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Static pelvic tilt impacts functional cup position in total hip arthroplasty (THA). In the current study we investigated the effect of kinematic pelvic changes on cup position. In the course of a prospective controlled trial postoperative 3D-computed tomography (CT) and gait analysis before and 6 and 12 months after THA were obtained in 60 patients. Kinematic pelvic motion during gait was measured using Anybody Modeling System. By fusion with 3D-CT, the impact of kinematic pelvic tilt alterations on cup anteversion and inclination was calculated. Furthermore, risk factors correlating with high pelvic mobility were evaluated. During gait a high pelvic range of motion up to 15.6° exceeding 5° in 61.7% (37/60) of patients before THA was found. After surgery, the pelvis tilted posteriorly by a mean of 4.0 ± 6.6° (p < .001). The pelvic anteflexion led to a mean decrease of −1.9 ± 2.2° (p < .001) for cup inclination and −15.1 ± 6.1° (p < .001) for anteversion in relation to the anterior pelvic plane (APP). Kinematic pelvic changes resulted in a further change up to 2.3° for inclination and up to 12.3° for anteversion. In relation to the preoperative situation differences in postoperative cup position ranged from −4.4 to 4.6° for inclination and from −7.8 to 17.9° for anteversion, respectively. Female sex (p < .001) and normal body weight (p < .001) correlated with high alterations in pelvic tilt. Kinematic pelvic changes highly impact cup anteversion in THA. Surgeons using the APP as reference should aim for a higher anteversion of about 15° due to the functional anteflexion of the pelvis during gait.

Solution combustion synthesis followed by annealing in air led to the MPTB‐related phosphates (Rh1/6W5/6O3)8(PO2)4, (Ir1/6W5/6O3)8(PO2)4 (a=5.258(2) Å, b=6.538(3) Å, c=17.322(8) Å), (Rh1/9W8/9O3)12(PO2)4 and (Rh2/21W19/21O3)14(PO2)4. Single‐crystals of the mixed‐metal (Rh,W)‐MPTBs at m=4 and at m=7 were grown by chemical vapor transport (CVT). Their crystal structures have been refined from X‐ray single‐crystal data {(Rh,W)‐MPTB at m=4: P212121, Z=1, a=5.2232(3) Å, b=6.4966(3) Å, c=17.3819(9) Å, R1=0.032, wR2=0.075 for 1714 unique reflections, 1524 with Fo>4σ(Fo), 66 variables, 1 constraint, composition from refinement (Rh0.15W0.85O3)8(PO2)4; (Rh,W)‐MPTB at m=7: P21/n, Z=1, a=5.2510(4) Å, b=6.4949(5) Å, c=26.685(2) Å, β=90.30(1)°, R1=0.060, wR2=0.163 for 2074 unique reflections, 1894 with Fo>4σ(Fo), 100 variables, comp. from ref. (Rh0.07W0.93O3)14(PO2)4}. These structure refinements show unexpected distribution of Rh and W over the available metal sites. Further characterization (powder reflectance and magnetic measurements) of the (Rh,W)‐MPTB at m=4 and at m=7 suggest for both phases a homogeneity range with respect to the Rh/W ratio and the presence of small amounts of W5+ besides Rh3+ and W6+. Results of the ligand field analysis for the reference material Rh(PO3)3, which is containing the octahedral chromophore [RhIIIO6], are reported (Δo=23200 cm−1, B=490 cm−1).

Thermodynamic properties such as density, vapor pressure, heat of evaporation, and the speed of sound for three pure reference fluids were computed applying various common equations of state over a fairly wide range of pressures and temperatures. The results obtained by rather basic equations of state were held against those from sophisticated reference equations, and contour plots were drawn indicating the respective error margins. Thereby, it was quantitatively illustrated within which limits cubic equations of state can be used for reasonably accurate calculations of various properties.

Objective: the role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods: in this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. Results: the copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation: in our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies., European Union (EU); Horizon 2020; European Research Council (ERC); Research and Innovation Programme; EScORIAL; IWT; FWO-Vlaanderen; United Kingdom Medical Research Council; Neurodegenerative Disease Research (JPND); Netherlands; ZONMW; BRAIN-MEND; NIH/NINDS; Italian Ministry of Health; Fondazione Regionale per la Ricerca Biomedica Regione Lombardia; Science Foundation Ireland; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Foundation Netherlands; PPP Allowance; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre; Fondazione Italiana di Ricerca per la SLA - AriSLA; Exomefals; Novals; ALS Association; E-RARE JTC Project Repetomics

INTRODUCTION This study proposes guidelines for motor unit number index (MUNIX) recording and analysis. METHODS MUNIX was measured in control participants and in patients with amyotrophic lateral sclerosis. Changes in MUNIX values due to E1 electrode position, number of surface electromyography interference pattern (SIP) epochs, SIP epoch duration, force of contraction, and outlier data points were investigated. RESULTS MUNIX depends on optimized compound muscle action potential (CMAP) amplitude. Individual muscles showed variations when the number of epochs was low or when the SIP duration was short. Longer SIP duration allowed better recognition of artifacts. MUNIX results were affected by SIP values at all force levels but was more affected when SIP area was low. DISCUSSION We recommend changing the E1 electrode position to maximize CMAP amplitude. Twenty or more SIP signals of 500-ms duration should be recorded by using force levels ranging from slight to maximum. Traces should be reviewed to identify and exclude signals with tremor or solitary spikes. Muscle Nerve 58: 374-380, 2018.

