocytosine (5FC) monotherapies with the combination of Flu plus 5FC and Flu plus AmB in a rabbit model of Candida albicans endocarditis, endophthalmitis, and pyelonephritis. The dose of Flu used was that which resulted in an area under the concentration-time curve in rabbits equivalent to that seen in humans who receive Flu at 1,600 mg/day, the highest dose not associated with central nervous system toxicity in humans. Quantitative cultures of heart valve vegetations, the choroid-retina, vitreous humor, and kidney were conducted after 1, 5, 14, and 21 days of therapy. All untreated controls died within 6 days of infection; animals treated with 5FC monotherapy all died within 18 days. In contrast, 93% of animals in the other treatment groups appeared well and survived until they were sacrificed. At day 5, the relative decreases in CFU per gram in the vitreous humor were greater in groups that received Flu alone and in combination with 5FC or AmB than in groups receiving AmB or 5FC monotherapies (P < 0.005) but were similar thereafter. In the choroid-retina, 5FC was the least-active drug. However, there were no differences in choroidal fungal densities between the other treatment groups. On days 5 and 14 of therapy, fungal densities in kidneys of AmB recipients were lower than those resulting from the other therapies (P < 0.001 and P ≤ 0.038, respectively) and AmB-plus-Flu therapy was antagonistic; however, all therapies for fungal pyelonephritis were similar by treatment day 21. While fungal counts in cardiac valves of Flu recipients were similar to those of controls on day 5 of therapy and did not change from days 1 to 21, AmB therapy significantly decreased valvular CFUs versus Flu at days 5, 14, and 21 (P < 0.005 at each time point). 5FC plus Flu demonstrated enhanced killing in cardiac vegetations compared with Flu or 5FC as monotherapies (P < 0.03). Similarly, the combination of AmB and Flu was more active than Flu in reducing the fungal density in cardiac vegetations (P < 0.03). However, as in the kidney, AmB plus Flu demonstrated antagonism versus AmB monotherapy in the treatment of C. albicans endocarditis (P < 0.05, P = 0.036, and P < 0.008 on days 5, 14, and 21, respectively).
PMCID: PMC89573  PMID: 10582868
3.  Transcriptional Regulation of Mouse δ-Opioid Receptor Gene* 
The Journal of Biological Chemistry  1999;274(33):23617-23626.
Three major types of opioid receptors, μ (MOR), δ (DOR), and κ (KOR), have been cloned and characterized. Each opioid receptor exhibits a distinct pharmacological profile as well as a distinct pattern of temporal and spatial expression in the brain, suggesting the critical role of transcription regulatory elements and their associated factors. Here, we report the identification of a minimum core promoter, in the 5′-flanking region of the mouse DOR gene, containing an E box and a GC box that are crucial for DOR promoter activity in NS20Y cells, a DOR-expressing mouse neuronal cell line. In vitro protein-DNA binding assays and in vivo transient transfection assays indicated that members of both the upstream stimulatory factor and Sp families of transcription factors bound to and trans-activated the DOR promoter via the E box and GC box, respectively. Furthermore, functional and physical interactions between these factors were critical for the basal as well as maximum promoter activity of the DOR gene. Thus, the distinct developmental emergence and brain regional distribution of the δ opioid receptor appear to be controlled, at least in part, by these two regulatory elements and their associated factors.
PMCID: PMC3394399  PMID: 10438544
5.  Oxidative Damage to the c-fos Gene and Reduction of Its Transcription After Focal Cerebral Ischemia 
Journal of neurochemistry  1999;73(3):1164-1174.
