Role of dopamine agonists in Parkinson's disease therapy.

Dopamine agonists are an important component of Parkinson's therapy. When weighing up the various therapy options, therapy with levodopa has recently been increasingly preferred due to its stronger efficacy and the ostensibly lower rate of side effects. The advantage of the lower incidence of motor complications during therapy with dopamine agonists was neglected. The occurrence of side effects can be explained by the different receptor affinity to the individual dopaminergic and non-dopaminergic receptors of the individual dopamine agonists. However, the different affinity to individual receptors also explains the different effect on individual Parkinson symptoms and can, therefore, contribute to a targeted use of the different dopamine agonists. Since comparative studies on the differential effect of dopamine agonists have only been conducted for individual substances, empirical knowledge of the differential effect is of great importance. Therefore, the guidelines for the treatment of Parkinson's disease do not consider the differential effect of the dopamine agonists. The historical consideration of dopamine agonists within Parkinson's therapy deserves special attention to be able to classify the current discussion about the significance of dopamine agonists.

In-situ measurement of pyrolysis and combustion gases from biomass burning using swept wavelength external cavity quantum cascade lasers.

Broadband high-speed absorption spectroscopy using swept-wavelength external cavity quantum cascade lasers (ECQCLs) is applied to measure multiple pyrolysis and combustion gases in biomass burning experiments. Two broadly-tunable swept-ECQCL systems were used, with the first tuned over a range of 2089-2262 cm-1 (4.42-4.79 µm) to measure spectra of CO2, H2O, and CO. The second was tuned over a range of 920-1150 cm-1 (8.70-10.9 µm) to measure spectra of ammonia (NH3), ethene (C2H4), and methanol (MeOH). Absorption spectra were measured continuously at a 100 Hz rate throughout the burn process, including inhomogeneous flame regions, and analyzed to determine time-resolved gas concentrations and temperature. The results provide in-situ, dynamic information regarding gas-phase species as they are generated, close to the biomass fuel source.

[Deep brain stimulation using simultaneous stereotactic electrode placement: an alternative to conventional functional stereotaxy?]. / Tiefe Hirnstimulation mittels simultaner stereotaktischer Elektrodenplatzierung : Eine Alternative zur konventionellen funktionellen Stereotaxie?

BACKGROUND: Deep brain stimulation (DBS) has become a reliable method in the treatment of movement disorders, e.g. idiopathic Parkinson's disease (IPD) and is technically based on stereotaxy. The Starfix® platform is a new type of stereotactic frame that allows an individualized and patient-optimized therapeutic regimen in IPD. OBJECTIVES: The aim of this study was to retrospectively compare the outcomes of IPD patients who underwent surgery with the use of conventional stereotactic frames (31 patients) to those who underwent implantation of DBS with the use of Starfix® frames (29 patients). MATERIAL AND METHODS: Surgery time, the unified Parkinson's disease rating scale III (UPDRS/III) score, L-dopa and L-dopa equivalent doses (LED) were compared prior to surgery as well as 4 weeks, 12 weeks, 6 months and 1 year postoperatively. RESULTS: The IPD-related symptoms improved significantly in both groups with respect to the UPDRS III score (conventional 69.6% vs. 72.4% Starfix®). After surgery significant reductions of L-dopa and LED were seen in both groups. Inherent advantages of the Starfix® platform included simultaneous positioning of the stimulating electrodes and a significant reduction in surgical time. CONCLUSION: In summary, both stereotactic procedures are reliable and safe procedures for the placement of stimulating electrodes as well as the stimulation effect achieved. The logistical uncoupling of presurgical planning from surgical therapy emphasizes the benefits of the individualized stereotactic procedure.

FTO and INSIG2 Genotyping Combined with Metabolic and Anthropometric Phenotyping of Morbidly Obese Patients.

