Luminosity-independent measurement of the proton-proton total cross section at √s=8 TeV.

The TOTEM collaboration has measured the proton-proton total cross section at √s=8 TeV using a luminosity-independent method. In LHC fills with dedicated beam optics, the Roman pots have been inserted very close to the beam allowing the detection of ~90% of the nuclear elastic scattering events. Simultaneously the inelastic scattering rate has been measured by the T1 and T2 telescopes. By applying the optical theorem, the total proton-proton cross section of (101.7±2.9) mb has been determined, well in agreement with the extrapolation from lower energies. This method also allows one to derive the luminosity-independent elastic and inelastic cross sections: σ(el)=(27.1±1.4) mb; σ(inel)=(74.7±1.7) mb.

Double diffractive cross-section measurement in the forward region at the LHC.

The first double diffractive cross-section measurement in the very forward region has been carried out by the TOTEM experiment at the LHC with a center-of-mass energy of sqrt[s]=7 TeV. By utilizing the very forward TOTEM tracking detectors T1 and T2, which extend up to |η|=6.5, a clean sample of double diffractive pp events was extracted. From these events, we determined the cross section σDD=(116±25) µb for events where both diffractive systems have 4.7<|η|min<6.5.

[MSA-QoL: disease-specific questionnaire to assess health-related quality of life in multiple system atrophy: validation of the German translation]. / MSA-QoL: spezifisches Bewertungsinstrument zur Erfassung der Lebensqualität bei Multisystematrophie : Validierung der deutschsprachigen Übersetzung.

BACKGROUND: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder which causes early sustained disability and quality of life impairment. Recently, a self-reported questionnaire focusing on MSA-specific symptoms (Multiple System Atrophy Quality of Life questionnaire, MSA-QoL) was developed in the English language. This article reports the validation of the German translation of the MSA-QoL. METHODS: Translation of the MSA-QoL was implemented in a 3-tiered approach including a forward translation, a back translation and an independent review. For the validation study 38 consecutive patients with MSA according to the consensus criteria were recruited by the participating centers in a German-Austrian cohort. Data were analyzed using standard psychometric procedures. RESULTS: As determined by the independent review, the German translation of the MSA-QoL was classified as fully equivalent to the English version. The validation study confirmed good psychometric properties of the rating scale. CONCLUSION: The German translation of the MSA-QoL was shown to be a reliable patient-reported rating scale to determine health-related quality of life in MSA patients.

[Parkinson's disease: cost-of-illness in an outpatient cohort]. / Morbus Parkinson: Krankheitskosten einer ambulanten Patientenkohorte.

OBJECTIVE: The aim of this study was to evaluate the direct and indirect costs in a cohort of German outpatients with Parkinson's disease (PD) and to identify major cost drivers in PD. METHODS: 91 PD patients were consecutively enrolled in the outpatient department of the neurological clinic at the University of Marburg, Germany. Patients had to fill out a standardised questionnaire at baseline and at a 3-month follow-up and report their health service resource utilisation for the past three months, retrospectively. In addition, information on clinical parameters of PD (UPDRS, Hoehn and Yahr stage) were assessed. For 86 patients, the direct and indirect cost data were analysed. Indirect costs were calculated by the human capital approach. RESULTS: Total costs per patient and 6-month period amounted to € 8,400 [95%CI 6,768-10,302]. Of these, 30% were indirect costs (€ 2,505 [95%CI 1,541-4,047]) and 70% were direct costs (€ 5,895 [95%CI 4,846-7,376]). The major parts of the direct costs were triggered by antiparkinsonian medication (€ 2,889 [95%CI 2,392-3,655]) and inpatient stays (hospital und rehabilitation, € 1,556 [95%CI 865-2,892]). A linear multivariate model with disease severity, disease duration, sleep disorders, psychosis and dystonia explained 24% of the variance of total costs and 33% of variance of direct costs, respectively. CONCLUSION: Parkinson's disease imposes a high financial burden on both patient and society. A reduced health-related quality of life reflects the individual patient's impairment by PD.

[Intravenous administration of lidocaine for perioperative analgesia. Review and recommendations for practical usage]. / Intravenös verabreichtes Lidocain zur perioperativen Schmerztherapie. Übersicht und praktische Handlungsempfehlungen.

