Biomedical subjects
Publications and source records attributed to S L Ho.
Agents potentially involved in the aetiology of idiopathic Parkinson's disease are discussed. These include factors regulating dopaminergic neurogenesis (Nurr 1, Ptx-3, and Lmx1b) and related proteins, together with genes involved in familial Parkinson's disease (alpha synuclein, parkin, and ubiquitin carboxy terminal hydroxylase L1), and endogenous and environmental agents.
OBJECTIVE: To test the efficacy, tolerance, and safety of low-dose oral estrogen in postmenopausal women with PD associated with motor fluctuations. BACKGROUND: Motor fluctuations in PD may be predictable or unpredictable, and eventually affect most patients after long-term levodopa therapy. Although estrogen can modulate nigrostriatal dopamine levels, its effects on PD are unclear. METHODS: Patients were randomized to receive conjugated estrogen (oral Premarin 0.625 mg daily; n = 20) or placebo (n = 20) in a double-blind, parallel-group, prospective study over 8 weeks. Existing antiparkinsonian drug regimes were kept unchanged. Changes in "on" and "off" periods using patient diaries, Unified Parkinson's Disease Rating Scale (UPDRS) score, timed tapping score, and Hamilton Depression Scale score were determined by one rater. Subgroup analyses were also performed on patients with only predictable motor fluctuations. RESULTS: Both treatment groups were similar in age, duration of disease and menopause, antiparkinsonian medication, and compliance with test medication and diary assessments. "On" and "off" times, and motor score (UPDRS subscale III) improved with estrogen, using the Mann-Whitney U test (p < 0.05 after Bonferroni adjustment). Mean "on" time improved by 7% (9 hours/week of awake time) in estrogen-treated patients versus a deterioration of 0.5% (1.4 hours) in placebo-treated patients (95% confidence interval, [CI] of mean difference, 5.73 to 14.9). Mean "off" time improved by 4% (4.4 hours/week of awake time) in estrogen-treated patients versus no change in placebo-treated patients (95% CI, 1.54 to 7.16). Mean subscale III score improved by 3.5 points in estrogen-treated patients versus 0.4 in placebo-treated patients (95% CI, 1.02 to 5.18). No other significant changes were observed (p > 0.05). Subgroup analyses in patients with only predictable motor fluctuations showed similar results, except improvement in mean subscale III score was marginally not significant (p = 0.07; 95% CI, 1.06 to 6.24). Five patients on estrogen had facial flushing, three had lower abdominal discomfort, and two had mild withdrawal vaginal bleeding. The adverse events were mild and resolved without sequelae. CONCLUSION: Low-dose estrogen is a safe and effective adjunct therapy to existing antiparkinsonian treatment in reducing motor disability in postmenopausal women with PD associated with motor fluctuations.
At clinically relevant concentrations, volatile anaesthetic agents influence neutrophil function. Our hypothesis was that sevoflurane would inhibit neutrophil apoptosis and consequently influence the postoperative pro-inflammatory state. In order to identify selectively the effect of the anaesthetic agent sevoflurane, we studied patients undergoing minimally stimulating (cataract) surgery randomly allocated to receive either sevoflurane (n = 11) or local anaesthesia (n = 12). Venous blood samples were taken immediately prior to anaesthesia and at 1, 8 and 24 h thereafter. The rate of neutrophil apoptosis, plasma concentration of cytokines and differential white cell count were measured. The rates of neutrophil apoptosis and plasma concentrations of IL-1beta, TNF-alpha and IL-8 at each time point were similar in the two groups. IL-6 concentrations increased significantly and to a similar extent compared to preanaesthetic levels at 8 and 24 h. This study demonstrates that sevoflurane does not influence the rate of neutrophil apoptosis, cytokine concentrations and neutrophil count following cataract surgery.