We investigated oxidative damage to the c-fos gene and to its transcription in the brain of Long—Evans rats using a transient focal cerebral ischemia and reperfusion (FCIR) model. We observed a significant (p < 0.001) increase in the immunoreactivity to 8-hydroxy-2′-guanine (oh8G) and its deoxy form (oh8dG) in the ischemic cortex at 0–30 min of reperfusion in all 27 animals treated with 15–90 min of ischemia. Treatment with a neuronal nitric oxide synthase (nNOS) inhibitor, 3-bromo-7-nitroindazole (60 mg/kg, i.p.), abolished the majority but not all of the oh8G/oh8dG immunoreactivity. Treatment with RNase A reduced the oh8G immunoreactivity, suggesting that RNA may be targeted. This observation was further supported by decreased levels of mRNA transcripts of the c-fos and actin genes in the ischemic core within 30 min of reperfusion using in situ hybridization. The reduction in mRNA transcription occurred at a time when nuclear gene damage, detected as sensitive sites to Escherichia coli Fpg protein in the transcribed strand of the c-fos gene, was increased 13-fold (p < 0.01). Our results suggest that inhibiting nNOS partially attenuates FCIR-induced oxidative damage and that nNOS or other mechanisms induce nuclear gene damage that interferes with gene transcription in the brain.
PMCID: PMC2709844  PMID: 10461908
Stroke; DNA repair; Oxidative stress; Gene expression; Neuroregeneration; Apoptosis
6.  Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail* 
The Journal of biological chemistry  1999;274(9):5415-5421.
Signal transduction by the erythropoietin receptor (EPOR) is activated by ligand-mediated receptor homodimerization. However, the relationship between extracellular and intracellular domain oligomerization remains poorly understood. To assess the requirements for dimerization of receptor cytoplasmic sequences for signaling, we overexpressed mutant EPORs in combination with wild-type (WT) EPOR to drive formation of heterodimeric (i.e. WT-mutant) receptor complexes. Dimerization of the membrane-proximal portion of the EPOR cytoplasmic region was found to be critical for the initiation of mitogenic signaling. However, dimerization of the entire EPOR cytoplasmic region was not required. To examine this process more closely, we generated chimeras between the intracellular and transmembrane portions of the EPOR and the extracellular domains of the interleukin-2 receptor β and γc chains. These chimeras allowed us to assess more precisely the signaling role of each receptor chain because only heterodimers of WT and mutant receptor chimeras form in the presence of interleukin-2. Coexpression studies demonstrated that a functional receptor complex requires the membrane-proximal region of each receptor subunit in the oligomer to permit activation of JAK2 but only one membrane-distal tail to activate STAT5 and to support cell proliferation. Thus, this study defines key relationships involved in the assembly and activation of the EPOR signal transduction complex which may be applicable to other homodimeric cytokine receptors.
PMCID: PMC2388248  PMID: 10026152
9.  Randomised trial of different rates of feeding in acute diarrhoea 
Archives of Disease in Childhood  1999;81(6):487-491.
OBJECTIVE—To compare the effect of different feeding frequencies on the speed of recovery from diarrhoea.
METHODS—A randomised, non-blinded trial provided 0.452 MJ/kg/day as either 6 or 12 feeds of cows' milk each day to 262 hospitalised male infants aged 3-12 months with acute diarrhoea. Stool frequency, stool weight, body weight, and diarrhoea complications were monitored until recovery or for 14days.
RESULTS—A proportional hazards regression model controlling for age, diarrhoea aetiology, and severity of dehydration on admission revealed that the frequently fed group had a significantly shorter duration of diarrhoea (hazards ratio, 1.29; 95% confidence interval, 1.002 to 1.653). Frequently fed infants had a significantly greater weight gain and significantly lower faecal frequency and faecal weight.
CONCLUSIONS—Breast feeding remains the preferred method of feeding infants with acute diarrhoea, but feeding cows' milk to adequately nourished infants with acute diarrhoea is safe and is more rapidly effective if provided in frequent feeds with low energy loads.

PMCID: PMC1718146  PMID: 10569964
11.  Presentation of autoantibody to proliferating cell nuclear antigen in patients with chronic hepatitis B and C virus infection 
Annals of the Rheumatic Diseases  1999;58(10):630-634.
OBJECTIVES—To study the association of antibodies to proliferating cell nuclear antigen (PCNA) in patients with chronic hepatitis B (HBV) and C (HCV) virus infection.
METHODS—Sera from 243 patients with chronic HBV infection; 379 patients with chronic HCV infection; 80 patients with systemic lupus erythematosus (SLE); 28 patients with rheumatoid arthritis; 15 patients with Sjogren's syndrome; eight with polymyositis; eight with primary biliary cirrhosis; and 33 healthy control subjects were tested for the presentation of anti-PCNA antibodies by enzyme linked immunosorbent assay (ELISA) and immunoblotting using recombinant PCNA as antigen. The distribution of immunoglobulin isotypes of anti-PCNA antibody was measured by ELISA assay.
