Serum and cerebrospinal fluid urate levels in synucleinopathies versus tauopathies.

BACKGROUND: Low levels of serum urate are associated with a higher risk of Parkinson's disease (PD). Higher serum and cerebrospinal fluid (CSF) urate levels are associated with slower rates of clinical decline in PD and in multiple system atrophy (MSA). AIMS: To compare CSF and blood urate levels in healthy controls, patients with synucleinopathies and with tauopathies. METHODS: We investigated urate levels in serum and CSF from 18 healthy controls, 19 patients with synucleinopathies (six patients with PD and 13 with MSA), and 24 patients with tauopathies (18 with progressive supranuclear palsy and six with corticobasal degeneration). None of the patients were treated with dopaminergic medications. RESULTS: No significant differences were seen when comparing serum and CSF urate levels from controls across the parkinsonian diagnostic groups. However, in men, serum urate levels were significantly lower in the synucleinopathy group compared with the tauopathy group (P = 0.046), although with a broad overlap. CONCLUSION: Our study suggests that urate levels might provide new insights into the potential pathophysiological mechanisms underlying Parkinsonism and thereby contribute to the future management of these disorders.

Anal sphincter electromyography in patients with newly diagnosed idiopathic parkinsonism.

OBJECTIVES: The differential diagnosis of patients with idiopathic parkinsonism is difficult, especially early in the course of the disease. External anal sphincter electromyography (EAS-EMG) has been reported to be of value in the differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA). Patients with MSA are reported to have pathological EAS-EMG and patients with PD are reported to have significantly less pathological EAS-EMG results. Comparisons between patients with parkinsonian disorders have usually been made many years into the disease, and thus it is largely unknown if the results of EAS-EMG can be used to distinguish the different diagnoses in the early phase of the disease. MATERIALS AND METHODS: We investigated 148 newly diagnosed patients with idiopathic parkinsonism from a population-based incidence cohort (100 definite PD, 21 probable PD, 16 MSA, 11 progressive supranuclear palsy, and 40 controls) with EAS-EMG within 3 months of their first visit and, in the majority of patients, before start of treatment with dopaminergic drugs. The clinical diagnoses were made using established clinical diagnostic criteria after a median follow-up of 3 years. RESULTS: All patient groups had more pathological EAS-EMG results than controls. No EAS-EMG differences were found between the patient groups, especially not between PD and MSA. CONCLUSIONS: External anal sphincter electromyography examination cannot separate the different parkinsonian subgroups from each other in early course of the diseases.

Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease.

BACKGROUND: This interim 12-month analysis is a part of an open-label, observational, prospective study on health outcomes and cost impact of levodopa/carbidopa intestinal gel (LCIG, Duodopa) in Parkinson disease (PD). The specific aim was to investigate clinical and health-related quality of life (HRQoL) effects in routine care. METHODS: Unified PD rating scale (UPDRS) was the primary efficacy measurement. PD QoL questionnaire 39 (PDQ-39) assessed HRQoL. Subjects were assessed at baseline, ≥3 months after surgery, and then every 3 months. RESULTS: Twenty-seven treatment-naïve subjects when started with LCIG showed a decrease in UPDRS score that was statistically significant throughout the year: UPDRS total score (mean ± SD), baseline = 52.1 ± 16.1, N = 27, month 0 (first visit; at least 3 months after permanent LCIG) = 43.1 ± 16.7, N = 27, P = 0.003; month 12 = 42.5 ± 22.6, n = 25, P = 0.017. PDQ-39 results also showed a tendency for improvement: PDQ-39 (mean ± SD), baseline = 33.6 ± 10.8, N = 27, month 0 = 27.1 ± 11.8, N = 27, P = 0.001; 12 months = 28.8 ± 12.8, n = 23, P = 0.126. CONCLUSIONS: LCIG provides functional improvement beginning at first visit that is sustained for 12 months.

A new automated implementation of the Posturo-Locomotion-Manual (PLM) method for movement analysis in patients with parkinson's disease.