Obesity is a major health problem worldwide. Associations of obesity with common variants of the fat mass- and obesity-associated gene (FTO) and insulin-induced gene 2 (INSIG2) have been reported in various studies. We aimed to further investigate the association of 2 single nucleotide polymorphisms (SNPs), rs9939609 in FTO and rs7566605 in INSIG2, with body mass index (BMI) and other anthropometric and metabolic parameters in subjects with morbid obesity (BMI ≥40). SNPs rs9939609 and rs7566605 were genotyped in 124 unrelated morbidly obese patients (mean BMI = 50, range 40.1-77.1) from Mainz, Germany, and in 253 normal controls without a history of morbid obesity. Metabolic and anthropometric parameters were analyzed in 109 of the 124 patients, and associations with the genotype data were examined. The high-risk AA genotype for FTO rs9939609 was observed in 32.3% of patients versus 15.8% of controls (p = 0.0004) and was associated with an increased obesity risk [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.53-4.21]. The intermediate-risk AT genotype was found in patients and controls at similar frequencies (48.4 vs. 48.6%, OR = 0.99). The low-risk TT genotype for rs9939609 was found in 19.4% of patients (35.5% of controls; p = 0.0013) and was associated with a decreased risk for morbid obesity (OR = 0.43, CI = 0.26-0.73). In contrast, INSIG2 rs7566605 showed no association with obesity in our patients. Evaluation of metabolic data indicated associations between the high-risk FTO genotype (rs9939609_AA) and increased levels of serum glutamic oxaloacetic transaminase (GOT) and between the high-risk INSIG2 genotype (rs7566605_CC) and lower waist-to-hip ratio and lower hemoglobin A1c (HbA1c) levels. Our results confirm an association of the FTO SNP with extreme obesity. However, we found no association of the potential obesity risk allele of INSIG2 in our sample and thus cannot confirm an association of the INSIG2 CC genotype with obesity. We identified an association between the high-risk FTO genotype (rs9939609_AA) and higher GOT levels, which could possibly reflect the increased frequency of nonalcoholic steatohepatitis with obesity. We also detected associations of the high-risk INSIG2 genotype (rs7566605_CC) with lower waist-to-hip ratios and lower HbA1c levels, which may indicate amelioration of impaired glucose tolerance and type 2 diabetes for patients with this genotype after bariatric surgery.

A new temporal window for inducing depressant associative plasticity in human primary motor cortex.

OBJECTIVE: Spike-timing dependent plasticity (STDP) usually refers to synaptic plasticity induced by near-synchronous activation of neuronal input and neuronal firing. However, some models of STDP predict effects that deviate from this tight temporal synchrony. We aimed to characterise the induction of STDP using paired associative stimulation (PAS) when the pre-synaptic input arrives in primary motor cortex (M1) at (i) intermediate intervals (50-80 ms; PAS(50),..PAS(80)) before the post-synaptic neuron is activated and (ii) long intervals (100-450 ms; PAS(-100),..PAS(-450)) after the post-synaptic neuron is activated. PAS at near-synchronicity (PAS(25)) was applied for comparison. METHODS: To characterise the physiological effects of the different PAS protocols, we examined short- and long-interval intra-cortical inhibition; intra-cortical facilitation and short- and long-latency afferent inhibition, in addition to recording MEPs in 45 healthy individuals. RESULTS: MEP amplitude was reduced at PAS intervals between -250 and -450 ms, increased with PAS(25), and unaltered at the remaining intervals. There was no change in intra-cortical inhibitory or facilitatory circuits following any PAS protocol. CONCLUSIONS: These findings provide evidence of a previously unreported temporal window in which PAS induces a depression of corticospinal excitability in human M1. SIGNIFICANCE: Establishing new temporal rules for STDP broadens its applicability for therapeutic usage in future.

Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. The phenotypic features of patients with clinically significant CNV were compared with those without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.

Focal hand dystonia: lack of evidence for abnormality of motor representation at rest.

OBJECTIVE: To examine whether the corticospinal system emanating from the primary motor cortex may be organized to facilitate generation of dystonic movements. METHODS: In this cross-sectional observational study, finger movement (FM) representations were assessed in 10 patients with focal hand dystonia (FHD) and 10 matched healthy controls by transcranial magnetic stimulation during rest. Evoked finger movements of the right hand were recorded using an instrumented data glove. Patterns of finger joint movements were analyzed using cluster analysis. Principal component analysis and centers of gravity for finger movement representations and motor evoked potentials recorded from the abductor pollicis brevis and abductor digiti minimi muscles were computed. For comparison, high-resolution somatosensory evoked potentials (SSEP) were recorded after electrical stimulation of the thumb (D1) or little finger (D5) in the same patients. Source reconstruction for the N20 SSEP component was performed using a dual-dipole model. RESULTS: Stimulation of the resting motor cortex did not reveal overt abnormalities in FHD, neither with respect to finger joint movement patterns nor with respect to the topologic organization of finger movements or intrinsic hand muscle representations. However, in line with previous reports, the distance between the dipole sources of D1 and D5 in the somatosensory cortex (S1) was smaller in patients with FHD, suggesting disruption of homuncular finger representations in S1. CONCLUSIONS: Our findings may imply that abnormality of motor organization in focal hand dystonia arises principally only during activation, when abnormal somatosensory representations are functionally integrated.