RESULTS—By ELISA, anti-PCNA antibodies were detected in 30 (12.3%) patients with chronic HBV infection, 71 (18.7%) patients with chronic HCV infection, and five (6.3%) patients with SLE. The inhibition of binding with these sera by purified PCNA was shown to exceed 71%. By immunoblotting, the frequency of anti-PCNA in patients with chronic HBV and HCV infection was 17 of 243 (7%) and 41 of 379 (11%), respectively. Absorption studies on indirect immunofluorescence showed the typical nuclear speckled staining pattern by anti-PCNA sera was abolished by preincubation of sera with PCNA. Anti-PCNA antibody was not detected in sera from patients with autoimmune diseases except SLE. Anti-PCNA antibodies in patients with chronic HBV and HCV infection were predominantly IgG.
CONCLUSION—These data suggest that anti-PCNA antibody are also present in patients with chronic HBV and HCV infection. Anti-PCNA antibody may not be specific for SLE.

PMCID: PMC1752782  PMID: 10491362
12.  Randomised, double blind, placebo controlled study of interferon β-1a in relapsing-remitting multiple sclerosis analysed by area under disability/time curves 
OBJECTIVES—The commonly employed outcome measures on disability and relapse rates in treatment trials of relapsing-remitting multiple sclerosis have well demonstrated sensitivity to treatment effects, but their clinical interpretation is problematic. An alternative method of analysis, which is more clinically meaningful and statistically appropriate to a condition with a fluctuating disease course, uses the summary measure statistic "area under the disability/time curve (AUC)", to estimate each patient's total in trial morbidity experience.
METHODS—The AUC technique was applied in an intention to treat analysis of serial disability data derived from the expanded disability status scale (EDSS), the Scripps neurologic rating scale (SNRS), and the ambulation index (AI), collected during a double blind, randomised, placebo controlled, phase III trial of subcutaneous interferon β-1a (INFβ-1a) in relapsing-remitting multiple sclerosis (PRISMS Study). The results were compared with the often quoted "conventional" end point of mean change in rating scores from baseline to trial completion. Analyses were also carried out on subgroups with entry EDSS stratified above and below 3.5.
RESULTS—EDSS data analysed by AUC normalised to baseline scores disclosed that both doses of IFNβ-1a (22 or 44 µg) were superior to placebo (p= 0.008 and 0.013, respectively). In addition, the high dose (44 µg) was more beneficial than placebo using SNRS (p= 0.038) and AI data (p= 0.039). AUC analysis of SNRS scores also showed that for patients with baseline EDSS>3.5, the 44 µg (but not the 22 µg) dose was more advantageous than placebo (p=0.028).
CONCLUSIONS—Summary measure analysis using the AUC of serial disability/time plots, confirms and extends the results of conventional end point analysis of disability from the PRISMS Study data. AUC evaluations show that high dose INFβ-1a (44 µg three times weekly) was beneficial on all of the clinical rating scale scores used in this study. This method provides a statistically powerful and clinically meaningful assessment of treatment effects on in trial disability in patients with multiple sclerosis with fluctuating and highly heterogeneous disease courses.

PMCID: PMC1736573  PMID: 10486390
13.  Telomerase activity in gestational trophoblastic disease. 
Journal of Clinical Pathology  1999;52(8):588-592.
