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1.  Performance of a motor task learned ON levodopa deteriorates when subsequently practiced OFF 
Studies in animals and in people with Parkinson's Disease (PD) demonstrate complex effects of dopamine on learning motor tasks; its effect on retention of motor learning has received little attention. Recent animal studies demonstrate that practicing a task in the OFF state, when initially learned in the ON state, leads to progressive deterioration in performance.
We measured the acquisition and retention of 3 different motor tasks in the presence and absence of levodopa. Twenty individuals with Hoehn and Yahr Stage 1.5-3 PD practiced the tasks for two, 4-day weeks, half practicing ON levodopa the first week and OFF the second week. The other half practiced OFF levodopa both weeks. The tasks were: 1. alternate tapping of two keys, 2. moving the body toward two targets on a posturography device and 3. mirror drawing of a star.
For the finger tapping and body movement tests, those who practiced ON the first week had a progressive decline in performance with practice during Week 2, while subjects OFF during Week 1 maintained or improved. In contrast, for the mirror task, subjects ON levodopa initially had much more difficulty completing the task compared to subjects who practiced OFF. Both groups improved with practice during the first week and had flat performance the second week.
These data suggest that performance of speed-accuracy tasks learned in the ON state may progressively worsen if practiced in the OFF state. In addition, performance, but not learning, of some tasks may be impeded by levodopa.
PMCID: PMC3943672  PMID: 24132873
levodopa; learning; Parkinson's
2.  Cognitive and motor function in long duration PARKIN PD 
JAMA neurology  2014;71(1):62-67.
The long term cognitive outcome in PARKIN-PD patients is unknown. This data may be meaningful when counseling PARKIN-PD patients.
Among early-onset PD (EOPD) patients with long disease durations, we assessed cognitive and motor performances, comparing compound heterozygote/homozygote PARKIN carriers to non-carriers
Cross sectional study
Seventeen movement disorders centers
Forty-four participants in the Consortium on Risk for Early-Onset PD (CORE-PD) with PD duration greater than median (>14 years), including PARKIN compound heterozygotes/homozygotes combined (n=21), and non-carriers (n=23).
Main outcome measures
Unified Parkinson’s Disease Rating Scale Part III (UPDRS), Clinical Dementia Rating (CDR) and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose.
Compound heterozygote/homozygote PARKIN mutation carriers had earlier AAO of PD (p<0.001) and were younger (p=0.004) at time of examination than non-carriers. They performed better on the MMSE (p=0.010) and were more likely to receive lower scores on the CDR (p=0.003). In multivariate analyses, PARKIN compound heterozygotes/homozygotes performed better on the UPDRS Part III (p=0.017), and on tests of attention (p=0.022), memory (p=0.025) and visuospatial (p=0.024) domains.
Conclusions and Relevance
Cross-sectional analyses demonstrate better cognitive and motor performance in compound heterozygote/homozygote PARKIN EOPD carriers than non-carriers with long disease duration, suggesting slower disease progression. Longitudinal follow up is required to confirm these findings.
PMCID: PMC3947132  PMID: 24190026
3.  Exploring Outcome Measures for Exercise Intervention in People with Parkinson's Disease 
Parkinson's Disease  2013;2013:572134.
Background. It is widely believed that exercise improves mobility in people with Parkinson's disease (PD). However, it is difficult to determine whether a specific type of exercise is the most effective. The purpose of this study was to determine which outcome measures were sensitive to exercise intervention and to explore the effects of two different exercise programs for improving mobility in patients with PD. Methods. Participants were randomized into either the Agility Boot Camp (ABC) or treadmill training; 4x/week for 4 weeks. Outcome measures were grouped by the International Classification of Function/Disability (ICF). To determine the responsiveness to exercise, we calculated the standardized response means. t-tests were used to compare the relative benefits of each exercise program. Results. Four of five variables at the structure/function level changed after exercise: turn duration (P = 0.03), stride velocity (P = 0.001), peak arm speed (P = 0.001), and horizontal trunk ROM during gait (P = 0.02). Most measures improved similarly for both interventions. The only variable that detected a difference between groups was postural sway in ABC group (F = 4.95; P = 0.03). Conclusion. Outcome measures at ICF body structure/function level were most effective at detecting change after exercise and revealing differences in improvement between interventions.