OBJECTIVE: The Posturo-Locomotion-Manual (PLM) test, which uses an optoelectronic laboratory system, has here been further developed into an automated, more user-friendly, standardized tool for movement analysis named the QbTestMotus. This paper compares the accuracy of QbTestMotus to the PLM test, in particular the automated data analysis. METHODS: Both QbTestMotus and the PLM recorded data simultaneously from the same 61 patients. The correlation coefficients of movement time (MT), postural time (P), locomotion time (L), and manual time (M) were calculated between the systems. The absolute differences between the result parameters for each patient were also studied. Finally, the differences in MT between the systems were compared with the positive responses in the levodopa (L-dopa) challenges as measured in the PLM test for 11 patients. RESULTS: The comparisons in all the 61 patients showed high correlation coefficients for all four parameters. The absolute differences between the parameters were small and had small standard deviations, and the decreases in MT because of L-dopa in the positive L-dopa responders were much larger than the absolute difference between the systems. CONCLUSION: The PLM test and QbTestMotus are equivalent along all parameters, thus indicating that the test quality is equivalent between the PLM test and the automated QbTestMotus system.

Light subunit of neurofilament triplet protein in the cerebrospinal fluid after subthalamic nucleus stimulation for Parkinson's disease.

OBJECTIVES: Cerebrospinal fluid (CSF) levels of neurofilament triplet protein (NFL), a non-specific marker of neuronal damage, are normal in Parkinson's disease (PD) but increased after brain trauma and in several neurological disorders. Using longitudinal CSF-NFL measurements as an indicator of neuronal damage, this study investigated the impact of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on the brain, directly following the surgical intervention and in chronically treated patients with PD. MATERIALS AND METHODS: CSF-NFL levels were measured consecutively in eight patients with PD before and after STN-DBS treatment. RESULTS: CSF-NFL levels were normal prior to STN-DBS and increased sharply during the first 2 weeks post-operatively, but normalized after 12 months or more. CONCLUSION: The STN-DBS procedure leads to an acute but limited neuronal damage, as expected. However, normal CSF-NFL levels at 12 months post-operatively and beyond suggest the absence of any long-term neuronal damage caused by long-term STN-DBS stimulation.

Autonomic innervation in multiple system atrophy and pure autonomic failure.

BACKGROUND: Pure autonomic failure (PAF) and multiple system atrophy (MSA) are both characterised by chronic dysautonomia although presenting different disability and prognosis. Skin autonomic function evaluation by indirect tests has revealed conflicting results in these disorders. Here, the authors report the first direct analysis of skin sympathetic fibres including structure and function in PAF and MSA to ascertain different underlying autonomic lesion sites which may help differentiate between the two conditions. METHODS: The authors studied eight patients with probable MSA (mean age 60±5 years) and nine patients fulfilling diagnostic criteria for PAF (64±8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability. RESULTS: MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with a long disease duration, morphological abnormalities and/or a slightly decreased autonomic score could be found in the leg reflecting a mild postganglionic involvement. CONCLUSION: Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.

Short-term effects of repetitive transcranial magnetic stimulation on speech and voice in individuals with Parkinson's disease.

The main characteristics of dysarthria in Parkinson's disease (PD) are monotony of pitch and loudness, reduced stress, variable speech rate, imprecise consonants, and breathy and harsh voice. Earlier treatment studies have shown that dysarthria is less responsive to both pharmacological and surgical treatments than other gross motor symptoms. Recent findings have suggested that repetitive transcranial magnetic stimulation (rTMS) may have a beneficial effect on vocal function in PD. In the present study, 10 individuals with mild PD and no or minimal dysarthria were treated with rTMS as well as placebo stimulation in a blinded experiment. Stimulation was delivered using a frequency of 10 Hz and a stimulation intensity of 90% of the motor threshold. The site of stimulation was the cortical area corresponding to the hand, on the hemisphere contralateral to the patient's most affected side. The participants were audio-recorded before and after both rTMS and sham stimulation. Acoustic analysis was performed on 3 sustained /a:/ for each of the 4 conditions, and analyzed both for the whole group as well as for men and women separately. Results showed that there were no significant differences between any of the conditions regarding duration of sustained fricative or sustained vowel phonation, diadochokinetic rates or intelligibility. Above all, the results of acoustic analyses showed an effect of placebo; there was a significant reduction in fundamental frequency (F(0)) variation, pitch period perturbation, amplitude period perturbation, noise-to-harmonics ratio and coefficient of variation in F(0) between the recordings performed before compared to after sham stimulation.

Cytochrome P450 2E1 gene polymorphisms/haplotypes and Parkinson's disease in a Swedish population.

