Biomedical subjects
Publications and source records attributed to P Chan.
A 30-year-old white male presented with hematuria, proteinuria and normal renal function following a flu-like illness. IgA was mildly elevated but C3 and C4 levels were normal in serum. Renal biopsy showed a mesangial proliferative nephritis with immunohistochemical features of IgA nephritis but with an unusual pattern and distribution of deposits in glomerular, tubular and Bowman's capsular basement membranes.
The missense G209A mutation at exon 4 of the alpha-synuclein gene was recently found to be responsible for familial Parkinson's disease (PD) in a large kindred of Italian descent. We studied 100 typical PD patients with onset before age 51, both with and without a family history of PD. We did not find this alpha-synuclein missense mutation in any patient, but it was present in a symptomatic member of the Contursi family.
A missense mutation of the alpha-synuclein gene has been associated with parkinsonism in a large Italian kindred. Recently, alpha-synuclein was also identified in Lewy bodies. Using reverse transcribed-polymerase chain reaction (RT-PCR) technique, we sequenced the entire coding region of the alpha-synuclein gene using brain tissue from 24 pathologically proven Parkinson's disease cases. No mutations were found in any of the patients, suggesting that a mutation at the coding region of the alpha-synuclein gene is unlikely to be responsible for nigrostriatal degeneration in typical sporadic Parkinson's disease.
The relation between intravascular radiographic contrast media (RCM) and myointimal hyperplasia after percutaneous transluminal angioplasty is not known. We have investigated the cytotoxic effects of RCM on human vascular smooth muscle cells (VSMCs) and their effect on the growth of these cells. The cytotoxic effects of RCM were studied using human VSMCs. The cells after being grown to confluency were exposed for 60 min to 250 mgI ml-1 of diatrizoate, ioxaglate, iopromide, iotrolan and saturated mannitol solutions. The control group was treated with only 15% fetal calf serum (FCS) containing medium. The viability of the cells was examined using the trypan blue exclusion test. The effect of RCM on growth was assessed by exposing the VSMCs after growth arrest, for either 15 or 60 min to 250 mgI ml-1 of diatrozoate, ioxaglate, iopromide, iotrolan and saturated mannitol solution. There was no significant change in the viability of the VSMCs after 60 min exposure to iopromide, iotrolan, saturated mannitol solution, and after 15 min exposure to diatrizoate or ioxaglate. After exposure to diatrizoate or ioxaglate for 60 min, 16.5 +/- 2.2% or 9.2 +/- 2.6% dead cells were found, respectively (p < 0.05 versus control). In the growth assay of VSMCs, diatrizoate, ioxaglate and saturated mannitol solutions reduced the growth rate (p < 0.05 versus control). No significant change was observed with iopromide and iotrolan. In conclusion, ionic RCM have cytotoxic and cytostatic effects on VSMCs while non-ionic media have no effects. There is no direct stimulatory effect of contrast media on the growth of VSMCs. The cytotoxic and cytostatic effects of contrast media seems to be both osmolality and chemotoxicity dependent. Low osmolar non-ionic RCM are not likely to contribute to the mechanisms responsible for myointimal hyperplasia after angioplasty.
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Nurse scheduling consists of assigning shifts and rest to nurses for each day, on a time schedule, taking in account legal and collective constraints, and individual wishes. The Nurse Scheduling Problem (NSP) is a highly difficult and complicated problem that has already be explored using several operational research methods. Nevertheless, those methods are not flexible enough to match the individual requests from nursing staff and they don't allow for effective management of unforeseen absences. This paper explores the use of a Constraint Programming (CP) to build Gymnaste, which is since June 1997 a available package, after five years of a slow research and development process. We describe the way the problem is modeled, the constraints typology, and the interface. In fact, the NSP is also an ill defined problem, making the man computer interface critical to let the user chose the best heuristics. Gymnaste is currently beta-tested on several pilot sites. Schedules have been generated very quickly, typically in less than a minute for 20-30 persons over 4 weeks. An evaluation process is running, which preliminary results also show some interesting sociological and organizational aspects.
Nocturnal leg cramps is a common and troublesome problem in elderly individuals, and their etiology is unknown. Treatment with quinine is a common practice, but the effectiveness of the drug is doubtful and adverse drug effects are common. This randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of vitamin B complex capsules (fursulthiamine 50 mg, hydroxocobalamin 250 micrograms, pyridoxal phosphate 30 mg, and riboflavin 5 mg) in 28 elderly patients with hypertension who had severe nocturnal leg cramps that disturbed their sleep. Self-reported ratings of leg cramp frequency, duration, and intensity were used to evaluate severity of nocturnal leg cramps. Both the patients taking vitamin B capsules (n = 14) and those taking placebo (n = 14) received medications three times daily, and were examined regularly at 2-week intervals for 3 months. After 3 months, 86% of the patients taking vitamin B had prominent remission of leg cramps, whereas those taking placebo had no significant difference from baseline. Treatment with vitamin B complex significantly reduced the frequency, intensity, and duration of nocturnal leg cramps. Because quinine is not without potential for side effects, and vitamin B complex is a relatively safe and effective alternative, clinicians should reconsider the treatment of choice for nocturnal leg cramps.
