Does high-dose coenzyme Q10 improve oxidative damage and clinical outcomes in Parkinson's disease?

Evidence on the efficacy of high-dose coenzyme Q10 (CoQ10) in Parkinson's disease (PD) is conflicting. An open-label dose-escalation study was performed to examine the effects of CoQ10 on biomarkers of oxidative damage and clinical outcomes in 16 subjects with early idiopathic PD. Each dose (400, 800, 1200, and 2400 mg/day) was consumed daily for 2 weeks. High-dose CoQ10 was well tolerated and improvements in the total Unified Parkinson's Disease Rating Scale (median, 37 vs. 27; p=0.048) were observed following study completion. Plasma F2-isoprostanes (adjusted for arachidonate) were significantly reduced in the 400-1200 mg/day dose range, but increased at 2400 mg/day dosage. A similar pattern of change was observed with serum phospholipase A2 activities. Levels of plasma all trans-retinol, plasma total tocopherol, serum uric acid, and serum total cholesterol were unchanged despite an increase in the CoQ10 dosage. Subjects with symptomatic benefits from CoQ10 (decrease in total UPDRS >10 points) had lower baseline plasma ubiquinol (p=0.07, Mann-Whitney U test) and decreased F2-isoprostanes per unit arachidonate (p=0.04, Wilcoxon Signed-Ranks test). These results lead to the hypothesis that the therapeutic response to CoQ10 depends on baseline levels of ubiquinol and whether the dosage of CoQ10 used can ameliorate the burden of oxidative damage.

Stimulated skin wrinkling for predicting intraepidermal nerve fibre density.

OBJECTIVE: To determine the usefulness of stimulated skin wrinkling using EMLA and water immersion in detecting abnormal intraepidermal nerve fibre density. METHODS: In a prospective study of patients with predominantly sensory polyneuropathy, we tested sensitivity and specificity of stimulated skin wrinkling using EMLA and water immersion in detecting abnormal intraepidermal nerve fibre density (IENFD). RESULTS: EMLA stimulated wrinkling showed a sensitivity of 81.6% and specificity of 74.7% in detecting abnormal IENFD and water wrinkling a sensitivity of 71.4% and specificity of 73%. The positive and negative predictive values for detecting abnormal IENFD were 88.3% and 63.3% for EMLA wrinkling, for water wrinkling 83.3% and 57.4%. Intra-observer EMLA score variability was good with no change in assignment of wrinkling and inter-observer score variability resulted in 1-5 changes in wrinkling score which translated into a change of the wrinkling status from normal to abnormal on two occasions. CONCLUSIONS: Stimulated skin wrinkling correlates well with abnormal intraepidermal nerve fibre density. SIGNIFICANCE: Our study suggests that EMLA induced stimulated skin wrinkling is a useful alternative parameter for predicting abnormal intraepidermal nerve fibre density.

Relationship between circulating vascular endothelial growth factor and its soluble receptors in adults with dengue virus infection: a case-control study.

BACKGROUND: We performed a case-control study to assess the relationship between vascular endothelial growth factor (VEGF) and its soluble receptors (sVEGFR-1 and 2) in adult patients with dengue fever (DF) and dengue hemorrhagic fever (DHF). METHODS: We recruited 60 adult patients (34 DF and 26 DHF) with serologically-confirmed dengue infections, 10 patients with non-hemorrhagic infections, and 31 community-based healthy volunteers. The levels of VEGF, sVEGFR-1, and sVEGFR-2 were measured and the differences in these markers were compared using one-way analysis of variance (ANOVA), which was adjusted for multiple comparisons. RESULTS: We observed lower VEGF levels in DF and DHF compared to study controls (p<0.01). sVEGFR-1 was higher in DHF than DF, whilst sVEGFR-2 was lower in DF and DHF compared to study controls (all p<0.01). In DHF, lower VEGF levels were observed in older patients. The use of a single marker, sVEGFR-1>350 pg/ml, was predictive of DHF. CONCLUSION: The changes in VEGF and its soluble receptors highlight the importance of vascular permeability cytokines in the pathogenesis of DHF.

Comparison of a simple method for quantitation of intraepidermal nerve fibres with a standard image analysis method using hypothenar skin.

OBJECTIVES: To compare a simpler method for counting intraepidermal nerve fibres with a standard computer based image analysis method in normal subjects with skin taken from the hypothenar region. METHODS: In 40 healthy controls (mean age 41.1 years, range 21-71, 24 Chinese, 11 Indian, 5 Malay, 30 females) intraepidermal nerve fibres per length of epidermis were determined using immunoperoxidase staining with the panaxonal antibody PGP 9.5. Under brightfield microscopy, two methods of determining the length of the epidermis were compared. A simpler method employing a microscope intraocular lens ruler was compared with the more complex gold standard using image software analysis . RESULTS: Intraepidermal nerve fibres per length of epidermis using the intraocular ruler method were 3.07 nerve fibres/mm (2SD 1.56). The image software analysis obtained values of 3.05 nerve fibres/mm (2SD 1.54). Correlation between the two tests was excellent (r=0.999 p= or <0.00001). Epidermal nerve fibre counts from hypothenar skin are lower than in more proximal sites. CONCLUSION: A simple method for counting intraepidermal nerve fibres produces results similar to those using standard software image analysis. This should help the implementation of this technique for wider use.