AIMS: To investigate the pattern of telomerase activity in hydatidiform mole as compared with normal placenta and choriocarcinoma, and to determine the prognostic significance of telomerase activity in hydatidiform mole. METHODS: Telomerase activity in 35 cases of hydatidiform mole, 35 normal placentas, one choriocarcinoma sample, and two choriocarcinoma cell lines (JAR, JEG3) was determined using the sensitive polymerase chain reaction based telomeric repeat amplification protocol (TRAP) assay. Two cases of breast carcinoma and two cases of ovarian carcinoma were also included as positive controls in the telomerase assay. RESULTS: Telomerase activity was detected in 11 of 30 early placentas (36.7%), one of five term placentas (20%), five of 27 hydatidiform moles which regressed spontaneously (18.5%), and six of eight hydatidiform moles which developed persistent trophoblastic disease (75%) (including three which developed metastases). Hydatidiform moles which subsequently developed persistent disease, especially those which metastasised, were more likely to express telomerase activity (p < 0.01). However, there was no significant difference in the frequency of telomerase activity between early placentas and hydatidiform mole. Strong telomerase activity was observed in choriocarcinoma tissue, choriocarcinoma cell lines, and ovarian and breast carcinomas. CONCLUSIONS: Telomerase activation occurs in hydatidiform mole with a similar incidence to early normal placentas. This supports the concept that hydatidiform mole is essentially an abnormal conceptus. There is an association between telomerase activation and the development of persistent trophoblastic disease. Further study is warrant to confirm the prognostic significance of telomerase activity in hydatidiform mole.
PMCID: PMC500949  PMID: 10645228
15.  Human right and left colon differ in epithelial cell apoptosis and in expression of Bak, a pro-apoptotic Bcl-2 homologue 
Gut  1999;45(1):45-50.
BACKGROUND—Propensity to colonic neoplasia differs between the right and left colon.
AIMS—To examine whether this difference may be related to regional differences in epithelial apoptosis, in expression of a proapoptotic regulatory protein, Bak, and in proliferation.
PATIENTS—Individuals with no history of colorectal neoplasia.
METHODS—Archival blocks of colorectal tissues were immunostained for proliferating cells (antibody to Ki-67 antigen), and Bak expression (polyclonal antiserum). Cells containing DNA strand breaks, a marker of apoptosis, were identified by terminal deoxyuridine nucleotidyl nick end labelling (TUNEL).
RESULTS—There were fewer TUNEL positive epithelial cells in the right colon (mean 1.2 (SE 0.1)% of all epithelial cells) than the left colon (2.2 (0.1)%, p<0.0001) or rectum (2.2 (0.3)%, p<0.05). Bak expression was less common in the right colon (mean 46 (2.3)% of epithelial cells immunoreactive) than the left colon (66 (2.7)%, p<0.0001), or rectum (67 (2.3)%, p<0.001). Bak expression and TUNEL positivity were highly positively correlated (p<0.0001). In contrast to apoptosis, mean whole crypt proliferation labelling index was similar throughout the colorectum (right colon: 15.6 (3.2)%; left colon: 13.5 (1.2)%; rectum: 13.3 (2.3)%).
CONCLUSION—The percentage of proliferating colonic epithelial cells is constant throughout the colon, but fewer epithelial cells undergo Bak mediated apoptosis in the right than in the left colon or rectum. This suggests that colonocytes may be lost by methods other than apoptosis in the right colon.

Keywords: programmed cell death; Bcl-2; cell cycle; cell proliferation; colon carcinogenesis
PMCID: PMC1727558  PMID: 10369703
16.  Evaluation of corneal thickness and topography in normal eyes using the Orbscan corneal topography system 
AIMS—To map the thickness, elevation (anterior and posterior corneal surface), and axial curvature of the cornea in normal eyes with the Orbscan corneal topography system.
METHODS—94 eyes of 51 normal subjects were investigated using the Orbscan corneal topography system. The anterior and posterior corneal elevation maps were classified into regular ridge, irregular ridge, incomplete ridge, island, and unclassified patterns, and the axial power maps were grouped into round, oval, symmetric bow tie, asymmetric bow tie, and irregular patterns. The pachymetry patterns were designated as round, oval, decentred round, and decentred oval.
