Objective measures for the progression of Parkinson's disease.
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Binding Sites↗
Biomedical subjects
B Snow
Publications and source records attributed to B Snow.
Vsx1, a rapidly evolving paired-like homeobox gene expressed in cone bipolar cells.
The paired-like homeodomain (HD) protein Chx10 is distinguished by the presence of the CVC domain, a conserved 56 amino acid sequence C-terminal to the HD. In mammals, Chx10 is essential both for the proliferation of retinal progenitor cells and for the formation or survival of retinal bipolar interneurons. We describe the cloning and characterization of a mouse Chx10 homologue, Vsx1; phylogenetic analysis suggests that Vsx1 and its putative vertebrate orthologues have evolved rapidly. Vsx1 expression in the adult is predominantly retinal. Whereas Chx10 is expressed both in retinal progenitors in the developing eye and apparently in all bipolar cells of the mature retina, Vsx1 expression is first detected in the eye at postnatal day 5, where it is restricted to cone bipolar cells.
Amino Acid Sequence↗
Regulation of PTEN transcription by p53.
PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
Animals↗
Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel.
Gamma-aminobutyric acid (GABA)B receptors couple to Go to inhibit N-type calcium channels in embryonic chick dorsal root ganglion neurons. The voltage-independent inhibition, mediated by means of a tyrosine-kinase pathway, is transient and lasts up to 100 seconds. Inhibition of endogenous RGS12, a member of the family of regulators of G-protein signalling, selectively alters the time course of voltage-independent inhibition. The RGS12 protein, in addition to the RGS domain, contains PDZ and PTB domains. Fusion proteins containing the PTB domain of RGS12 alter the rate of termination of the GABA(B) signal, whereas the PDZ or RGS domains of RGS 12 have no observable effects. Using primary dorsal root ganglion neurons in culture, here we show an endogenous agonist-induced tyrosine-kinase-dependent complex of RGS12 and the calcium channel. These results indicate that RGS12 is a multifunctional protein capable of direct interactions through its PTB domain with the tyrosine-phosphorylated calcium channel. Recruitment of RGS proteins to G-protein effectors may represent an additional mechanism for signal termination in G-protein-coupled pathways.
Animals↗
The conserved PI3'K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila.
Akt (or PKB) is an oncogene involved in the regulation of cell survival. Akt is regulated by phosphatidylinositol 3-OH kinase (PI3'K) signaling and has shown to be hyperactivated through the loss of the PTEN tumor suppressor. In Drosophila, insulin signaling as studied using the Drosophila IRS-4 homolog (Chico) has been shown to be a crucial regulator of cell size. We have studied Drosophila Akt (Dakt1) and have shown that it is also involved in the regulation of cell size. Furthermore we have performed genetic epistasis tests to demonstrate that in Drosophila, PI3'K, PTEN and Akt comprise a signaling cassette that is utilized during multiple stages of development. In addition, we show that this signaling cassette is also involved in the regulation of cell survival during embryogenesis. This study therefore establishes the evolutionary conservation of this signaling pathway in Drosophila. Oncogene (2000) 19, 3971 - 3977.
Animals↗
Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial.
OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.
Adult↗
HIV vaccine: how long must we wait?
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AIDS Vaccines↗
Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease.
We have previously demonstrated that fetal nigral grafts can survive, reinnervate the striatum, and mediate clinically relevant recovery in a patient with Parkinson's disease (PD). Most previous autopsy cases have failed to identify meaningful numbers of viable grafted cells suggesting that differences in critical transplant variables determine graft viability. The present study evaluated the structural and functional correlates of fetal nigral transplantation in a second PD patient who received fetal nigral grafts according to our previously published transplant protocol. A 61-year-old woman with severe PD received bilateral fetal nigral grafts to the postcommissural putamen from seven donor fetuses (four right side and three left side) aged 6.5-9 weeks postconception. This patient died 19 months after surgery from a cause unrelated to the transplant surgery. Her postoperative clinical course was characterized by improved motor and activities of daily living scores during "off time," reduced "off time," and increased "on" time without dyskinesia. Positron emission tomography (PET) scans revealed a bilateral and progressive increase in fluorodopa (FD) uptake within the grafted putamen. Postmortem examination of the right hemisphere revealed large oval-shaped grafts containing more than 138,000 tyrosine-hydroxylase-immunoreactive (TH-ir) neurons. Grafted cells formed a seamless border with the host and provided dense TH-ir innervation to 78% of the host postcommissural putamen. Graft-mediated sprouting of host fibers was not observed. These data provide essential confirmation that, under appropriate transplant conditions, grafted nigral neurons can survive, reinnervate the host striatum, and provide clinical benefit to PD patients. These findings also support the concept that improved motor function and striatal FD uptake on PET after nigral grafting in PD are the result of the viability of grafted neurons and graft-derived reinnervation of the host striatum.
Brain Tissue Transplantation↗
Dopa-responsive, nonprogressive juvenile parkinsonism: report of a case.
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Age of Onset↗
Receptor-specific adhesion and clinical disease in Plasmodium falciparum.