Cytochrome P450 2E1 (CYP2E1), which inter alia is located in dopamine containing neurons in the substantia nigra, has been hypothesized to be of importance for the pathophysiology of Parkinson's disease (PD), either by its production of reactive oxygen species (ROS) or by its capability to detoxify putative neurotoxins. Numerous polymorphisms in the coding and non-coding regions of the gene for this enzyme have been reported. Different variants may account for inter-individual differences in the activity of the enzyme or production of ROS. In this study, the CYP2E1 gene was examined in a control population (n = 272) and a population with PD (n = 347), using a tag-single nucleotide polymorphism (tSNP) approach founded on HapMap Data. Six tSNPs were used in the analysis and haplotype block data were obtained. In case of significance, the SNP was further examined regarding early/late age of disease onset and presence of relatives with PD. We found an association between allele and genotype frequencies of the C/G polymorphism at intron 7 (rs2070676) of this gene and PD (P value of 0.026 and 0.027, respectively). Furthermore, analysis of the rs2070676 polymorphism in subgroups of patients with age of disease onset higher than 50 years and those not having a relative with PD also demonstrated a significant difference with controls. This was seen in both genotype (corresponding to P value = 0.039 and 0.032) and allele (P = 0.027 and 0.017 respectively) frequency. As a representative of many polymorphisms or in possible linkage disequilibrium with other functional variants, it is possible that rs2070676 could influence the regulation of the enzyme. In conclusion, our results display an association between the rs2070676 polymorphism and PD. Additional investigations are needed to elucidate the importance of this polymorphism for the activity of CYP2E1 and PD susceptibility.

Comparison of apomorphine and levodopa infusions in four patients with Parkinson's disease with symptom fluctuations.

BACKGROUND: Motor fluctuations in patients with advanced Parkinson's disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed. AIMS OF THE STUDY: We present a subanalysis from a randomized crossover clinical trial where levodopa infusion as monotherapy was compared with any other combination of pharmacotherapy in fluctuating patients. Four patients used apomorphine infusion and oral levodopa in the comparator arm. The results of these four patients are presented in detail. METHODS: The duration of the trial was 3 + 3 weeks. Patients were video-recorded half-hourly on two non-consecutive days of both treatment arms. Blinded video ratings were used. Patient self-assessments of motor function and quality-of-life (QoL) parameters were captured using an electronic diary. RESULTS: Ratings in moderate to severe "off" state ranged 0-44% on apomorphine infusion and 0-6% on levodopa infusion. Moderate to severe dyskinesias were not recorded in any of the treatments. QoL was reported to be improved in all patients on duodenal levodopa infusion. CONCLUSIONS: Monotherapy with duodenal infusion of levodopa was more efficacious and brought greater QoL than combination therapy with apomorphine infusion in these fluctuating patients.

Minimized weight gain between hemodialysis contributes to a reduced risk of death.

UNLABELLED: The risk of death is higher in dialysis patients compared to age matched healthy subjects, the main reason being cardiovascular. This prospective study investigated if the extent of ultrafiltration was of importance for the outcome. MATERIAL AND METHODS: 88 hemodialysis patients were included and followed prospectively. The outcome was registered in regard to death, acute myocardial infarction or coronary vascular intervention. The extent of ultrafiltration needed at dialysis was calculated as a mean during the observation period as were other variables. The mean extent of ultrafiltration was compared for patients who had survived without end-points (group 1, n=53) versus those who reached any end-point during the period (group 2, n=35). RESULTS: In total, 40% of the patients reached end-point during the observation period. There was no difference at baseline between the groups in regard to age, prevalence of diabetes mellitus or history of previous cardiovascular disease, KT/V, residual renal function ultrafiltration need, C-reactive protein, s-albumin, cholesterol, LDL-cholesterol, HDL-cholesterol, appetite or wellbeing, while triglyceride was lower in group 2 (p=0.035). The observation period for group 1 was at a mean 24.7 months (SD13.1) and for those in group 2 at a mean 13.8 (+/-11.7 months, p<0.001). Patients representing group 1 at 24 and 30 months had less need of ultrafiltration than those in group 2. Thus, the need of ultrafiltration was about 27% lower at 24 months (for 29 persons in group 1: 3.63+/-1.93 weight% versus 4.97+/-1.70 weight% for 9 patients from group 2, p=0.046) and 46% at 30 months (for 18 from group 1: 3.48+/-1.95 versus 6.45+/-1.55 for 3 from group 2, p=0.030). C-reactive protein did not differ significantly between the groups during the period. CONCLUSION: After a prolonged period of 24 months the extent of ultrafiltration need seems to be important for the outcome of the patients. Thereby those with higher need of ultrafiltration had worse prognosis. It seems important to motivate patients to reduce the extent of fluid intake between dialysis to prolong survival.