Lidocaine is commonly used for regional anesthesia and nerve blocks. However, recent clinical studies demonstrated that intravenous perioperative administration of lidocaine can lead to better postoperative analgesia, reduced opioid consumption and improved intestinal motility. It can therefore be used as an alternative when epidural analgesia is contraindicated, not possible or not feasible. Apart from the sodium channel blocking effects relevant for regional anesthesia, lidocaine also has anti-inflammatory properties. Lidocaine can obviously inhibit the priming of resting neutrophilic granulocytes, which, simplified, may reduce the liberation of superoxide anions, a common pathway of inflammation after multiple forms of tissue trauma. At the authors' institutions intravenous lidocaine is primarily used for postoperative pain relief following abdominal surgery and is given as a bolus dose of 1.5-2.0 mg/kg body weight (BW) injected over 5 min followed by an infusion of 1.5 mg/kg BW/h intraoperatively and 1.33 mg/kg BW/h postoperatively in the recovery room or in the intensive care unit (ICU). The lidocaine infusion is stopped in the recovery room 30 min before discharge or in the ICU at the latest after 24 h. Lidocaine is not used on normal wards. This overview summarizes the current evidence for the intravenous administration of lidocaine for patients undergoing different types of surgery and gives practical advice for its use.

Longitudinal study of the socioeconomic burden of Parkinson's disease in Germany.

OBJECTIVE: To determine the health economic burden on patients with Parkinson's disease (PD) in Germany over a 12-month observation period and provide a comprehensive analysis of cost-driving factors. METHODS AND PATIENTS: Patients with PD (n = 145) were recruited from two clinical departments, two office-based neurologists and 12 GPs. Clinical evaluations were performed at baseline, 3, 6 and 12 months. Disease severity was measured using the Unified Parkinson's Disease Rating Scale (UPDRS). Cost data were assessed based on a patient diary and via personal structured interviews at the respective time-points. Costs were calculated from the societal perspective (2009 euro). Cost-driving factors were identified by multivariate regression analysis. RESULTS: Mean annual costs totalled euro20 095 per patient. Amongst direct costs, the highest expenditures (euro13 158) were for drugs (euro3526) and inpatient care including nursing homes (euro3789). Indirect costs accounted for 34.5% (euro6937) of total costs. Costs of home care provided by family accounted for 20% of direct costs. Cost-driving factors were identified for total costs (UPDRS, fluctuations, dyskinesia and younger age), direct costs (UPDRS, fluctuations), patient expenditures (UPDRS, depression) and drug costs (younger age). CONCLUSION: Parkinson's disease has a chronic course with growing disability and considerable socioeconomic burden. Disease progression leads to an increasing number of patients who require costly institutionalized care. Home care is a major factor influencing patients' families. Healthcare programmes aimed at reducing the burden of PD on society and individuals should consider cost-driving factors of PD.

Disease modifying treatment trials in Parkinson's disease: how to balance expectations and interests of patients, physicians and industry partners?

BACKGROUND: The advent of therapeutic strategies designed to modify the disease course in Parkinson's disease has raised great expectations in the currently conducted clinical trials. However, we see ethical challenges in the cooperation of industry and clinical partners, specifically evident in the way recruitment is performed.We here discuss the different positions and challenges of all involved to set the stage for a study and recruitment culture taking into account the expectations of all: (i) patients and their caregivers, ready to take the considerable burden of clinical trials in hope for the development of disease-modifying treatments; (ii) physicians and study nurses, obligated to the patients' well-being and benefit who accompany and supervise patients closely as basis for the performance of elaborate clinical trials (iii) industrial partners, investing years of efforts and finances to develop new treatments. CONCLUSIONS: We conclude that the current competitive race for enrollment in clinical studies in PD is challenging the primary goal to ensure patients' benefit and formulate requests to the industrial partners to encounter these concerns.

Clinical risk-benefit assessment of dopamine agonists.

Dopamine agonists (DAs) have proven efficacy as monotherapy in early Parkinson's disease (PD) for preventing motor complications such as dyskinesia and as adjunct therapy as the disease progresses. Further, it is increasingly evident that at least some DAs may provide additional benefits, such as reduction in depressive symptoms and treatment of refractory tremor. Different side-effect profiles have been associated with levodopa and ergot or non-ergot DA treatment, such as sudden onset of sleep, reduced impulse control, hallucination, and cardiovascular fibrosis. This paper discusses the evidence for specific associations between particular treatments and side effects as well as the clinical implications for patient care. Ultimately, the choice depends on the risk-benefit assessment as it applies to the individual patient's clinical profile and the physician's preference.

The prevalence of the G2019S and R1441C/G/H mutations in LRRK2 in German patients with Parkinson's disease.

BACKGROUND AND PURPOSE: The prevalence of the heterozygous G2019S and R1441C/G/H mutations in LRRK2 in patients with Parkinson's disease (PD) has shown a great variability depending on the sample population. Here we investigated the prevalence of these mutations in a large cohort of German PD patients (n = 1049). RESULTS: We observed heterozygous G2019S mutations in five patients with apparently sporadic late-onset PD (LOPD; n = 3) and young-onset PD (YOPD) (one sporadic and one familial), respectively, resulting in an overall prevalence of 0.5%. No R1441C/G/H mutation was found in our sample. DISCUSSION: In summary, the overall prevalence of the G2019S mutation in German PD patients is apparently somewhat lower than in patients from other nearby European countries. In contrast to previous reports, the G2019S mutation was also observed in apparently sporadic German LOPD patients.