One important factor in the virulence of infections with Plasmodium falciparum is the adherence of infected erythrocytes to small vessel endothelium. In infections that lead to serious, life-threatening disease accumulation of large numbers of infected cells in particular organs is thought to lead to organ dysfunction or failure. This is of particular relevance when the affected organ is the brain, leading to the development of cerebral malaria. Many different endothelial receptors for infected red blood cells have been identified. Some receptors such as CD36 and thrombospondin are used by all parasite isolates, whereas others such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule (VCAM) are used by a subset of field and laboratory isolates. While it has been speculated that the ability to bind or affinity of binding to a particular endothelial receptor may be related to the pattern of disease, only studies with limited numbers of patients have been carried out to date and these have been in general inconclusive. Here we have taken parasite isolates from 150 patients with defined clinical syndromes as well as isolates from 50 healthy but parasitized community controls and quantitatively assessed their binding to purified endothelial receptors in vitro. Our results show that disregarding the level of adhesion, all parasites bind to CD36, most bind to ICAM-1, few bind to VCAM, and almost none bind to E-selectin. In assessing the degree of binding we show that 1) binding to all receptors was reduced in parasites taken from severely anemic patients; 2) binding to CD36 is identical in parasites from cerebral malaria patients and community controls but slightly elevated in parasites from nonsevere cases; and 3) binding to ICAM-1 is highest in cerebral malaria patients. Because rosette formation by uninfected cells has also been a phenotype associated with disease severity and one that may interfere in vitro with receptor binding, we also assessed rosette formation in all isolates. In this study the highest level of rosette-forming parasites was found in the anemic group and not the cerebral malaria group. Stratifying the data for the frequency of rosette formation showed that the above results were not significantly altered by this phenomenon. Our data are not consistent with a role for binding to CD36 in the development of severe disease but show an association between the degree of binding to ICAM-1 and clinical illness in nonanemic patients.
Anemia↗
A case-control study of Parkinson's disease in a horticultural region of British Columbia.
We compared personal histories of 127 cases and 245 controls to identify possible environmental risk factors for idiopathic parkinsonism (IP). Of our controls, 121 had cardiac disease (CD) and 124 were randomly selected from electoral lists (voters). Using logistic regression and adjusting for sex and age, we ran separate analyses: IP versus CD and IP versus voters. A full occupational history was collected, as was known contact with all pesticides associated with the tree fruit sector of the agricultural industry. We found a significant association between IP and having had an occupation in which exposure through handling or directly contacting pesticides was probable, but no specific chemicals were associated with IP. We conclude that although occupations involving the use of agricultural chemicals may predispose to the development of IP, it seems likely that the pathogenesis is multifactorial rather than related to a specific agent.
Aged↗
Transplantation of fetal mesencephalic tissue in Parkinson's patients.
Patients with idiopathic Parkinson's disease who had become refractory to medical treatment underwent unilateral stereotactic transplantation of mesencephalic tissue obtained from 7- to 9-week-old postconception fetuses. Small pieces of tissue, less than 1 mm, were deposited in 9 sites in the putamen and 3 in the caudate. Patients were 4 men and 3 women and aged from 42 to 59 years (mean 50). Symptom durations were from 9 to 21 years (mean 14). The examinations were done at 3- to 4-month intervals pre- and postoperatively. Patients were examined for a minimum of 1 year postoperatively. The examinations consisted of neurological and general physical examinations, UCLA Parkinson's Disability Scale, Hoehn and Yahr rating and United Parkinson's Disease Rating Scale (PDRS), all in both 'on' and 'off' states. Video recordings and timed tests of a number of motor tests were performed. Patients also completed 7 consecutive days of hourly self-assessments prior to each visit. Fluorodopa PET scans were obtained pre- and 6 and 15 months postoperatively. The operations took place from mid-July 1992 to January 1993. Postoperative states have been free of complications. All have been on immunosuppressants. Levodopa was transiently decreased in the postoperative period, but raised to approximately the preoperative level thereafter. In late March 1993, 3 patients appeared to show modest improvement in the UCLA and UPDRS scales and in the patients' self-assessments.
Adult↗
Normal CAG repeat length in the Huntington's disease gene in senile chorea.
There is a widely held belief that most patients presenting with senile chorea have late-onset Huntington's disease (HD) with an unknown family history. We measured CAG trinucleotide repeat expansion in the HD gene in four patients with a clinical presentation of senile chorea and found that CAG repetition lengths were normal. These findings support senile chorea as being a distinct clinical entity that is nosologically separate from late-onset HD.
Aged↗
Parkinsonism caused by petroleum waste ingestion.
A 20-year-old laborer developed moderate parkinsonism 1 week after accidentally ingesting a petroleum waste mixture. Parkinsonism persisted for 3 months and then began to improve, although subtle signs remained 29 months after exposure. 6-Fluorodopa-labeled positron emission tomography (6-FD PET) performed 3 months postexposure revealed a striatal dopamine rate constant level of 0.170 ml/striatum/min, nearly 3 SD below the mean for age-matched controls. However, subsequent PETs demonstrated 6-FD PET rate constants not significantly different than controls. Although the causative agent has not yet been identified, this case suggests that compounds capable of causing parkinsonism may exist in commonly used petroleum products.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
A scoring error in the Mini-Mental State test.
A scoring error is identified in the Mini-Mental and the Modified Mini-Mental State test. The major effect of this error is to produce a gap in the total score distribution of the test, resulting in a potential spurious underestimation of the score. Two possible remedies are suggested to resolve this problem.
Attention↗
Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
BACKGROUND: Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism. METHODS: We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation. RESULTS: Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications. CONCLUSIONS: Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Parkinson's disease: a case-control study of occupational and environmental risk factors.
We compared personal histories of 57 cases and 122 age-matched controls to identify possible environmental determinants of Parkinson's disease (PD). Odds ratios (OR) adjusted for sex, age, and smoking were computed using stepwise logistic regression. We found a statistically significant increased risk for working in orchards (OR = 3.69, p = 0.012, 95% CI = 1.34, 10.27) and a marginally significant increased risk associated with working in planer mills (OR = 4.11, p = 0.065, 95% CI = 0.91, 18.50). A Fisher's exact test of the association between PD development and (1) paraquat contact, and (2) postural tremor gave statistically significant probability estimates of 0.01 and 0.03, respectively. The relative risk of PD decreased with smoking, an inverse relationship supported by many studies.
Aged↗