Where has all the botox gone? (how) will we ever learn... using monoclonal antibodies to track botulinum toxin.

Botulinum toxin (BTX) is an important therapeutic tool in the treatment of overactive skeletal and smooth muscles, as well as hypersecretory and painful disorders. Despite advances in our understanding of how BTX works, much remains to be elucidated, such as how BTX ameliorates pain, how it produces weakness remote from the site of injection and the fate of the heavy and light chain components of the BTX molecule following endocytosis into the presynaptic membrane. BTX, conjugated to radionuclides, allows investigators to track the molecule both in vitro and in vivo. However, altering the BTX molecule may cause structural changes or pharmacokinetic and pharmacodynamic alterations, and disrupt its normal action. We propose instead to bind the biomarkers (appropriate dyes, radionuclides or MRI contrast agents) to monoclonal antibodies directed against either heavy or light chain components of BTX, thus allowing administration of native (i.e. unaltered) BTX.

Topical botulinum toxin to treat hyperhidrosis? No sweat!

Palmar, plantar and axillary hyperhidrosis, though benign, may be burdensome and occupationally restrictive, even hazardous. Treatment modalities range from topical antiperspirants, iontophoresis, systemic medications such as anticholinergics and benzodiazepines and injections of botulinum toxin, to thoracic sympathectomy. Intradermal injections of botulinum toxin (BTX), though effective, are painful especially when multiple injections are required. Iontophoretic administration of BTX has been described, the BTX entering the eccrine sweat glands via the sweat pores and through the sweat ducts. We postulate that BTX can be administered topically, either unassisted or assisted by application of an electrical gradient, low-frequency ultrasound or excipients such as dimethylsulfoxide. We examine the rationale and feasibility for such a treatment modality and route of administration.

Vasomotor dysfunction in carpal tunnel syndrome.

Little attention has been paid to small-fiber dysfunction in carpal tunnel syndrome (CTS) although its symptoms are common. This study investigates vasomotor dysfunction, which is controlled by small nerve fibers, in patients with CTS compared with control subjects. Vasomotor function was quantified by measuring, with laser Doppler velocimetry, skin vasoconstriction induced by a eutectic mixture of local anesthetic (EMLA) cream over digit tips 3, 4, and 5. Hands with CTS (n = 32) compared with controls (n = 19) demonstrated significantly reduced vasoconstriction in digits 3 and 4, but not digit 5. A blood flow ratio (digit 3/5) of less than 0.73 identified CTS in 69% with 68% specificity. Testing for vasomotor dysfunction in CTS allows for more comprehensive neurophysiological testing, which is heavily biased towards large nerve fibers.

Water immersion and EMLA cause similar digit skin wrinkling and vasoconstriction.

Water immersion skin wrinkling tests limb sympathetic vasoconstrictor function. We have recently shown that water immersion wrinkling is accompanied by digit vasoconstriction and postulated that vasoconstriction is the main underlying mechanism. To test this further, we applied vasoconstrictive cream (EMLA) to the distal digit and compared the degree of skin wrinkling and digit blood flow reduction with those after water immersion. In 25 healthy volunteers (6 male, 19 female; mean age, 35 yr) subjected to EMLA and water immersion, both clinical wrinkling scores and reduction in digit blood flow (mean of 2.01 and 2.29 cm/s, respectively) were nearly identical. Control using aqueous cream resulted in minimal skin wrinkling and nonsignificant reduction in digit artery flow (P = 0.170). These data further support that water immersion skin wrinkling is mediated by vasoconstriction. The EMLA cream patch test may develop into a useful screening test for hand sympathetic vasoconstrictor function.

Water-immersion wrinkling is due to vasoconstriction.

The underlying mechanism of the water-immersion skin wrinkling test, which is used as a test of sympathetic nerve function, remains elusive. We investigated changes of blood circulation in the hand occurring with water-immersion wrinkling by measuring the velocity of ulnar and digital artery blood flow, and of digit skin blood flow, in healthy subjects before and during wrinkling. Wrinkling was accompanied by significant reduction in blood flow velocity in all vessels, with a maximum in digital vessels. Our data show that water-immersion wrinkling is a function of digit pulp vasoconstriction. This test of sympathetic function can now be quantified using parameters of blood flow velocity, enabling its more widespread and accurate use.