Inadvertent malposition of a transvenous pacing lead in the left ventricle.

We report the case of inadvertent malpositioning of a pacemaker lead in the left ventricle. The lead went through an open foramen ovale from the right to the left atrium and through the mitral valve into the left ventricle. After a review of the literature, we decided to anticoagulate the patient and leave the electrode in place. During a follow-up period of 16 months, there were no clinical complications.

Induction of single-strand breaks in DNA of mice after inhalation of vinyl chloride.

Female mice were exposed to 500 ppm vinyl chloride (VC) for 6 h/day 5 days/week for 1-8 weeks. Groups of mice were killed at different times during this period. DNA damage, expressed as single-strand breaks (SSB), was studied in liver, kidneys, lungs, spleen and brain. The level of SSB increased in liver, kidneys, spleen and lungs with time of exposure and reached a plateau for kidneys and lungs after 80 and 120 h of exposure. In spleen there was only a slight increase in the SSB, and in brain no detectable increase was found.

Three industrial solvents investigated for tumor promoting activity in the rat liver.

Dioxane, perchloroethylene, and trichloroethylene were investigated as rat liver altered foci promoters in an initiation/promotion protocol. Animals were initiated with diethylnitrosamine, 30 mg/kg, injected i.p. 24 h after 2/3 partial hepatectomy. The chemical under study was administered by gavage once a day, 5 times a week for 7 weeks. Ten days after the last administration the animals were killed. Liver sections were stained for gamma-glutamyl-transpeptidase (GGT) and the number and total volume of GGT-positive foci was studied. Dioxane (1000 mg/kg) significantly increased the number and total volume of foci while a marginal effect was noted for the high dose of trichloroethylene (1100 mg/kg). A high dose of perchloroethylene (1100 mg/kg) had no effect.

Mammary tumours in Sprague-Dawley rats after initiation with DMBA followed by exposure to 50 Hz electromagnetic fields in a promotional scheme.

In order to test whether a transient-producing intermittent magnetic field (MF) acts as a promoter in rat mammary tumour development, a study of a 50 Hz sinusoidal MF with flux densities of 0.25 and 0.5 mT was performed on female Sprague-Dawley rats. A single administration of 7 mg of 7,12-dimethyl-benz[a]anthracene (DMBA) was given by gavage to 52-day-old animals. After 1 week, exposure to an intermittent (15 s on/15 s off) transient-associated magnetic field was started. MF exposure was performed for 19 or 21 h per day up to 25 weeks, when the study was terminated. Twice a week a careful examination with palpation for tumours was done. Tumour incidence, the number of tumours per animal, tumour volume and tumour weight were recorded. A total of 70% of MF-exposed animals developed tumours. For animals exposed to DMBA alone the correspondent figure was 71.7%. No statistical differences were seen either for tumour-bearing animals or for the total number of tumours. A slightly larger total tumour weight and tumour volume was seen for animals exposed to 0.25 mT MF. These differences were not statistically significant.

Endocrine responses of ovariectomized ewes to i.c.v. infusion of urocortin.

Urocortin is a novel corticotropin-releasing factor-like peptide, first isolated from the rat midbrain, which has anorexigenic properties, possibly associated with its involvement in the stress axis. Urocortin has been implicated in blood pressure regulation, ACTH release and feed intake, but its role as an integral component of the reproduction-nutrition axis has not been examined. The present experiment was designed to determine the effects of i.c.v. infusion of urocortin on feed intake and endocrine profiles of LH, GH, IGF-I, cortisol and leptin in ovariectomized ewes. Ewes were fitted with two laterocerebroventricular cannulae and urocortin was continuously infused in a linearly increasing manner from 0.001 microg/h on day 0, to a maximum of 31.6 microg/h on day 5. Blood samples were collected via jugular catheters at 10 min intervals for 4 h on day 1, 3 and 5, and assayed by RIA for LH, GH, IGF-I, cortisol and leptin. All ewes were allowed free access to feed and water, and feed intake was recorded daily. Urocortin-infused ewes responded with a significant decrease in feed intake beginning on day 1 (P<0.02) and were aphagic for the remainder of the experiment. Serum concentrations of LH were elevated in individual samples from urocortin-treated compared with saline-treated ewes on day 3 (treatment x day x sample, P=0.05), but were not different on day 1 or 5. Mean serum concentrations of GH increased (P<0.04) over days with urocortin treatment, although concentrations of IGF-I were not influenced by treatment (P>0.5). Serum concentrations of cortisol were markedly increased by urocortin treatment (P<0.001). Leptin tended to be influenced by treatment and day (P=0.08), with leptin levels tending to be elevated in urocortin-treated vs saline-treated ewes on day 5 (P=0.08). The ability of urocortin to decrease feed intake while increasing LH, GH, cortisol and leptin provides evidence that urocortin is not only an integral component of the stress axis, but possibly of the nutrition-reproduction axis in sheep.