Features of probable multiple system atrophy patients identified among 4770 patients with parkinsonism enrolled in the multicentre registry of the German Competence Network on Parkinson's disease.

We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enrolled in the multicentre registry of the German Competence Network on Parkinson's disease (PD) according to the established consensus criteria to characterize their clinical presentation. Analyses of more than 100 recorded clinical items revealed several specifics: I) 50% of patients with probable MSA had asymmetry of symptoms at disease onset and tremor at rest was present in 25%; II) a positive response to levodopa was recorded in 51% of patients identified initially with severe autonomic failure and cerebellar ataxia; III) a positive family history was recorded in 11% (n = 23), two of these patients were identified with spinocerebellar ataxia type 3 (SCA3). Thus asymmetry of symptoms, tremor at rest and a positive response to levodopa are not as specific for idiopathic PD as believed previously. Patients with SCA3 may present with the clinical features of MSA.

Autonomic dysfunction in 3414 Parkinson's disease patients enrolled in the German Network on Parkinson's disease (KNP e.V.): the effect of ageing.

We analysed non-motor symptoms (NMS) related to autonomic dysfunction in 3414 patients with Parkinson's disease (PD) enrolled in the multicentre registry of the German Competence Network on PD. Orthostatic hypotension (> 20 mmHg systolic or > 10 mmHg diastolic) was reported for 10% of women and 11% of men, urinary incontinence for 22% of women and 21% of men, sexual dysfunction for 8% of women and 30% of men (50% of whom reported erectile dysfunction) and sleep disturbances for 43% of women and 35% of men. Autonomic symptoms occurred in a frequency similar to severe disabling dyskinesia which was reported for 16% of women and 11% of men. A logistic regression analyses with age, sex and disease duration as covariates revealed a significant correlation of orthostatic hypotension and urinary incontinence with age and disease duration whilst sexual dysfunction was related to age only. These observations suggests that the effects of the PD process and ageing contribute to non-levodopa responsive NMS. Sleep disturbances were more common in women and a correlation was found with disease duration only supporting the notion that sleep is specifically affected in PD.

Experimental pain sensitivity in multiple system atrophy and Parkinson's disease at an early stage.

BACKGROUND: Chronic spontaneous pain is a clinically relevant non-motor symptom in multiple system atrophy (MSA) and Parkinson's disease (PD). Experimental pain sensitivity, reflecting the mechanisms of nociception and pain perception leading to clinical pain, is known to be enhanced in both diseases at advanced stages. Also, this study aimed at investigating experimental pain sensitivity already at an early stage (i.e. symptom duration ≤5 years). METHODS: Experimental pain sensitivity was assessed by investigating the nociceptive flexion reflex (NFR, reflecting spinal nociception) and heat and electrical pain thresholds. 'Off-drug' MSA (n = 11) and PD (n = 14) patients selected at an early stage of the disease were compared to healthy controls (HC, n = 27). MSA patients had either parkinsonian (MSA-P, n = 5) or cerebellar (MSA-C, n = 6) subtypes. RESULTS: Compared to HC, MSA patients had lower heat pain sensitivity, whereas PD patients had reduced NFR threshold. MSA and PD patients did not differ from HC regarding other variables. MSA-P and MSA-C patients did not differ, either. CONCLUSIONS: Impaired sensory discrimination and attention deficits could contribute to the reduced perception of heat pain in MSA, whereas in PD, local changes in spinal excitability or a diminished dopaminergic descending inhibition might impact on the motor efference of the NFR to reduce its threshold to nociceptive afferent information. WHAT DOES THIS STUDY ADD?: This study investigated experimental pain sensitivity at an early stage in MSA and PD.

Development and evaluation of the Parkinson Psychosis Questionnaire A screening-instrument for the early diagnosis of drug-induced psychosis in Parkinson's disease.