PMCID: PMC3657411  PMID: 23738230
4.  A meta-regression of the long-term effects of deep brain stimulation on balance and gait in PD 
Neurology  2010;75(14):1292-1299.
Deep brain stimulation (DBS) alleviates the cardinal Parkinson disease (PD) symptoms of tremor, rigidity, and bradykinesia. However, its effects on postural instability and gait disability (PIGD) are uncertain. Contradictory findings may be due to differences the in stimulation site and the length of time since DBS surgery. This prompted us to conduct the first meta-regression of long-term studies of bilateral DBS in the subthalamic nucleus (STN) and globus pallidus interna (GPi).
Eleven articles reported a breakdown of the Unified Parkinson's Disease Rating Scale score before and beyond 3 years postsurgery (mean 4.5 years). Random effects meta-regression revealed that DBS initially improved PIGD compared to the OFF medicated state before surgery, but performance declined over time and extrapolation showed subjects would reach presurgery levels 9 years postsurgery. ON medication, DBS improved PIGD over and above the effect of medication before surgery. Nevertheless, for the STN group, PIGD progressively declined and was worse than presurgery function within 2 years. In contrast, GPi patients showed no significant long-term decline in PIGD in the medicated state. Improvements in cardinal signs with DBS at both sites were maintained across 5 years in the OFF and ON medication states.
DBS alone does not offer the same improvement to PIGD as it does to the cardinal symptoms, suggesting axial and distal control are differentially affected by DBS. GPi DBS in combination with levodopa seemed to preserve PIGD better than did STN DBS, although more studies of GPi DBS and randomized controls are needed.
= deep brain stimulation;
= globus pallidus interna;
= Parkinson disease;
= postural instability and gait disability;
= subthalamic nucleus;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC3013496  PMID: 20921515
5.  A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2 
Neurology  2010;75(13):1189-1194.
To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study.
We studied 1,686 control subjects (mean age 66.1 ± 13.1 years) and 2,091 patients with PD (mean onset age 58.3 ± 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake.
A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1–4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2–9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 ± 8.6 heterozygous vs 58.5 ± 11.8 normal).
This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD.
= autosomal recessive juvenile parkinsonism;
= confidence interval;
= copy number variation;
= moving average plots;
= multiplex ligation-dependent probe amplification;
= NeuroGenetics Research Consortium;
= odds ratio;
= Parkinson disease.
PMCID: PMC3013490  PMID: 20876472
6.  A Novel X-linked 4-Repeat Tauopathy with Parkinsonism and Spasticity 
The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson’s disease (PD), additional PD loci are likely to exist. We recently identified a multi-generational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant 4-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and 4-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3.
PMCID: PMC3123999  PMID: 20629132
Genetic linkage; Parkinson’s disease/parkinsonism; X-linked parkinsonism; X-linked spastic paraparesis; tauopathy
7.  The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy 
British Journal of Cancer  2010;102(3):553-560.
The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRα).
Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI50). FRα expression was determined by western blotting and that of FRα, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT–PCR. Immunohistochemistry for FRα was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed.
A wide range of GI50 values was obtained for the cell lines, H2452 cells being the most sensitive (GI50 22 nM) and RS5 cells having a GI50 value greater than 10 μM. No FRα protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRα was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRα and the outcome of pemetrexed treatment, and no significant difference between histological subtypes.
Response to treatment with pemetrexed does not depend on the presence of FRα.