The ability to predict drug deposition of inhaled drugs used in cystic fibrosis (CF) is important if there is a need to target specific doses of drug to the lungs of individual patients. The gold standard of measuring pulmonary deposition is the quantification of an aerosolized radiolabel either mixed with the drug solution or tagged directly to the compound of interest. Accuracy of the quantification could be assured if there is agreement between the amount of radioactivity before and after administration. Before administration, the radiolabel is concentrated in the well of the nebulizer, whereas after administration, it is distributed throughout the nebulizer, the expiratory filter and connectors, and the upper airway, stomach, trachea, and lung. Not only is the geometry of the distribution that is presented to the gamma camera different, but there are different attenuation factors for the various body tissues. The primary aim of this study was to evaluate the accuracy of the quantification of deposition. Secondary goals were to compare in vitro nebulizer performance with that measured in vivo during the deposition study. Eighty milligrams of tobramycin and technetium bound to human serum albumin was administered to 10 normal adults using a Pari LC Jet Plus (Pari Respiratory Equipment, Inc., Richmond, VA) breath-enhanced nebulizer. Techniques were developed that allowed for the accounting of 99 +/- 2% of the initial radioactivity. The fraction of the rate of lung deposition to total body deposition was the in vivo respirable fraction (0.62 +/- 0.07), which closely agreed with in vitro measurements of respirable fraction (0.62 +/- 0.04). Drug output measured from the change in weight and concentration in the nebulizer systematically overestimated drug output measured by the deposition study. The results indicate that 11.8 of the initial 80 mg would be deposited in the lungs. This technique could be adapted to accurately quantify the amount of deposition on any inhaled therapeutic agent, but caution must be used when extrapolating performance of a nebulizer on the bench to expected deposition in patients.
Particle size of nebulized aerosols can be measured directly using laser diffraction or by evaluating aerodynamic properties by cascade impaction. As of today, there are no generally accepted standards for measuring particle size distribution from nebulizers. Laser diffraction has been questioned because of potential evaporative losses of the small particles at the edge of the plume, causing an apparent shift in the particle size distribution and thus a larger mass median diameter (MMD). When particle-sizing wet aerosols, cascade impaction may give rise to an apparent shift in the distribution, resulting in a smaller mass median aerodynamic diameter (MMAD) due to evaporative losses of aerosol droplets as they enter the impactor at ambient temperature. The modified low-flow Marple 296 Personal Cascade Impactor (MPCI) is currently being proposed as the European standard for wet aerosol analysis to minimize evaporative losses during sampling. The present study compared the particle size distribution of salbutamol and sodium cromoglycate aerosols nebulized by the Pari LC Star, using laser diffraction (Malvern Mastersizer X; MMX) and cascade impaction (Andersen Cascade Impactor [ACI] and the commercially available MPCI), which was either at ambient temperature or cooled to the nebulized aerosol temperature (10 degrees C). MMDs obtained with the MMX were virtually identical to the MMADs measured with both impactors when cooled with no significant differences in geometric standard deviation (sigma(g)). When the impactors were operated at ambient temperature, MMADs were smaller (18 to 30%) with a significantly larger sigma(g) (p < 0.05) compared to the MMX. These findings suggest that droplet distribution data for wet aerosol where evaporation process has not been minimized must be viewed with caution. There was no evidence suggesting a significant evaporative loss of small droplets from the edge of the plume during laser particle sizing. The MPCI does not minimize evaporative losses of aerosol particles during sampling.
In many plants, cysteine proteinases play essential roles in a variety of developmental and physiological processes. In rice (Oryza sativa), REP-1 is a primary cysteine proteinase responsible for the digestion of seed storage proteins to provide nutrients to support the growth of young seedlings. In the present study, the gene encoding REP-1 was isolated, characterized, and designated as OsEP3A. An OsEP3A-specific DNA probe was used to study the effect of various factors on the expression of OsEP3A in germinating seeds and vegetative tissues of rice. The expression of OsEP3A is hormonally regulated in germinating seeds, spatially and temporally regulated in vegetative tissues, and nitrogen-regulated in suspension-cultured cells. The OsEP3A promoter was linked to the coding sequence of the reporter gene, gusA, which encodes beta-glucuronidase (GUS), and the chimeric gene was introduced into the rice genome. The OsEP3A promoter is sufficient to confer nitrogen regulation of GUS expression in suspension-cultured cells. Histochemical studies also indicate that the OsEP3A promoter is sufficient to confer the hormonal regulation of GUS expression in germinating seeds. These studies demonstrate that in rice the REP-1 protease encoded by OsEP3A may play a role in various physiological responses and processes, and that multiple mechanisms regulate the expression of OsEP3A.
