Coronary events and coronary care: MONICA project.
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Coronary Disease↗
Biomedical subjects
M Schulzer
Publications and source records attributed to M Schulzer.
Coronary events and coronary care: MONICA project.
Explore the source record for details and available documents.
Coronary Disease↗
Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry.
Chronic myeloid leukemia (CML) is a clonal, multilineage myeloproliferative disorder characterized by the Philadelphia chromosome (Ph) and a marked expansion of myeloid cells. Previous studies have indicated that the telomere length in blood cells may indicate their replicative history. However, the large variation in telomere length between individuals complicates the use of this parameter in CML and other hematologic disorders. To circumvent this problem, we compared the telomere length in peripheral blood or bone marrow cells with purified normal (Ph(-)) T lymphocytes from the same CML patient using fluorescence in situ hybridization and flow cytometry. Overall telomere fluorescence was significantly reduced in Ph(+) cells from patients with CML compared to blood leukocytes from normal individuals (P < 0.001) or normal (Ph(-)) T lymphocytes from the same individuals (n = 51, P < 0.001). Cells from patients in accelerated phase or blast phase (AP/BP) showed significantly shorter average telomere length than cells from patients in chronic phase (CP, P = 0.02) or cytogenetic remission (CR, P = 0.03). Patients in CP who subsequently developed BP within 2 years had significantly shorter telomeres than those who did not develop BP for at least 2 years (P < 0.05). Accelerated replication-dependent telomere shortening in Ph(+ )versus Ph(-) leukocytes supports previous evidence that Ph(+) stem cells cycle more actively than their counterparts in normal individuals. Our data further suggest that telomere shortening may serve as a surrogate marker of disease progression in patients with CP CML, supporting a mechanistic link between CML stem cell turnover, genetic instability, and malignant evolution in this disease. (Blood. 2000;95:1883-1890) (Blood. 2000;95:1883-1890)
Adolescent↗
Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations.
We used [18F]6-fluorodopa (FD) positron emission tomography (PET) to examine the severity of nigrostriatal dopaminergic dysfunction in 67 patients with Idiopathic Parkinsonism (IP), 52 with fluctuations and 15 with a stable response to levodopa. FD uptake (Ki) was reduced by 12% in the caudate (p = 0.08) and by 28% in the putamen (p = 0.0004) of patients with fluctuations compared to those with a stable response. However, there was considerable overlap of FD Ki values between the two groups. The fluctuators had a longer symptom duration (11.6 +/- 5.7 years) than the patients with a stable response to levodopa (4.3 +/- 2.4 years; p < 0.0001) and the age of onset of symptoms was earlier in the fluctuators (43.9 +/- 8.9 versus 54.1 +/- 10.4; p = 0.0004). Similar reductions in FD Ki in the fluctuators persisted following adjustment for these variables (7.5% in the caudate and 26% in the putamen; p = n.s. and 0.007, respectively). When smaller groups (n = 15 each) were matched for duration of symptoms, the reduction in caudate Ki in the fluctuators was only 1.9% (p = n.s.), but there was still a 24% reduction in putamen Ki (p = 0.05). These findings suggest that fluctuators and non-fluctuators may differ in the severity of their nigrostriatal damage and provide modest support for the hypothesis that fluctuations may in part reflect altered "buffering" capacity of dopaminergic nerve terminals. However, the considerable overlap between groups suggests that other factors such as altered postsynaptic mechanisms and/or increased turnover of dopamine may make a substantial contribution to the development of motor fluctuations.
Antiparkinson Agents↗
Post-traumatic cervical dystonia: a distinct entity?