PMCID: PMC2822938  PMID: 20051956
Folate receptor α; mesothelioma; pemetrexed; cell lines; immunohistochemistry
8.  Multiple balance tests improve the assessment of postural stability in subjects with Parkinson's disease 
Clinicians often base the implementation of therapies on the presence of postural instability in subjects with Parkinson's disease (PD). These decisions are frequently based on the pull test from the Unified Parkinson's Disease Rating Scale (UPDRS). We sought to determine whether combining the pull test, the one‐leg stance test, the functional reach test, and UPDRS items 27–29 (arise from chair, posture, and gait) predicts balance confidence and falling better than any test alone.
The study included 67 subjects with PD. Subjects performed the one‐leg stance test, the functional reach test, and the UPDRS motor exam. Subjects also responded to the Activities‐specific Balance Confidence (ABC) scale and reported how many times they fell during the previous year. Regression models determined the combination of tests that optimally predicted mean ABC scores or categorised fall frequency.
When all tests were included in a stepwise linear regression, only gait (UPDRS item 29), the pull test (UPDRS item 30), and the one‐leg stance test, in combination, represented significant predictor variables for mean ABC scores (r2 = 0.51). A multinomial logistic regression model including the one‐leg stance test and gait represented the model with the fewest significant predictor variables that correctly identified the most subjects as fallers or non‐fallers (85% of subjects were correctly identified).
Multiple balance tests (including the one‐leg stance test, and the gait and pull test items of the UPDRS) that assess different types of postural stress provide an optimal assessment of postural stability in subjects with PD.
PMCID: PMC2077684  PMID: 16484639
functional reach; one‐leg stance; Parkinson's disease; stability; UPDRS
10.  Axial hypertonicity in Parkinson’s disease: Direct measurements of trunk and hip torque 
Experimental neurology  2007;208(1):38-46.
A cardinal feature of Parkinson’s disease (PD) is muscle hypertonicity, i.e. rigidity. Little is known about the axial tone in PD or the relation of hypertonia to functional impairment. We quantified axial rigidity to assess its relation to motor symptoms as measured by UPDRS and determine whether rigidity is affected by levodopa treatment. Axial rigidity was measured in 12 PD and 14 age-matched controls by directly measuring torsional resistance of the longitudinal axis to twisting (±10°). Feet were rotated relative to fixed hips (Hip Tone) or feet and hips were rotated relative to fixed shoulders (Trunk Tone). To assess tonic activity only, low constant velocity rotation (1°/s) and low acceleration (<12°/s2) were used to avoid eliciting phasic sensorimotor responses. Subjects stood during testing without changing body orientation relative to gravity. Body parts fixed against rotation could translate laterally within the boundaries of normal postural sway, but could not rotate. PD OFF-medication had higher axial rigidity (p<0.05) in hips (5.07 Nm) and trunk (5.30 Nm) than controls (3.51 Nm and 4.46 Nm, respectively), which didn’t change with levodopa (p>0.10). Hip-to-trunk torque ratio was greater in PD than controls (p<0.05) and unchanged by levodopa (p=0.28). UPDRS scores were significantly correlated with hip rigidity for PD OFF-medication (r=0.73, p<0.05). Torsional resistance to clockwise versus counter-clockwise axial rotation was more asymmetrical in PD than controls (p<0.05), however, there was no correspondence between direction of axial asymmetry and side of disease onset. In conclusion, these findings concerning hypertonicity may underlie functional impairments of posture and locomotion in PD. The absence of a levodopa effect on axial tone suggests axial and appendicular tone are controlled by separate neural circuits.
PMCID: PMC2144734  PMID: 17692315
Parkinson’s disease; muscle tone; hypertonicity; rigidity; levodopa; axial musculature
11.  hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours 
British Journal of Cancer  2007;96(5):762-768.