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BACKGROUND: Neurovascular contact (NVC) with the root exit zone (REZ) of the ipsilateral facial nerve is associated with hemifacial spasm (HFS), but unresolved issues remain. OBJECTIVES: To 1) determine the frequency of symptomatic and nonsymptomatic NVC, 2) determine the features of NVC associated with HFS, and 3) correlate severity of HFS to these features. METHODS: Two independent, blinded, prospective assessments of high-resolution MR and MR angiography (MRA) images were performed on Chinese cases (HFS: n = 44; age-matched control subjects: n = 20). RESULTS: Over 88% of 44 symptomatic sides in patients with HFS had NVC of the ipsilateral facial nerve. At least 80% of symptomatic sides involved NVC at the anterior aspect of the REZ [REZ(ant.)]. Although NVC was observed in approximately half of nonsymptomatic sides, at least 70% of them were not at REZ(ant.). NVC at the cisternal and intracanalicular portions of the facial nerve were not associated with HFS. Half of our patients with HFS had bilateral NVC, but none had bilateral symptoms. Most of our MR/MRA images showed that the size and position of the arterial branches of the vertebrobasilar system were markedly asymmetric. Of patients with bilateral NVC, over 83% had asymmetric NVC sites. The anterior inferior cerebellar artery was the most common vessel involved in NVC, but was not significantly associated with HFS. Most of the NVC involved one vessel at one contact point with no indentation. The development of HFS was significantly associated with nerve indentation in NVC. The development and severity of HFS were not associated with multiple contact points in NVC. No significant interobserver variability existed between the blinded assessments. CONCLUSIONS: MRI/MR angiography are accurate, fast, and safe in characterizing neurovascular contact (NVC) at the brainstem. The site of NVC and ipsilateral facial nerve indentation in NVC are significant determinants for the development of hemifacial spasm (HFS). The lack of bilateral NVC at the anterior aspect of the root exit zone of the facial nerve could explain in part the lack of bilateral symptoms. The development and severity of HFS are not associated with a specific blood vessel or multiple contact points in NVC.
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Tuberculous infection of the central nervous system is common in Hong Kong. A 39-year-old woman presented with isolated right sixth nerve palsy which was non-progressive for 10 months. Neuro-imaging revealed a right pontine lesion. Cerebrospinal fluid (CSF) examination showed lymphocytic meningitis with negative bacteriological and cytological studies. Empirical antituberculous drugs with initial corticosteroid resulted in improved CSF parameters. A diagnosis of cerebral tuberculoma complicated by meningitis was made. She subsequently deteriorated clinically and radiologically. Despite a number of clinical features which were atypical of leptomeningeal metastasis, adenosquamous carcinoma was found on biopsy. Her relatively indolent clinical course might be due to the initial corticosteroid treatment. This report illustrates the importance of early tissue diagnosis in uncertain cases of chronic lymphocytic meningitis.
Four polymorphic sites (C/T188, C/T2938, G/C4268, G/A1934) in the cytochrome P4502D6 (debrisoquine 4-hydroxylase) gene were investigated for their association with sporadic Parkinson's disease (PD). Three mutant alleles (C/T188, C/T2938 and G/C4268) result in amino acid changes which could alter the substrate specificity or alter its ability to metabolize their substrates; the fourth (G/A1934) causes a loss of enzyme activity. The study was carried out in two ethnically homogenous populations: Chinese (123 PD patients, 124 controls); and Caucasian (95 PD patients, 62 controls). Haplotype status, which took into account amino acid changes at three polymorphic sites, was deduced from genotyping results in order to investigate whether substrate specificity was important rather than loss of enzyme activity. There was no gender difference in the distribution of the alleles in either race. There was, however, significant association among the three polymorphic sites (C/T188, C/T2938, G/C4268) in both ethnic groups. T/T188:C/C2938:C/C4268 is the most common genotype in the Chinese population, in contrast to C/C188:C/T2938:C/G4268 (followed by C/C188:C/C2938:G/G4268) in Caucasians. All 69 of the sub-group of Chinese patients tested were homozygous for the wild-type allele at the G/A1934 polymorphic site. Neither the CYP2D6 allele nor haplotype was associated with PD in either ethnic group.
To study the economic implications of epilepsy in Hong Kong, a cost-of-illness study was performed on a retrospective cohort of medically treated patients from a regional hospital. A societal perspective was examined. Utilization data from 1992 to 1996 were reviewed to obtain the direct costs. Lost productivity was used as a proxy for estimating the indirect costs. Future cost projected over 10 years was derived by incorporating model parameters. Of 745 records reviewed, total direct costs added up to USD 0.98 million and indirect costs to USD 1.32 million. Regarding the overall direct costs, hospitalization was the most consumptive item among patients with a shorter history of epilepsy and those with suboptimal seizure control. The mean total cost per patient increased steadily from 1992 to 1996 except for those with long-standing remission, and was highest in patients with medically refractory epilepsy in terms of both the actual value and rate of increment. Parameters with the most leverage on future cost would be unemployment rate and annual discount rate. The overall economy of the society would exert a major effect on the future cost of epilepsy, in particular, for patients with poorly controlled disease.