RESULTS—The thinnest point on the cornea was located at an average of 0.90 (SD 0.51) mm from visual axis and had an average thickness of 0.55 (0.03) mm. In 69.57% of eyes, this point was located in the inferotemporal quadrant, followed by the superotemporal quadrant in 23.91%, the inferonasal quadrant in 4.35%, and the superonasal quadrant in 2.17%. Among the nine regions of the cornea evaluated (central, superotemporal, temporal, inferotemporal, inferior, inferonasal, nasal, superonasal, and superior) the central cornea had the lowest average thickness (0.56 (0.03) mm) and the superior cornea had the greatest average thickness (0.64 (0.03) mm). The mean simulated keratometry (SimK) was 44.24 (1.61)/43.31 (1.66) dioptres (D) and the mean astigmatism was 0.90 (0.41) D. Island (71.74%) was the most common elevation pattern observed in the anterior corneal surface, followed by incomplete ridge (19.57%), regular ridge (4.34%), irregular ridge (2.17%), and unclassified (2.17%). Island (32.61%) was the most common topographic pattern in the posterior corneal surface, following by regular ridge (30.43%), incomplete ridge (23.91%), and irregular ridge (13.04%) patterns. Symmetric bow tie was the most common axial power pattern in the anterior cornea (39.13%), followed by oval (26.07%), asymmetric bow tie (23.91%), round (6.52%), and irregular (4.53%) patterns. In the pachymetry maps, 47.83% of eyes had an oval pattern, and round, decentred oval, and decentred round were observed in 41.30%, 8.70%, and 2.18% of eyes, respectively.
CONCLUSION—The information on regional corneal thickness, corneal elevation and axial corneal curvature obtained with the Orbscan corneal topography system from normal eyes provides a reference for comparison with diseased corneas. The Orbscan corneal topography system is a useful tool to evaluate both corneal topography and corneal thickness.

PMCID: PMC1723104  PMID: 10381661
17.  Image quality in polypseudophakia for extremely short eyes 
AIM—To evaluate the image quality produced by polypseudophakia used for strongly hypermetropic and nanophthalmic eyes.
METHODS—Primary aberration theory and ray tracing analysis were used to calculate the optimum lens shapes and power distribution between the two intraocular lenses for two example eyes: one a strongly hypermetropic eye, the other a nanophthalmic eye. Spherical aberration and oblique astigmatism were considered. Modulation transfer function (MTF) curves were computed using commercial optical design software (Sigma 2100, Kidger Optics Ltd) to assess axial image quality, and the sagittal and tangential image surfaces were computed to study image quality across the field.
RESULTS—A significant improvement in the axial MTF was found for the eyes with double implants. However, results indicate that this may be realised as a better contrast sensitivity in the low to mid spatial frequency range rather than as a better Snellen acuity. The optimum lens shapes for minimum spherical aberration (best axial image quality) were approximately convex-plano for both lenses with the convex surface facing the cornea. Conversely, the optimum lens shapes for zero oblique astigmatism were strongly meniscus with the anterior surface concave. Correction of oblique astigmatism was only achieved with a loss in axial performance.
CONCLUSIONS—Optimum estimated visual acuity exceeds 6/5 in both the hypermetropic and the nanophthalmic eyes studied (pupil size of 4 mm) with polypseudophakic correction. These results can be attained using convex-plano or biconvex lenses with the most convex surface facing the cornea. If the posterior surface of the posterior intraocular lens is convex, as is commonly used to help prevent migration of lens epithelial cells causing posterior capsular opacification (PCO), then it is still possible to achieve 6/4.5 in the hypermetropic eye and 6/5.3 in the nanophthalmic eye provided the anterior intraocular lens has an approximately convex-plano shape with the convex surface anterior. It was therefore concluded that consideration of optical image quality does not demand that additional intraocular lens shapes need to be manufactured for polypseudophakic correction of extremely short eyes and that implanting the posterior intraocular lens in the conventional orientation to help prevent PCO does not necessarily limit estimated visual acuity.

PMCID: PMC1723085  PMID: 10340971
19.  Cholinergic blockade inhibits gastro-oesophageal reflux and transient lower oesophageal sphincter relaxation through a central mechanism 
Gut  1999;44(5):603-607.
BACKGROUND—Atropine, an anticholinergic agent with central and peripheral actions, reduces gastro-oesophageal reflux (GOR) in normal subjects and patients with gastro-oesophageal reflux disease (GORD) by inhibiting the frequency of transient lower oesophageal sphincter relaxation (TLOSR). 
AIMS—To compare the effect of methscopolamine bromide (MSB), a peripherally acting anticholinergic agent, with atropine on the rate and mechanism of GOR in patients with GORD. 