The effect of EGF and gefitinib on two EGFR-positive human bladder cancer cell lines has been investigated using array-based gene expression profiling. The most prominent transcript, increased up to 6.7-fold by EGF compared with controls in RT112 cells, was human early growth response protein 1 (hEGR1). This induction was prevented by gefitinib. The hEGR1 mRNA in EGF-treated samples was reduced in the presence of gefitinib, as was hEGR1 protein in cell lysates. In the RT4 cells, hEGR1 expression was halved in the presence of EGF and gefitinib in combination. In bladder tumour samples, there was a significant correlation between hEGR1 mRNA detected by RT-PCR and EGFR detected by ligand binding, (P=0.042). The induction by EGF of the hEGR1 gene, mRNA and protein in RT112 cells, and its inhibition by gefitinib, together with the detection of hEGR1 mRNA in bladder tumours, suggests that hEGR1 may be important in the EGFR growth-signalling pathway in bladder cancer and should be further investigated for its prognostic significance and as a potential therapeutic target.
PMCID: PMC2360087  PMID: 17311025
Gefitinib; EGR1; array analysis; EGF-receptor; bladder tumours
12.  Gefitinib (‘Iressa’, ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2 
British Journal of Cancer  2004;90(8):1679-1685.
PMCID: PMC2409696  PMID: 15083203
gefitinib; epidermal growth factor receptor; bladder cell lines; MMPs; TIMPs
13.  Matrix metalloproteinase-1 is induced by epidermal growth factor in human bladder tumour cell lines and is detectable in urine of patients with bladder tumours. 
British Journal of Cancer  1998;78(2):215-220.
The matrix metalloproteinases are a family of enzymes that degrade the extracellular matrix and are considered to be important in tumour invasion and metastasis. The effect of epidermal growth factor (EGF) on matrix metalloproteinase-1 (MMP1) production in two human bladder tumour cell lines, RT112 and RT4, has been investigated. In the RT112 cell line, an increase in MMP1 mRNA levels was found after a 6-h incubation with EGF, and this further increased to 20-fold that of control levels at 24- and 48-h treatment with 50 ng ml(-1) of EGF. MMP2 mRNA levels remained constant over this time period, whereas in the RT4 cells no MMP2 transcripts were detectable, but MMP1 transcripts again increased with 24- and 48-h treatment with 50 ng ml(-1) of EGF. MMP1 protein concentration in the conditioned medium from both cell lines increased with 24- and 48-h treatment of the cells and the total MMP1 was higher in the medium than the cells, demonstrating that the bladder tumour cell lines synthesize and secrete MMP1 protein after continuous stimulation with EGF. MMP1 protein was detected in urine from patients with bladder tumours, with a significant increase in concentration with increased stage and grade of tumour. MMP1 urine concentrations may therefore be a useful prognostic indicator for bladder tumour progression.
PMCID: PMC2062898  PMID: 9683296
15.  Phorbol ester and bryostatin effects on growth and the expression of oestrogen responsive and TGF-beta 1 genes in breast tumour cells. 
British Journal of Cancer  1991;64(4):671-676.