Chinese populations have been protected from coronary heart disease by a low fat diet and low plasma lipids. Fat intake has increased in more affluent populations but coronary heart disease mortality has remained relatively low. Further increases in dietary fat in young people and rising rates of diabetes in the older population may increase the prevalence of hyperlipidaemia and vascular disease.
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To evaluate the short-term safety and efficacy of low-dose (10 mg) simvastatin in hypercholesterolemic, hypertensive elderly Chinese patients receiving antihypertensive treatment, a randomized, double-blind, placebo-controlled, 3-month trial was conducted. The patients had a total plasma cholesterol level of at least 250 mg/dL and had been, for at least 3 months, consuming a standard lipid-lowering diet (American Heart Association Step 1 Diet). Elderly hypertensive patients (n = 76) were randomized to receive treatment with either placebo (n = 38) or simvastatin (n = 38). The dosage consisted of 10 mg simvastatin daily during the 3-month trial. During that period, in the simvastatin group, plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased significantly (27% and 33%, respectively) compared with those levels in plasma in the placebo group. The plasma levels of high-density lipoprotein cholesterol increased (7%), whereas triglyceride levels slightly decreased (8%). There were no serious side effects, and simvastatin was generally well tolerated. Fasting hyperinsulinemia also improved (-21%) after 3 months of simvastatin therapy. Results of this study confirmed that a low dose (10 mg) of simvastatin daily is a safe and effective method of reducing plasma levels of total and low-density lipoprotein cholesterol in hypercholesterolemic, hypertensive elderly patients receiving concurrent antihypertensive drug therapy, and that it has the additional potential benefit of reducing plasma levels of insulin.
This study compared the incidence of cough with the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the diuretic metolazone with angiotensin II receptor antagonist losartan in elderly hypertensive patients with previous histories of ACE inhibitor-induced cough. A randomized, double-blind, stratified, parallel-group comparison of lisinopril at 10 mg, losartan at 50 mg, and metolazone at 1 mg, each given once daily for a maximum of 10 weeks, was performed in four hypertension clinics in four centers in two countries. Cough was detected by a questionnaire (the primary end point) given to elderly patients with hypertension, and the cough frequency was quantified by a visual analog scale (a secondary end point). A total of 84 elderly patients with hypertension, all who were nonsmokers with ACe inhibitor-induced cough and were confirmed by lisinopril rechallenge then placebo dechallenge, were randomized to the three treatment groups. The incidence of cough with losartan (18%) was significantly lower than with lisinopril (97%) and similar to that for metolazone (21%). Cough frequency evaluated by the visual analog scale was significantly lower for losartan than for lisinopril and similar to that for metolazone. The specific, selective angiotensin II receptor antagonist losartan is associated with a decrease in the incidence of cough in patients with previous ACE inhibitor-induced cough.
The objectives of the present study were to characterize the surface expression of low density lipoprotein receptor (LDL-R) in Epstein-Barr virus transformed lymphocytes (EBV-L) and to determine the applicability of the cellular system for the study of familial hypercholesterolemia. The EBV-L subsets and LDL-R expression were determined by immuno-cytofluorimetry. The LDL-R expression in EBV-L which consisted of mostly B cells was no different among antigenic subsets. EBV-L cultured in lipoprotein deficient serum demonstrated a 9.3-fold higher LDL-R expression than primary lymphocytes. Lovastatin caused an additional 1.9-and 1.4-fold increase in EBV-L and primary lymphocytes respectively. This difference in lovastatin response is statistically significant (paired t-test, P < 0.001). 54% of the high LDL-R expression in EBV-L was related to the changes in proliferation measured as stimulation index (SI). LDL and lovastatin modulated the LDL-R expression without affecting SI. FH subjects demonstrated 2% (homozygote, n = 1) and 44.6 +/- 12.3% (heterozygotes, n = 35) in LDL-R expression of controls (n = 30). This maintenance of the FH phenotype and the intrinsically high LDL-R expression in EBV-L make the cellular system suitable for the study of FH as well as the regulation of LDL-R.