The amount of drug that is delivered by nebulization is a combination of the physical properties of the agent being nebulized, the performance of the nebulizer, and the pattern of breathing of the patient. To avoid biological variation, mechanical models of breathing are frequently employed during the evaluation of the performance of a device. For simplicity, many investigators use sinusoidal models of breathing to calculate the expected inhaled mass, although some use square waves and other more complex models. Most assume that the duration of inspiration (Ti) is half of the total respiratory time (Ttot). This study compared the calculated inhaled mass from which the expected pulmonary deposition was estimated from the actual pattern of breathing of 43 children with cystic fibrosis (CF) breathing from an unvented nebulizer with a low dead volume and appropriate particle size distribution with that from a sinusoidal pattern of breathing using the same tidal volume (VT) and respiratory rate. The respiratory duty cycle (Ti/Ttot) was 0.45 +/- 0.05, which meant that less time was spent during inspiration than that found in a pure sinusoidal pattern. The difference between the predicted deposition from the actual pattern of breathing and that calculated from the sinusoidal model was 12 +/- 7%, which correlated with the respiratory rate (r = 0.67, P < 0.001). The degree of lung disease did not influence the discrepancy between the two values. In general, the actual VTs and respiratory rates were less in the patients than those employed in mechanical models of pediatric breathing. Although some patients had respiratory patterns that could be represented accurately with a sinusoidal model, most did not, and there were wide variations from child to child. These results suggest that there are both systematic and random errors arising from the use of a sinusoidal waveform to mimic respiratory events in patients.
The prevalence of clinically apparent peripheral neuropathy in systemic lupus erythematosus is reported to be between 2% to 18%. The purpose of this prospective case-control study was to determine the prevalence of peripheral neuropathy (PN) using electrodiagnostic criteria. Subgroup analysis was performed to determine whether PN correlated with disease activity, renal involvement, or serum immune markers. Fifty-four systemic lupus erythematosus patients and 30 controls were recruited in the study. The right median, ulnar, peroneal, tibial, and sural sensory and motor nerve conduction studies were obtained. PN in our study was defined as any abnormal values in motor and sensory distal latency, sensory action potential, motor action potential, or conduction velocity affecting 2 or more nerves. Of the 54 patients studied, PN was present in 15 patients (27.8%) of which 4 were symptomatic. There was a significant correlation between PN and anti-SM antibody, and there was a trend showing decreased motor and sensory action potential amplitudes in our systemic lupus erythematosus group compared to the controls. This observation was also seen in an active disease group when compared to those with inactive disease. The amplitude of the action potential was more often affected than the distal latency, and sensory nerves were more susceptible than motor nerves. The sural sensory action potential amplitude appears to be the most sensitive indicator of PN which may be used as an index to monitor disease activity.
Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is a ubiquitous enzyme that is crucial to the metabolism of carcinogenic catechols and catecholamines. Regulation of human COMT gene expression may be important in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression, and hypertension. The gender difference in human COMT activity and variations in rat COMT activity during the estrous cycle led us to explore whether estrogen can regulate human COMT gene transcription. Our Northern analyses showed that physiological concentrations of 17-beta-estradiol (10(-9)-10(-7) M) could decrease human 1. 3-kilobase COMT mRNA levels in MCF-7 cells in a time- and dose-dependent manner through an estrogen receptor-dependent mechanism. Two DNA fragments immediately 5' to the published human COMT gene proximal and distal promoters were cloned. Sequence analyses revealed several half-palindromic estrogen response elements and CCAAT/enhancer binding protein sites. By cotransfecting COMT promoter-chloramphenicol acetyltransferase reporter genes with human estrogen receptor cDNA and pSV-beta-galactosidase plasmids into COS-7 cells, we showed that 17-beta-estradiol could down-regulate chloramphenicol acetyltransferase activities, and COMT promoter activities dose-dependently. Functional deletion analyses of COMT promoters also showed that this estrogenic effect was mediated by a 280 base pair fragment with two putative half-palindromic estrogen response elements in the proximal promoter and a 323-base pair fragment with two putative CCAAT/enhancer binding protein sites in the distal promoter. Our findings provide the first evidence and molecular mechanism for estrogen to inhibit COMT gene transcription, which may shed new insight into the role of estrogen in the pathophysiology of different human disorders.
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