BACKGROUND/OBJECTIVE: The incidence of head/neck trauma preceding cervical dystonia (CD) has been reported to be 5-21%. There are few reports comparing the clinical characteristics of patients with and without a history of injury. Our aim was to compare the clinical characteristics of idiopathic CD (CD-I) to those with onset precipitated by trauma (CD-T). METHODS: We evaluated 114 consecutive patients with CD over a 9-month period. All patients were interviewed using a detailed questionnaire and had a neurological examination. Their clinical charts were also reviewed. RESULTS: Fourteen patients (12%) had mild head/neck injury within a year preceding the onset of CD. Between the two groups (CD-I and CD-T), the gender distribution (F:M of 3:2), family history of movement disorders (32% vs. 29%), the prevalence of gestes antagonistes (65% vs. 64%), and response to botulinum toxin were similar. There were non-specific trends, including an earlier age of onset (mean ages 43.3 vs. 37.6), higher prevalence of neck pain (86% vs. 100%), head tremor (67% vs. 79%), and dystonia in other body parts (23% vs. 36%) in CD-T. CONCLUSIONS: CD-I and CD-T are clinically similar. Trauma may be a triggering factor in CD but this was only supported by non-significant trends in its earlier age of onset.
Adult↗
Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease.
We investigated the role of dopamine neurons in the manifestation of levodopa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stereotypy and contraversive rotation. After 4 weeks of levodopa treatment, rats with mild and severe AIM were assigned to two treatment subgroups. The graft subgroup received embryonic ventral mesencephalic tissue into the striatum, whilst the sham-graft subgroup received vehicle only. Rats continued to receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a ligand for dopamine transporter, and in situ hybridization histochemistry for mRNAs encoding postsynaptic markers. Levodopa-induced AIM significantly improved in grafted rats. The severity of AIM correlated inversely with the density of dopamine nerve terminals in the striatum (P < 0. 001), with almost no AIM when the density of dopamine nerve terminals was >10-20% of normal. Embryonic dopamine neuronal grafts normalized not only mRNA expression for preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by levodopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P < 0.001) and also with PDyn mRNA in the direct pathway (P < 0.001). We conclude that embryonic dopamine neuronal grafts may improve levodopa-induced dyskinesia by restoring altered activities of postsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic nerve terminals is restored above a 'threshold' level.
Animals↗
Long term outcome of unilateral pallidotomy: follow up of 15 patients for 3 years.
OBJECTIVES: With the advent of new antiparkinsonian drug therapy and promising results from subthalamic and pallidal stimulation, this study evaluated the long term efficacy of unilateral pallidotomy, a technique which has gained popularity over the past decade for the management of advanced Parkinson's disease. METHODS: The 15 patients reported here are part of the original cohort of 24 patients who underwent posteroventral pallidotomy for motor fluctuations and disabling dyskinesias 3 years ago as part of a prospective study. Evaluation scales included the unified Parkinson's disease rating scale, the Goetz dyskinesia scale, and the Purdue pegboard test. RESULTS: When compared with the prepallidotomy scores, the reduction in the limb dyskinesias and off state tremor scores persisted on the side contralateral to pallidotomy at the end of 3 years (dyskinesias were reduced by 64% (p<0.01) and tremor by 63% (p<0.05). Other measures tended to deteriorate. The dosage of antiparkinsonian medications did not change significantly from 3 months prepallidotomy to 3 years postpallidotomy. CONCLUSIONS: Although unilateral pallidotomy is useful in controlling the contralateral dyskinesias and tremor 3 years after surgery, all other early benefits disappear and activities of daily living continue to worsen.
Activities of Daily Living↗
Intravenous tissue plasminogen activator for acute ischemic stroke: A Canadian hospital's experience.