The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) (10 nM) produce a marked reduction in the growth, measured by thymidine uptake, of MCF-7 cells in full growth medium, but had only a small effect on MDA-MB-231 and T47D cells. Bryostatin alone also inhibited growth but to a lesser extent than seen with TPA. The effect of TPA on MCF-7 cells was partially reversed by bryostatin, added simultaneously or after TPA, suggesting bryostatin does not simply mimic TPA in this system. Even though both are believed to act via effects on protein kinase C, bryostatin appears to act as antagonist to the effect of TPA as well as a partial agonist on its own. When the oestrogen receptor positive MCF-7 and T47D cells were maintained in charcoal stripped serum, the increase in DNA synthesis on stimulation with oestradiol was inhibited with 50 nM TPA in MCF-7 cells but not in T47D cells. The effects of these treatments on the expression of two well characterised oestrogen responsive genes pNR2(pS2) and pNR100 (Cathepsin-D) were examined. Rather than preventing transcription of these oestrogen responsive genes, TPA alone increased pNR2 and pNR100 levels in MCF-7 cells and the combined effect of oestradiol and TPA had a marked synergistic effect in increasing the transcript levels of these genes. In T47D cells pNR2 transcripts were not detected and the increase in pNR100 mRNA levels were not affected by TPA. We conclude that the inhibitory effects of TPA on the growth stimulation of MCF-7 cells by oestradiol was not due to a general inhibition of the expression of oestrogen responsive genes. An alternative possibility examined was that the growth inhibitory effect of TPA on MCF-7 cells might be due to stimulation of TGF-beta 1, acting as an autocrine inhibitory growth factor. Oestradiol treatment of MCF-7 cells reduced the levels of TGF-beta 1 mRNA whereas TPA produced a marked increase. The combined effect of TPA and oestradiol further increased TGF-beta 1 mRNA above the levels seen with TPA alone. Bryostatin had little effect on TGF-beta 1 expression either alone or in combination with oestradiol. These observations are consistent with the hypothesis that the inhibitory effect of TPA on MCF-7 cells may be partly due to autocrine inhibition by TGF-beta 1.
PMCID: PMC1977682  PMID: 1911215
16.  Influence of fluctuations of plasma large neutral amino acids with normal diets on the clinical response to levodopa. 
Plasma large neutral amino acids (LNAAs) compete with levodopa for entry into the brain. Fluctuations in plasma LNAA concentrations could therefore contribute to variability in clinical response to levodopa. The hourly plasma levodopa, plasma LNAAs and clinical response were investigated in 11 fluctuating Parkinsonian patients on a regular hospital diet. The fluctuations in plasma levodopa were 2 to 3 times greater than the fluctuations of plasma LNAAs. The correlation between clinical response and plasma levodopa was substantially improved in only one patient by considering plasma LNAAs and calculating relative levodopa flux into brain. Although plasma LNAAs significantly increased during the day, the patients' clinical status did not uniformly deteriorate and mean afternoon clinical scores correlated better with mean plasma levodopa and levodopa flux than with mean plasma LNAAs. Minimum effective concentrations of levodopa for clinical response did not correlate with 9 am LNAA concentrations. It is concluded that in most patients, the relatively small variation in plasma LNAAs in comparison with the large variations in plasma levodopa indicates that fluctuations in LNAA are not an important contributor to the fluctuating response to levodopa.
PMCID: PMC1032296  PMID: 2738591
17.  Ophthalmic Graves' disease in monozygotic twins 
Postgraduate Medical Journal  1976;52(607):285-287.
A pair of identical female twins with ophthalmic Graves' disease is described. Monozygosity was confirmed by analysis of blood groups and red cell isoenzymes. Thyroid status was assessed by standard tests (serum thyroxine (Thyopac-4), protein-bound iodine, Thyopac-3 and thyroid uptake of 131I). In addition, serum triiodothyronine and the response in thyroid stimulating hormone to thyrotrophin releasing hormone was measured. Circulating autoantibodies to thyroid tissue were detected in both sisters by complement fixation and immunofluorescence methods but long acting thyroid stimulator was not found.
PMCID: PMC2496513  PMID: 1085447
18.  Neonatal Hyperthyroidism and Long-acting Thyroid Stimulator Protector 
British Medical Journal  1974;4(5946):695-696.
Neonatal hyperthyroidism has been thought to result from transplacental passage of long-acting thyroid stimulator (L.A.T.S.) from a mother with Graves's disease. A case is presented here in which no L.A.T.S. was detected in the mother or neonate but another immunoglobulin, L.A.T.S. protector, a specific human thyroid stimulator, was shown to be present in the mother's serum. This stimulator may have been the cause of the neonatal hyperthyroidism.
PMCID: PMC1612809  PMID: 4479947

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