METHODS—Oesophageal motility and pH were recorded for 120 minutes in 10 patients with GORD who were studied on three separate occasions. For the first two recording periods, either atropine (15 µg/kg bolus, 4 µg/kg/h infusion) or saline were infused intravenously. MSB (5 mg orally, four times daily) was given for three days prior to the third recording period. 
RESULTS—Atropine significantly reduced basal LOS pressure (12.6 (0.17) mm Hg to 7.9 (0.17) mm Hg), and the number of TLOSR (8.1 (0.56) to 2.8 (0.55)) and reflux episodes (7.0 (0.63) to 2.0 (0.43)) (p<0.005 for all comparisons). MSB reduced basal LOS pressure (12.6 (0.17) to 8.7 (0.15) mm Hg, p<0.005), but had no effect on the frequency of TLOSR (8.1 (0.56) to 7.5 (0.59)) and reflux episodes (7.0 (0.63) to 4.9 (0.60)) (p>0.05). 
CONCLUSION—In contrast to atropine, MSB has no effect on the rate of TLOSR or GOR in patients with GORD. Atropine induced inhibition of TLOSR and GOR is most likely mediated through a central cholinergic blockade. 

Keywords: gastro-oesophageal reflux; cholinergic blockade; transient lower oesophageal sphincter relaxation
PMCID: PMC1727499  PMID: 10205193
21.  Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis 
OBJECTIVE—The association between brain atrophy and permanent functional deficits in multiple sclerosis and the temporal relation between atrophy and the clinical disease course have seldom been investigated. This study aims to determine the amount of infratentorial and supratentorial atrophy in patients by comparison with healthy controls, to establish the relation between atrophy and disability, and to derive the rates of volume loss in individual patients from their estimated disease durations.
METHODS—Three dimensional acquired MRI was performed on 20 relapsing-remitting and 20 secondary progressive multiple sclerosis patients and 10 control subjects. Volume data on infratentorial and supratentorial structures were obtained using the Cavalieri method of modern design stereology in combination with point counting. Corpus callosal sectional area and "T2 lesion load" were also determined.
RESULTS—Significantly reduced infratentorial and cerebral white matter volumes and corpus callosal sectional areas occurred in all patients compared with controls (p=0.0001-0.004). Mean estimates of volume loss in the cohort were −21%,−19%,−46%, and−12% for the brain stem, cerebellum, upper cervical cord and white matter, respectively, and −21% for the corpus callosal sectional area. Analysis of the amount of atrophy (volume differences between patients and controls) showed that upper cervical cord and cerebral white matter atrophy correlated with the expanded disability status scale (r=−0.37 and −0.37, p=0.018-0.023) and the Scripps neurologic rating scale scores (r=+0.49 and +0.43, p= 0.002-0.007). There was no relation between estimated volume loss in the supratentorial and infratentorial compartments. The "T2 lesion load" was associated with ventricular enlargement and corpus callosal atrophy (r=+0.50 and−0.55, p=0.0003-0.0012). Infratentorial atrophy rates correlated with baseline exacerbation rates (r=−0.50 to−0.48, p=0.0016-0.0021) and were higher in relapsing-remitting than secondary progressive patients (p=0.009-0.02).
CONCLUSIONS—Significant cerebral and spinal cord volume reductions occurred in both patient subgroups compared with controls. Functional correlates were found with estimated volume loss in the upper cervical cord and cerebral white matter. Particularly for infratentorial structures, estimated rates of atrophy were higher in relapsing-remitting than secondary progressive patients, suggesting that atrophy, perhaps mainly due to tract degeneration, begins early in multiple sclerosis and may relate predominantly to acute inflammatory events, with or without other gradual non-inflammatory processes later in the disease course.