Halogen production from aqueous tropospheric particles.

Box model studies have been performed to study the role of aqueous phase chemistry with regard to halogen activation for marine and urban clouds and the marine aerosol as well. Different chemical pathways leading to halogen activation in diluted cloud droplets and highly concentrated sea salt aerosol particles are investigated. The concentration of halides in cloud droplets is significantly smaller than in sea-salt particles, and hence different reaction sequences control the overall chemical conversions. In diluted droplets radical chemistry involving OH, NO(3), Cl/Cl(2)(-)/ClOH(-), and Br/Br(2)(-)/BrOH(-) gains in importance and pH independent pathways lead to the release of halogens from the particle phase whereas the chemistry in aerosol particles with high electrolyte concentrations is controlled by non-radical reactions at high ionic strengths and relatively low pH values. For the simulation of halogen activation in tropospheric clouds and aqueous aerosol particles in different environments a halogen module was developed including both gas and aqueous phase processes of halogen containing species. This module is coupled to a base mechanism consisting of RACM (Regional Atmospheric Chemistry Mechanism) and the Chemical Aqueous Phase Radical Mechanism CAPRAM 2.4 (MODAC-mechanism). Phase exchange is described by the resistance model by Chemistry of Multiphase Atmospheric Systems, NATO ASI Series, 1986. It can be shown that under cloud conditions the bromine atom is mainly produced by OH initiated reactions, i.e. its concentration maximum is reached at noon. In contrast, the concentration level of chlorine atoms is linked to NO(3) radical chemistry leading to a smaller amplitude between day and night time concentrations. The contribution of radical processes to halogen atom formation in the particle phase is evident, e.g. by halogen atoms which undergo direct phase transfer. Furthermore, the application of the multiphase model for initial concentrations for sea-salt aerosols shows that the particle phase can act as a main source of halogen containing molecules (Cl(2), BrCl, Br(2)) which are photolysed in the gas phase to yield halogen atoms (about 70% of all Cl sources and more than 99% for Br).

Single- and multiple-dose pharmacokinetics of repaglinide in patients with type 2 diabetes and renal impairment.

OBJECTIVE: The primary objective of this single-centre, open-label, parallel-group study was to evaluate the pharmacokinetics and safety profile of the prandial glucose regulator repaglinide, following single and multiple dosing, in patients with type 2 diabetes with and without varying degrees of renal impairment. METHODS: The study comprised three screening visits, followed by a 7-day inpatient period. Thirty-four patients, with normal renal function (n = 12), mild-to-moderate renal dysfunction (n = 12) or severe renal dysfunction (n = 10), received a single 2-mg dose of repaglinide on day 1, followed by preprandial 2-mg doses with main meals (breakfast, lunch and dinner) on each of days 2-4. A final 2-mg dose of repaglinide was administered on day 5. RESULTS: Patients with mild-to-moderate renal impairment showed no significant differences in the pharmacokinetics of repaglinide, compared with patients with normal renal function. In the group of patients with severe renal dysfunction, the main pharmacokinetic finding was a longer half-life after multiple dosing. Rates of minor hypoglycaemia were similar in patients with severe, mild-to-moderate and no renal dysfunction. No major hypoglycaemic episodes occurred. CONCLUSION: Patients with type 2 diabetes and mild or moderate impairment of renal function may be treated with repaglinide without special precautions. If repaglinide is used in patients with severely impaired renal function, dose adjustment may be necessary if indicated by blood glucose measurements.

Sentinel lymph node mapping in colorectal cancer--a review.

Sentinel lymph node (SLN) mapping has been found to be highly effective in correctly predicting the nodal status for melanoma and for breast cancer. This study shows that SLN mapping also is highly successful in colorectal cancer, posing minimal cost and no complications. The procedure accurately determines the presence or absence of nodal micrometastasis in more than 96% of cases. This article reviews the in vivo and ex vivo techniques for SLN mapping in colorectal cancer, along with its limitations and pitfalls.

Regulation of protein and prostaglandin secretion in polarized primary cultures of caprine uterine epithelial cells.