BACKGROUND AND PURPOSE: In the United States, tissue plasminogen activator (tPA) was approved for treatment of acute ischemic stroke in 1996. Its use has only recently been approved in Canada. We sought to evaluate the safety, feasibility, and efficacy of treatment in a Canadian hospital setting. METHODS: A combined retrospective and prospective review is presented of 46 consecutive patients treated with intravenous tPA at our hospital with a treatment protocol similar to that of the National Institute of Neurological Disorders and Stroke (NINDS) trial. RESULTS: Symptomatic intracranial hemorrhage at 36 hours occurred in 1 patient (2.2%). The median time to treat was 165 minutes, with a median "door-to-needle" time of 84 minutes. Compared with patients presenting initially at our hospital, patients transferred from another institution for tPA therapy were treated closer to the 3-hour time window (mean 173 versus 148 minutes, P:<0.001) but had a shorter door-to-needle time (43 versus 102 minutes, P:<0.001). For every 10 minutes closer to the 3-hour time window that any patient arrived at the hospital, 7 minutes was saved in the door-to-needle time (correlation coefficient 0.9, P:<0.001). Patient outcome did not differ from that in the NINDS trial (P:>0.75). CONCLUSIONS: Our safety and patient outcome data compare favorably with NINDS and Phase IV data. Although a 3-hour treatment window was feasible, the median door-to-needle time lengthened as more treatment time was available and the door-to-needle time was beyond recommended standards. This review has prompted changes in our community to improve treatment efficiency.
Acute Disease↗
In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease.
Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug-naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD.
Aged↗
Head tremor in cervical dystonia.
OBJECTIVE: To compare the clinical characteristics, natural history, and therapeutic outcome of patients with cervical dystonia (CD) with head tremor (HT+) and without head tremor (HT-). METHODS: We prospectively evaluated 114 consecutive patients of CD over a 9-month period with a detailed questionnaire. Chi-square and t-tests were employed for statistical analysis. RESULTS: Seventy-eight (68.4%) patients had head tremor and 27 of them (34.6%) had tremor as one of the first symptoms. Age at onset of symptoms were similar in HT+ and HT- groups; however there was a higher prevalence in women in the former group (66.7% vs. 41.7%; p=0.01). HT+ patients had more frequent positive family history of essential-like hand/head tremor (21.8% vs. 5.5%; p<0.05), associated neck pain (92.3% vs. 77.8%: p<0.05), and essential-like hand tremor (40% vs. 8.3%; p<0.001). They also appeared to have more frequent history of preceding head/neck trauma (14.1% vs. 8.3%), frequent head rotation (88.5% vs. 69.4%) and antecollis (12.8% vs. 5.5%) but less often head tilt (37.2% vs. 47.2%) and gestes antagonistes (60.2% vs. 75%) than the HT- patients; however these differences were not statistically significant. The frequency of prior psychiatric illnesses, the incidence of dystonias in other parts of the body, frequency of retrocollis and shoulder elevation, and spontaneous remission were similar in the two groups. CONCLUSION: Head tremor is common in CD and is more commonly associated with hand tremor and family history of tremor or other movement disorders. This supports a possible genetic association between CD and essential tremor (ET). Linkage studies are required to evaluate the genetic association between CD and ET.
Adult↗
Metatarsalgia and rheumatoid arthritis--a randomized, single blind, sequential trial comparing 2 types of foot orthoses and supportive shoes.
OBJECTIVE: To compare the effects of semi-rigid and soft orthoses worn in supportive shoes, and supportive shoes worn alone, on metatarsal phalangeal (MTP) joint pain. MTP joint synovitis, and lower extremity function in patients with rheumatoid arthritis. METHODS: Twenty-eight subjects referred to occupational therapy received in random order 3 interventions for 12 week trials, separated by 2 week washouts. A crossover design compared effectiveness of interventions. RESULTS: Twenty-four subjects completed the study. A reduction in mean pain scores from baseline to final visits showed that semi-rigid orthoses had a highly significant effect on pain. Soft orthoses did not show a significant effect on pain from baseline to final visit, nor did shoes worn alone. None of the interventions had a significant effect on synovitis or function. CONCLUSION: Semi-rigid orthoses worn in supportive shoes were an effective treatment for metatarsalgia. Supportive shoes worn alone or worn with soft orthoses did not provide pain relief for metatarsalgia.