Central infusion of leptin into well-fed and undernourished ewe lambs: effects on feed intake and serum concentrations of growth hormone and luteinizing hormone.

Leptin has been implicated in the regulation of feed intake, growth, and reproduction. The objective of this study was to determine if centrally administered leptin would affect feed intake and the secretion of growth hormone (GH) and luteinizing hormone (LH) in ewe lambs. Eighteen ewe lambs were ovariectomized and fitted with intracerebroventricular (i.c.v.) cannulae. Lambs were randomly assigned to receive either a maintenance diet (fed), or a diet that provided 38% of maintenance requirements (diet-restricted) for 14 weeks. Subsequently, recombinant ovine leptin or vehicle was continuously infused, via i.c.v. cannulae, in a linearly increasing dose for 8 days, reaching a maximum of 1.25 microg/kg per h. Feed intake was recorded on days -1 to 7. Blood was collected via jugular cannulae every 10 min for 4 h on days 0, 2, 4, 6 and 8 for the determination of serum leptin, insulin, LH and GH. Leptin suppressed feed intake in fed lambs on days 4 to 7 (P<0.001), but had no effect on feed intake in diet-restricted lambs (P>0.25). Fed lambs had greater serum concentrations of leptin than diet-restricted lambs (P=0.007). Also, although not different on day 0 (pretreatment), on day 8 serum leptin concentrations were greater in leptin-treated lambs than in saline-treated lambs (P=0.003). Insulin was lower in diet-restricted than in fed lambs (P=0.003), but was not affected by leptin treatment (P=0.82). LH pulse frequencies were lower in diet-restricted lambs than in fed lambs (P=0.038), but were not affected by leptin treatment (P=0.85). Mean serum GH was greater in diet-restricted than in fed lambs (P<0.01). In diet-restricted lambs treated with leptin or saline, mean GH did not differ on day 0, but increased in response to leptin treatment (P<0.006). Treatment of fed lambs with leptin did not affect serum GH (P>0.32). From this work, we propose that leptin represents an important functional link between adipose stores and hypothalamic function in ruminants. We demonstrate that leptin concentrations change in response to reduced nutritional status, and that leptin has the ability to regulate multiple physiological processes in lambs, including both feed intake and secretion of GH.

Magnetic fields and cancer: animal and cellular evidence--an overview.

A few animal studies on the possible carcinogenic effect of magnetic fields have been published. They have been designed to reveal a possible tumor promotion obtained by applying continuous or pulsed alternating fields at flux densities varying between 0.5 microT and 30 mT on mice or rats initiated with different initiators. One study with 2 mT applied on DMBA-initiated mice may suggest a copromotive effect together with the promoter TPA. Another study on rats suggests an inhibitory effect by a magnetic field on rat liver foci formation, induced with DENA. Cell studies show that magnetic fields at some frequencies, amplitudes, and wave forms interact with biological systems. Thus effects have been seen, e.g., on enzymes related to growth regulation, on calcium balance in the cell, on gene expression, and on pineal metabolism and its excretion of the oncostatic melatonin. Cellular and physiologic studies thus suggest effects that may be related to cell multiplication and tumor promotion.

Extrapolation of carcinogenic risk from animal experiments in man.

When estimating the absolute risk of cancer, the shape of the dose--response curve in the region of doses where actual exposure of man occurs is of crucial importance. This shape is equally important for the determination of relative risks, as in the comparison of risks from alternative energy sources. Experimental and epidemiological studies are, for various reasons, unable to give sufficiently exact information concerning the dose response in the low dose region. Therefore, the discussion concerning dose--response relationships also has to consider biologically reasonable mechanisms for the origin of tumors.

Recent achievements and research initiated in the Swedish plastics and rubber industry.

The improvement in exposure conditions in the Swedish vinyl chloride producing industry is reported. The article comments on the technology and control methods by which the vinyl chloride concentration has been lowered to less than 1 ppm vinyl chloride. Two epidemiological retrospective cohort studies are presently under way on workers in PVC-utilizing industries and in the rubber industry.