In a previous study we demonstrated that trilinolein, a natural plant triacylglycerol, is a novel myocardial protective agent in vivo. The mechanism probably involves an antioxidant effect. This work investigated the mechanism of myocardial protection of trilinolein to determine if inhibition of calcium influx and alteration of activity of superoxide dismutase are involved. In isolated cardiomyocytes, pretreatment with trilinolein at a low concentration of 10(-9) M effectively reduced 45Ca2+ influx stimulated by hypoxia/normoxia by 34%. In isolated perfused rat heart subjected to 60 min global hypoxemia without reperfusion, pretreatment with 10(-7) M trilinolein for 15 min reduced infarct size by 37%. Assay of superoxide dismutase-mRNA by Northern blot analysis in in vivo rat heart subjected to 30 min ischaemia and 10 min reperfusion showed pretreatment with 10(-7) M trilinolein had a synergistic action with antioxidant systems preventing the rise in superoxide dismutase-mRNA. These results reconfirm the myocardial protection of trilinolein and suggest it may be related to antioxidant activity and inhibition of 45Ca2+ influx.
The complement system (C) is a major piece of the inflammatory processes triggered after tissue injury. Since implication of the C has been demonstrated during neurodegeneration and Wallerian degeneration, without being clearly explained, we investigated the expression of C4 and clusterin mRNA, at the lesion site, after rat sciatic nerve crush injury. This pilot study was then realized over 28 days during peripheral nerve regeneration. We determined mRNA expression levels in naive control animals (N) and 2, 7, 14 and 28 days (D) after crush experiment, by using semi-quantitative RT-PCR. We observed a basic constitutive expression of both mRNAs in group N. Clusterin mRNA level increased between D2 and D7 to reach 2.5-fold the basic level of expression (N) at D7 and D14, and slightly decreased until D28. C4 mRNA underwent a rapid and marked increase and represented 2-3-fold the N level from D2 to D14, then it decreased until D28 to return to the basic level of expression (N). These preliminary data exhibit very interesting individual variations in mRNA expression and show that a peripheral nerve trauma can stimulate the expression of C4 and clusterin mRNA at the lesion site.
Complement system activation within the central nervous system (CNS) is involved in demyelinating and neurodegenerative disorders, but the role of complement in the pathogenic process or in the repair remains unclear. Besides the direct lytic effects of complement on target cells (oligodendrocytes or neurons), complement can exert other functions through interaction of complement fragments with specific receptors. The C5a anaphylatoxin, an inflammatory peptide which is formed during complement activation, might play a role in the CNS pathogenesis, and activation and recruitment of glial cells by binding to its receptor (C5aR) on CNS cells. Using degenerate primers corresponding to homologous regions between human and mouse C5aR cDNAs, we have cloned a rat C5aR cDNA probe from rat monocytes RNAs after RT-PCR experiment. The rat C5aR probe isolated by this procedure allowed us to clone the rat C5aR cDNA-coding sequence using a library screening cloning strategy. This probe was also used to study the expression of the C5aR mRNA in the rat CNS. Northern blotting and RT-PCR experiments demonstrated the constitutive expression of C5aR mRNA in brain, spleen, kidney and lung. This transcript was also observed in primary culture of rat astrocytes. Microfluorimetry experiments demonstrated that C5aR expressed by astrocytes in culture is functional since the addition of C5a induced a dose-dependent increase of intracellular calcium concentration. The expression of the C5aR by astrocytes suggests new roles for the C5a anaphylatoxin in reactive astrogliosis to CNS injuries.
A multicenter, double-blind, placebo-controlled trial with multifactorial design was conducted to evaluate the safety and efficacy of the calcium-channel blocker diltiazem, in a sustained release preparation, and the angiotensin converting enzyme inhibitor, lisinopril, in the treatment of elderly Chinese patients with mild-to-moderate hypertension. In addition to the hypotensive effects of combinations of both drugs compared with monotherapy, all given once daily, the effect on quality of life was also evaluated. This study consisted of a 3 x 2 multifactorial design in which 156 women and men with a sitting diastolic pressure of between 95 mm Hg and 114 mm Hg, after a 4-week placebo washout phase, were randomized to one of six treatment groups for 12 weeks of active treatment. Monotherapy with diltiazem 120 or 240 mg produced increasing reductions of systolic and diastolic blood pressure. Compared with placebo, lisinopril 10 mg had an effect intermediate between the diltiazem doses. The combinations of diltiazem 240 mg + lisinopril 10 mg and diltiazem 120 mg + lisinopril 10 mg showed increased efficacy in reducing systolic and diastolic blood pressure compared to these drug doses used in monotherapy, but the effect of the combinations was less than predicted by an additive model. Although the total number of other adverse events reported was similar for all active treatment groups compared to placebo, lisinopril-induced cough was common with an incidence of 31% after rechallenge. Premature drug withdrawal was necessary in four of 78 patients receiving lisinopril, due to intractable cough. The combination of diltiazem 240 mg and lisinopril 10 mg was significantly more effective at reducing blood pressure than either drug alone; this additive effect did not result in a higher rate of adverse effects or impairment of quality of life. Thus, combination therapy with these agents was well tolerated and resulted in increased efficacy in these elderly patients.
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