Adult↗
Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood.
To study telomere length dynamics in hematopoietic cells with age, we analyzed the average length of telomere repeat sequences in diverse populations of nucleated blood cells. More than 500 individuals ranging in age from 0 to 90 yr, including 36 pairs of monozygous and dizygotic twins, were analyzed using quantitative fluorescence in situ hybridization and flow cytometry. Granulocytes and naive T cells showed a parallel biphasic decline in telomere length with age that most likely reflected accumulated cell divisions in the common precursors of both cell types: hematopoietic stem cells. Telomere loss was very rapid in the first year, and continued for more than eight decades at a 30-fold lower rate. Memory T cells also showed an initial rapid decline in telomere length with age. However, in contrast to naive T cells, this decline continued for several years, and in older individuals lymphocytes typically had shorter telomeres than did granulocytes. Our findings point to a dramatic decline in stem cell turnover in early childhood and support the notion that cell divisions in hematopoietic stem cells and T cells result in loss of telomeric DNA.
Adolescent↗
Reporting risks and benefits of therapy by use of the concepts of unqualified success and unmitigated failure: applications to highly cited trials in cardiovascular medicine.
BACKGROUND: The NNT (number needed to treat) and NNH (number needed to harm) are useful in conveying the results of clinical trials because they emphasize the effort that must be expended to accomplish a single, tangible outcome. But NNT conveys the effort required to achieve a positive outcome without distinguishing between the presence or absence of treatment-related adverse events. Similarly, NNH conveys harm without accounting for the achievement or lack of achievement of the benefit of therapy. Consequently, a mathematical model was developed to extend the NNT and NNH to represent the effort required to achieve "unqualified success" (NNTUS, treatment success without treatment-induced side effects) and "unmitigated failure" (NNHUF, lack of treatment success with treatment-induced side effects). METHODS AND RESULTS: NNTUS was calculated by adjusting the absolute risk reduction to allow for the probability of not incurring a treatment-related adverse event. NNHUF was similarly calculated by adjusting the absolute risk of incurring a treatment-related adverse event by the probability of not incurring any treatment-related benefit. The impact of conveying clinical trial data by the use of NNT, NNTUS, NNH, and NNHUF is illustrated by means of 11 highly cited trials identified systematically from the cardiovascular literature. The treatment effort measured by the NNTUS and the NNHUF was consistently higher than that given by the traditional NNT and NNH. These increments ranged from 1% to several hundred percent. CONCLUSIONS: The NNTUS and the NNHUF represent the treatment effort required on average to achieve 1 unqualified success and 1 unmitigated failure. NNTUS and NNHUF balance benefit and harm in an objective way and are relevant for making service delivery decisions.
Cardiovascular Diseases↗
Reassessment of unilateral pallidotomy in Parkinson's disease. A 2-year follow-up study.
Unilateral pallidotomy has gained popularity in treating the motor symptoms of Parkinson's disease. We present the results of a 2-year post-pallidotomy follow-up study. Using the Unified Parkinson's Disease Rating Scale (UPDRS), the Goetz dyskinesia scale and the Purdue Pegboard Test (PPBT), we evaluated 20 patients at regular intervals both off and on medications for 2 years post-pallidotomy. There were no significant changes in the dosages of antiparkinsonian medications from 3 months pre-pallidotomy to 2 years post-pallidotomy. On the side contralateral to the operation, the improvements were preserved in 'on'-state dyskinesia (83% reduction from pre-pallidotomy to 2 years post-pallidotomy, P < 0.001) and 'off'-state tremor (90% reduction from pre-pallidotomy to 2 years post-pallidotomy, P = 0.005). There were no statistically significant differences between pre-pallidotomy scores and those at 2 years post-pallidotomy in ipsilateral dyskinesia, axial dyskinesia, 'off'- or 'on'-state PPBT, 'off'-state Activities of Daily Living (ADL) and 'off'-state gait and postural stability. After 2 years, the 'on'-state ADL scores worsened by 75%, compared with pre-pallidotomy (P = 0.005). We conclude that 2 years after pallidotomy, the improvements in dyskinesia and tremor on the side contralateral to pallidotomy are preserved, while the initial improvements in most other deficits disappear, either because of progression of pathology or loss of the early efficacy achieved by surgery.