OBJECTIVE: Drug-induced psychosis is a frequent side-effect in the treatment of advanced Parkinson's disease (PD). We sought to develop and evaluate a brief instrument for early recognition of drug-induced psychosis in PD. METHODS: We developed the "Parkinson Psychosis Questionnaire" (PPQ), which consists of screening questions for typical early signs and psychotic symptoms in PD and which quantifies the frequency and severity of four clinical categories-sleep disturbances, hallucinations/illusions, delusions and orientation. We performed an internal validation of the PPQ in 50 unselected patients with parkinsonism. The Brief Psychiatric Rating Scale (BPRS) and the "Structurized Clinical Interview" (SCID) for DSM IV were applied to the same patients as external references. RESULTS: Of 50 subjects, 49 suffered from idiopathic PD and one from probable MSA-P. Hoehn and Yahr stages in "on" ranged from 1.5 to 4. Sensitivity of the PPQ test for drug-induced psychosis according to SCID was 100 % (95 % CI: 73.5%, 100%); while specificity was 92.1 % (95% CI: 78.6%, 98.3 %). The PPQ severity score was highly correlated with BPRS. We derived a linear prediction formula, which transformed PPQ into BPRS scores. CONCLUSION: The PPQ appears to be a suitable, and easily administered instrument for early diagnosis of drug induced psychosis in routine PD care. Whether the PPQ could also be a valuable tool for monitoring follow-up studies and therapeutic intervention trials remains to be tested.

Signaling pathways mediate the neuroprotective effects of GDNF.

We show that the glial cell line-derived neurotrophic factor (GDNF) activates the PI3K/Akt-signaling pathway in human neuroblastoma cells that express functional Ret-receptor complexes. Consistent with this finding we show PI3K-dependent Bad-inactivation by binding to 14-3-3 proteins in response to GDNF. Using differential display techniques we detected several cDNA clones differentially expressed after treatment with GDNF or 6-OHDA.

Glial cell line-derived neurotrophic factor protects dopaminergic neurons from 6-hydroxydopamine toxicity in vitro.

Glial cell line-derived neurotrophic factor (GDNF) is a potent and specific neurotrophic factor for dopaminergic neurons. GDNF has been previously shown to protect dopaminergic neurons from lesion-induced degeneration in vivo. In this study we investigated the effect of GDNF on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vitro. In dissociated cultures of embryonic rat mesencephalon, 6-OHDA exhibited a dose-dependent cytotoxicity on tyrosine hydroxylase (TH)-immunoreactive neurons. After pre-treatment with GDNF, however, 6-OHDA-induced loss of dopaminergic neurons was effectively reduced. It has been shown recently that GDNF signals through the receptor tyrosine kinase Ret and the GDNF receptor-alpha (GFR-alpha). By RT-PCR, we found both Ret- and GFR-alpha-genes to be expressed in the cultured mesencephalic cells. We propose that the neuroprotective effect of GDNF on 6-OHDA-treated dopaminergic neurons in vitro is most likely mediated by functional Ret receptor signaling pathways.

Predicting max HR and the HR-VO2 relationship for exercise prescription in obesity.

This research derived regression equations for predicting maximal heart rate (MHR) and examined the relationship between relative oxygen consumption (VO2) and heart rate (HR) in obese (N = 86, body fat > 30%, hydrostatic weighing) compared with normal-weight (N = 51, body fat < or = 30%) adults. Simultaneous measurements of HR and VO2 were recorded at rest and every minute during a maximal graded exercise test. When MHR was regressed on age, two distinct equations for the obese and normalweights were generated. The relationship between %MHR and %max VO2 was similar between groups (r = 0.83, obese; r = 0.87 normalweights). Likewise, when %max VO2 was regressed on %max heart rate range similar equations were derived fro the obese (r = 0.81) and normalweights (r = 0.84). Correlation between Karvonen's predicted HR at a submaximal VO2 and the true HR at that VO2 was 0.88, regardless of adiposity. These data indicate that when predicting MHR in normalweights the equation 220-Age can be used, but for obese individuals the equation 200-0.5 x Age is more accurate; each having 12 as a standard error of estimate. Once MHR is determined, either the straight percentage technique or Karvonen's method would be appropriate for prescribing exercise intensity for both populations.

[Intermittent apomorphine injections as rescue therapy for advanced Parkinson's disease. Consensus statement]. / Intermittierende Apomorphin-Injektionen als Rescue-Therapie beim fortgeschrittenen M. Parkinson. Konsensusstatement.

Intermittent subcutaneous apomorphine therapy should be considered in patients with advanced Parkinson's disease who experience recurrent off periods despite optimised oral treatment (according to guidelines), for reliable and quick reversal of these otherwise refractory periods. Such treatment is also called rescue therapy. At present, apomorphine injections with the apomorphine pen are underutilised, considering its current indications and contraindications. In the present consensus statement, concepts for the use of apomorphine are presented and discussed based on existing study results, indications, and contraindications. Recommendations for a practical approach are also provided.

Treatment of end-of-dose wearing-off in parkinson's disease: stalevo (levodopa/carbidopa/entacapone) and levodopa/DDCI given in combination with Comtess/Comtan (entacapone) provide equivalent improvements in symptom control superior to that of traditional levodopa/DDCI treatment.

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo (levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.

The European Multiple System Atrophy-Study Group (EMSA-SG).

Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.