Caprine uterine epithelial (UE) cells were cultured on Matrigel-coated filters. Transmission electron microscopy revealed polarized UE cells characterized by basally located nuclei, apical microvilli, convoluted lateral membranes, and junctional complexes. Domain-specific secretion of prostaglandins and radiolabeled proteins provide further evidence of functional epithelial cell polarity. Two experiments were conducted to evaluate factors controlling prostaglandin E2 (PGE) and prostaglandin F2alpha (PGF) secretion. In experiment one, steroid-treated (estradiol, progesterone, or estradiol + progesterone) polarized UE cells were treated with interferon tau (IFNtau) and/or oxytocin (OT). Steroid treatment did not influence PGE or PGF secretion. However, analysis of variance revealed an IFNtau by OT interaction (P < .01) for both PGE and PGF This interaction was caused by a reduction in PGE and PGF secretion by cultures receiving only IFNtau and the inability of IFNtau to block OT-induced release of PGE or PGF. In experiment 2, polarized UE cells were cultured in progesterone, with or without IFNtau, and sequentially challenged with estradiol and OT. Oxytocin stimulated the release of both PGE and PGF by polarized cUE cells (P < .01) and resulted in an increased accumulation of PGE (OT*domain; P < .01) in the basal compartment. Interferon tau did not influence PGE (P < .1) secretion. However, further analysis revealed that IFNtau reduced PGF secretion and was unable to block OT-induced PGF secretion (IFNtau*OT; P < .05) by polarized UE cells. Therefore, caprine UE cells form polarized monolayers and retain responsiveness to IFNtau and OT in vitro.

Continuous-wave 532-nm-pumped singly resonant optical parametric oscillator based on periodically poled lithium niobate.

We report a continuous-wave (cw) 532-nm-pumped singly resonant optical parametric oscillator (SRO) based on periodically poled lithium niobate. The pump source is a commercial 5-W cw diode-pumped, multilongitudinal-mode, intracavity-doubled Nd:YVO(4) laser. Using a four-mirror ring SRO cavity and single-pass pumping, we achieved subwatt internal oscillation threshold, 56% quantum efficiency, and output tuning from 917 to 1266 nm.

42%-efficient single-pass cw second-harmonic generation in periodically poled lithium niobate.

We present a full-wafer fabrication process for periodically poled lithium niobate with a 6.5-mum domain period. Samples that were 53 mm long and 0.5 mm thick were obtained with this process for single-pass cw 1064-nm Nd:YAG second-harmonic generation. These samples exhibited 78% of the ideal nonlinear coefficient, had a measured conversion efficiency of 8.5% /W in the low-power limit, and produced 2.7 W of cw 532-nm output with 6.5 W of cw input, which corresponds to 42% power conversion efficiency.

Characterization of a polarized porcine uterine epithelial model system.

A porcine uterine epithelial cell (pUE) culture system that retains structural and functional properties of the surface epithelium in vivo was developed. Uterine luminal epithelial cells were isolated after pancreatin-dispase enzymatic release of epithelium from hysterectomized gilts. Cells were seeded on Millicell filters precoated with Matrigel in 24-well plates and subsequently allowed to proliferate to confluence. Purity of the isolation was confirmed by the presence of > 99% cytokeratin-positive cells. Epithelial cells became polarized in vitro and compared favorably in morphology to uterine epithelial cells in situ once a transepithelial resistance of > 600 omega cm2 was established. Microscopic analysis confirmed the presence of a simple columnar epithelium with prominent microvilli on the apical cell surface and a well-developed junctional complex containing tight junctions, belt and spot desmosomes, and interdigitating lateral cell processes. Indirect immunofluorescence of the tight junction-associated protein, ZO-1, indicated the formation of tight junctional complexes in the subapical region of the polarized cells. Functional polarity of epithelial cultures was also verified by 1) electrical resistance measurements, 2) basal preference for the secretion of prostaglandins F2 alpha and E2, 3) apical preference for the release of 35S-methionine-incorporated secretory proteins, and 4) apically and basally distinct secretory protein profiles. Steroid treatment (estrogen, progesterone, or estrogen plus progesterone) of the polarized pUE cells affected the release of radiolabeled methionine-incorporated secretory proteins. In addition, the protein profiles as compared to samples treated with fetal bovine serum or charcoal/dextran-stripped fetal bovine serum were altered. Steroid treatments did not alter the electrical resistance or the basal preference for prostaglandin secretion. This culture system may be useful for in vitro analysis of maternal recognition of pregnancy paradigms as well as the study of the direct actions of hormones, prostaglandin secretion, and epithelial-stromal interactions.

Protein restriction in early pregnancy alters fetal and placental growth and allantoic fluid proteins in swine.