Aged↗
At issue: schizophrenia and rheumatoid arthritis: the negative association revisited.
A strong negative association between schizophrenia and rheumatoid arthritis (RA), implying low comorbidity, has been found in 12 of 14 previous studies, which we review. To this literature we add two recently acquired data sets encompassing 28,953 schizophrenia patients, only 31 of whom had comorbid RA. Integrating our new data into those of the previous nine studies, which stratified their populations according to psychiatric diagnosis, we obtain a median frequency of RA in schizophrenia populations of 0.09 percent and a mean frequency of 0.66 percent, well below the expected range of 1 percent. These data robustly support prior studies. We also present a meta-analysis evaluating the association between the two diseases by integrating information derived from nine data sets, each furnishing an estimate of the relative risk of RA in schizophrenia patients versus that in other psychiatric patients. We find that the estimated rate of RA among schizophrenia patients is only 29 percent of the corresponding rate in other psychiatric patients. Further, the relative risk of RA in schizophrenia patients versus that in the general population is even less than 29 percent and could be as low as one-third of this value. We present a new hypothesis involving the platelet activating factor system in an effort to account for this negative association and review the suggestions of other investigators toward this end. Finally, we consider the glutamatergic system dysfunction hypothesis of schizophrenia and suggest a possible common pharmacological approach that may ameliorate some of the symptomatology of both schizophrenia and RA.
Adult↗
Unilateral pallidotomy for reduction of parkinsonian pain.
OBJECT: The goal of this study was to determine whether unilateral pallidotomy reduces parkinsonian pain. METHODS: Twenty-one patients suffering from Parkinson's disease (PD) were followed prospectively for 1 year after they had undergone a unilateral pallidotomy to assess the procedure's effect on pain related to PD. Pain unrelated to PD was not studied. Patients scored the level of their PD pain on an ordinal scale (0-10 points) preoperatively and 6 weeks and 1 year postoperatively. The results were analyzed using Wilcoxon's paired-ranks test (with Bonferroni correction) and showed a significant reduction in overall pain scores at 6 weeks (p < 0.001) and 1 year (p = 0.001) following pallidotomy. Various types of PD pain are described and their possible pathophysiological mechanisms are presented. CONCLUSIONS: Unilateral pallidotomy significantly reduces pain attributable to Parkinson's disease.
Cohort Studies↗
Reproducibility studies with 11C-DTBZ, a monoamine vesicular transporter inhibitor in healthy human subjects.
UNLABELLED: The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. METHODS: The scan-to-scan variation of several measures used in PET data analysis was determined, including the radioactivity ratio (target-to-reference), plasma-input Logan total distribution volume (DV), plasma-input Logan Bmax/Kd and tissue-input Logan Bmax/Kd values. RESULTS: The radioactivity ratios, plasma-input Bmax/Kd and tissue-input Bmax/Kd all have higher reliability than plasma-input total DV values. In addition, measures using the occipital cortex as the reference region have higher reliability than the same measures using the cerebellum as the reference region. CONCLUSION: Our results show that DTBZ is a reliable PET tracer that provides reproducible in vivo measurement of striatal vesicular monoamine transporter density. In the selection of reference regions for DTBZ PET data analysis, caution must be exercised in circumstances when DTBZ binding in the occipital cortex or the cerebellum may be altered.
Adult↗
Age-dependent decline of dopamine D1 receptors in human brain: a PET study.
Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.
Adult↗