PMCID: PMC1736263  PMID: 10084530
22.  Modulating influence of cytochrome P-450 MspI polymorphism on serum liver function profiles in coke oven workers 
OBJECTIVES: It was reported previously that topside oven workers with heavy exposure to coke oven emissions had increased serum activities of hepatic aminotransferase in one coke oven plant. This study was conducted to investigate the modifying effect of CYP1A1 MspI polymorphism on liver function profiles in coke oven workers. METHODS: 88 coke oven workers from a large steel company in Taiwan were studied in 1995-6. Exposure was categorised by work area: topside oven workers and sideoven workers. Liver function profiles including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), r-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and total bilirubin (BIL) were examined in the morning after personal exposure measurements. The MspI polymorphism was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: Five of 23 (22%) topside oven workers and seven of 65 (11%) sideoven workers had the CYP1A1 MspI homozygous variant genotype. With sideoven workers with the combined wild type and heterozygous variant as the reference group in multiple regression models, it was found that topside oven workers with the combined traits had mean AST and ALT activities that were 21% and 46% higher (95% confidence interval (95% CI) 4% to 42% and 12% to 91%, respectively) than the reference group after adjusting for appropriate confounders. Also, topside oven workers with the homozygous variant trait had mean AST, ALT, and GGT activities that were 59%, 68%, and 157% higher (95% CI 21% to 109%, 6% to 168%, and 39% to 374%, respectively) than the reference group. The prevalence of an abnormal hepatocellular pattern (AST > 37 IU/l or ALT > 39 IU/l) was more common in the topside oven workers with the homozygous variant than in the sideoven workers with the other combined genotypes (adjusted odds ratio 9.9, 95% CI 1.2 to 82.3) after adjusting for appropriate confounders. CONCLUSIONS: The CYP1A1 MspI polymorphism may modify the biotransformation of coke oven emissions, which results in hepatocellular damage in coke oven workers.
PMCID: PMC1757713  PMID: 10448323
23.  Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro 
Gut  1999;44(1):127-136.
Background—Hepatic stellate cells play a key role in the pathogenesis of hepatic fibrosis. 
Aims—To examine the inhibitory effect of oestradiol on stellate cell activation. 
Methods—In vivo, hepatic fibrosis was induced in rats by dimethylnitrosamine or pig serum. In vitro, rat stellate cells were activated by contact with plastic dishes resulting in their transformation into myofibroblast-like cells. 
Results—In the dimethylnitrosamine and pig serum models, treatment with oestradiol at gestation related doses resulted in a dose dependent suppression of hepatic fibrosis with restored content of hepatic retinyl palmitate, reduced collagen content, lower areas of stellate cells which express α smooth muscle actin (α-SMA) and desmin, and lower procollagen type I and III mRNA levels in the liver. In cultured stellate cells, oestradiol inhibited type I collagen production, α-SMA expression, and cell proliferation. These findings suggest that oestradiol is a potent inhibitor of stellate cell transformation. 
Conclusion—The antifibrogenic role of oestradiol in the liver may contribute to the sex associated differences in the progression from hepatic fibrosis to cirrhosis. 

Keywords: hepatic stellate cells; hepatic fibrosis; oestradiol; α smooth muscle actin; retinyl palmitate
PMCID: PMC1760074  PMID: 9862839
24.  Distal versus proximal arm tremor in multiple sclerosis assessed by visually guided tracking tasks 
OBJECTIVES—To compare action tremor (AT) during manual tracking in normal subjects and patients with multiple sclerosis with tremor (MS-tremor group) and without tremor (MS-no tremor group), and to differentiate tremor occurring predominantly around the distal joint from that involving the proximal joints of the arm.
METHODS—Subjects performed both a visually guided ramp tracking task using wrist flexion/extension and a whole arm circle tracking task using shoulder movement. Action tremor at the wrist or shoulder was computed as the SD of the tracking velocity. The ratio of wrist:arm tremor was then calculated to differentiate distal from proximal tremor in the tested arm. Frequency spectra of the records were also examined.
RESULTS—During wrist tracking, AT in patients with multiple sclerosis contained a major frequency component at 4-5 Hz; the frequency was slightly lower during whole arm tracking. The ratio of wrist:arm tremor was significantly higher in the MS-tremor group. Of 12tested arms, eight had tremor significantly weighted towards the distal joint, only one towards the proximal joint, and three had a ratio inside the control range.
CONCLUSIONS—AT in the arms of patients with multiple sclerosis can be effectively differentiated into proximal or distal using these two different tracking tasks. Despite the variability of the effects of multiple sclerosis, most of the AT was distal rather than proximal in this group of patients. Possibly conduction block along the corticocerebellocortical pathways caused this distal tremor.

PMCID: PMC1736187  PMID: 9886449

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