This study was designed to determine the impact of protein malnutrition during early pregnancy on fetal and placental growth and on the protein synthesis capacity of placental and endometrial tissues. Twelve crossbred sows received 1.8 kg/d of a control (13% protein) or protein-restricted (0.5% protein) diet from the day of breeding to Day 63 of pregnancy, when dissections were performed on each conceptus unit. The de novo protein synthetic rate of placental and endometrial explants was measured using (35)S-methionine. These proteins and the proteins from amniotic and allantoic fluids were separated by polyacrylamide gel electrophoresis. Placental weight was significantly reduced in the sows fed the restricted diet, with a tendency for decreased fetal weight as well. No differences were found due to dietary treatment in de novo protein synthesis or in the electrophoretic patterns of secreted proteins of the placenta or endometrium. The apparent quantity of 3 proteins in the allantoic fluid of the restricted diet fetuses decreased, while 1 protein increased in comparison with that of the control fetuses. These data suggest that protein malnutrition in early pregnancy decreases placental growth, thereby decreasing both fetal growth and the opportunity for compensatory growth upon nutritional rehabilitation.

Effects of day of the estrous cycle or pregnancy on protein secretion by caprine endometrial tissues.

Our objectives were to evaluate temporal changes in protein secretion by endometrial explant cultures obtained from cycling or pregnant caprine does during the period of maternal recognition of pregnancy. Equal amounts of radiolabeled proteins from explant cultures were separated by one- and two-dimensional PAGE and visualized by fluorography. No consistent difference in proteins with molecular masses greater than 30 kDa was apparent when electrophoretic patterns were compared. However, on Days 18 and 21 of pregnancy there was an increase in the number and intensity of proteins having molecular masses between 18 and 22 kDa (pI = 6.2-7.2) when compared with endometrial secretory proteins obtained from goats on Day 18 of the estrous cycle. Three proteins were also detected in culture supernatants from endometrial explants obtained on Days 18 and 21 of pregnancy but not on Day 18 of the estrous cycle. A basic (pI > 7.5) 14-kDa protein could sometimes be resolved into two (or more) isoelectric variants. A second 14-kDa protein (pI = 6.9) and a less prominent 15-kDa protein (pI = 6.0) were also produced in response to the conceptus. These proteins then decreased in intensity, returning to levels characteristic of those earlier in pregnancy, by Day 30 of gestation. These caprine uterine secretory proteins may be involved in the process of maternal recognition of pregnancy.

Dexamethasone pharmacokinetics in clinically normal dogs during low- and high-dose dexamethasone suppression testing.

Dexamethasone pharmacokinetics was studied in 10 healthy dogs receiving high-dose administration of dexamethasone (dosage, 0.1 mg/kg of body weight, IV), alone or combined with ACTH (dosage, 0.5 U/kg, IV), or low-dose administration of dexamethasone (dosage, 0.01 mg/kg, IV) in an incomplete cross-over design. Serum samples were obtained at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 720, 1,080, 1,440, 1,920, 2,400, and 2,880 minutes after dexamethasone administration; dexamethasone was measured by radioimmunoassay validated for use in dogs. Dexamethasone pharmacokinetics was adequately described by a two-compartment first-order open model. Comparison of pharmacokinetics for the low- and high-dose protocols revealed dose dependence; area under the curve, mean residence time, clearance, and volume of distribution increased significantly when dexamethasone dosage increased. The elimination rate constant was significantly (P < 0.05) less, and the elimination half-life significantly greater for the high-dose protocols; however, the distribution rate constant and distribution half-life were not significantly different when high-dose protocols were compared with the low-dose protocol. Dose-dependent increases in volume of distribution and clearance may be related to saturation of protein-binding sites. Concurrent administration of ACTH did not affect dexamethasone disposition.

Dimethylnitrosamine-induced hepatotoxicosis in dogs as a model of progressive canine hepatic disease.

A model of toxin-induced progressive hepatitis is described in Beagles. The toxin, dimethylnitrosamine, was administered orally to 18 Beagles; 6 dogs comprised a control group. Clinical signs and laboratory test results were monitored as disease progressed and were used to determine the end point of disease. Following euthanasia, histologic lesions were scored and used to derive a total severity score for each dog. Severity scores were then used to allot the 18 dogs to 3 groups of hepatic disease, defined as mild, moderate, or severe. Changes in clinical laboratory test results, including tests of hepatic function, and clinical signs indicative of liver disease were described chronologically for all dogs. Group means of clinical laboratory test results and quantifiable clinical signs (eg, weight loss and ascitic fluid accumulation) were compared. This model offers several advantages, compared with other experimental models of canine hepatic disease. These include hepatospecificity, similarity to natural disease (eg, the development of multiple extrahepatic portosystemic shunts), and the ability to titrate the disease to a desired end point. The major disadvantages of this model were the toxic nature of the drug to human beings and the variation in individual animal response to the toxin, which precludes preassignment of animals into groups.