The cannabinoid receptor type 2 (CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [(18) F]RS-126 was obtained in ≥ 99% radiochemical purity with an average specific radioactivity of 98 GBq/μmol at the end of the radiosynthesis. [(18) F]RS-126 showed a logD7.4 value of 1.99 and is stable in vitro in rat and human plasma over 120 min, whereas 55% intact parent compound was found in vivo in rat blood plasma at 10 min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in in vivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [(18) F]RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [(18) F]RS-126 using PET imaging. In summary, [(18) F]RS-126 demonstrated high specificity toward CB2 receptor in vitro and in vivo and is a promising radioligand for imaging CB2 receptor expression. Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [(18) F]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in in vivo displacement experiments with rats. Time activity curve of [(18) F]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).

INTRODUCTION Motor unit number index (MUNIX) is a quick and feasible electrophysiological technique that estimates the number of motor neurons in limb muscles in healthy and amyotrophic lateral sclerosis (ALS) subjects. In this study we explored the feasibility, reliability, and differences of MUNIX in nasalis muscles in healthy subjects and ALS patients. METHODS MUNIX of the nasalis muscle of 50 healthy and 20 ALS subjects with bulbar involvement was compared. Functional impairment was evaluated by the ALS Functional Rating Scale-Revised and its bulbar subscore. RESULTS MUNIX was well tolerated and quickly performed. Bulbar ALS patients showed non-significant lower nasalis MUNIX values and a lower functional bulbar subscore. Intra- and interrater reliability showed high intraclass correlation coefficients (ICCs) in healthy subjects (0.87) and ALS patients (0.92). CONCLUSION MUNIX of the nasalis muscle is a reproducible method, but it showed no significant difference between healthy and bulbar ALS subjects and seems not to be a useful marker of disease progression in ALS. Muscle Nerve 54: 733-737, 2016.

Introduction Ultrasound has become a reliable method to detect fasciculations. There is disagreement as to whether fasciculations above the knee should raise the suspicion of a disorder even if there are no other signs of lower motor neuron abnormality. Methods Using ultrasonography, 3 arm and 3 leg muscles were investigated for 120 s, 45 min after 90-min handball training or a 5,000 meter run in a group of 25 men and 25 women handball players and 7 men who are amateur runners. Results All athletes had fasciculations in muscles above the knee. There were no fasciculations in the upper limb muscles in the runner group. In 21 men and 18 women handball players between 1 to 17 fasciculations in 2 min were detected. The number of fasciculations in the rectus femoris was 4-fold higher in the runners compared with the handball players (ratio 0.24; P = 0.037). Conclusions Fasciculations may occur in muscles above the knee in healthy subjects. The distribution of fasciculations primarily depends on the exercised muscles. Muscle Nerve, 2016 Muscle Nerve 54: 132-135, 2016 Muscle Nerve 54: 132-135, 2016.

Preoperative knowledge of femoral stem anteversion can reduce instability and impingement especially using the standard "cup first" technique in cementless total hip arthroplasty (THA). In this study, we asked whether stems at risk of retroversion or high anteversion (>20°) can be detected preoperatively using hip radiographs in two planes (anteroposterior and Lauenstein). In 123 patients undergoing cementless THA using a non-anatomic, non-modular, straight stem, low centered hip radiographs in two planes were obtained preoperatively and three-dimensional computed tomography (3D-CT) 6 week postoperatively. The novel developed Isthmus Ratio (iRatio) as the relation between canal isthmus and calcar isthmus in the anteroposterior and Lauenstein view was calculated by two observers twice in a 6-week interval. iRatio was compared to postoperative 3D-CT stem version measured by an independent and blinded, external institute. We found a correlation between mean radiographic iRatio and 3D-CT stem torsion of r = 0.578 (p

OBJECTIVE Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. METHODS We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. RESULTS Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10(-12) ) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10(-11) ) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10(-7) ) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10(-7) ). INTERPRETATION We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

The cannabinoid type 2 (CB2) receptor plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease and is therefore a very promising target for therapeutic approaches as well as for imaging. Based on the literature, we identified one 4-oxoquinoline derivative(designated KD2) as the lead structure. It was synthesized, radiolabeled and evaluated as a potential imaging tracer for CB2. [11C]KD2 was obtained in 99% radiochemical purity.Moderate blood–brain barrier (BBB) passage was predicted for KD2 from an in vitro transport assay with P- glycoprotein-transfected Madin Darby canine kidney cells. No efflux of KD2 by P-glycoprotein was detected. In vitro autoradiography of rat and mouse spleen slices demonstrated that [11C]KD2 exhibits high specific binding towards CB2. High spleen uptake of [11C]KD2 was observed in dynamic positron emission tomography(PET) studies with Wistar rats and its specificity was confirmed by displacement study with a selective CB2 agonist, GW405833. A pilot autoradiography study with post- mortem spinal cord slices from amyotrophic lateral sclerosis (ALS)patients with [11C]KD2 suggested the presence of CB2 receptors under disease conditions. Specificity of [11C]KD2 binding could also be demonstrated on these human tissues. In conclusion, [11C]KD2 shows good in vitro and in vivo properties as a potential PET tracer for CB2.

The growing need for organs and the scarcity of donors has resulted in an increased use of extended criteria donors. We report a case where a recipient of a cardiac graft was used as an organ donor. Death of the recipient occurred 9 days after transplantation and was attributed to presumed cerebral hemorrhage, which post mortem was diagnosed as invasive aspergillosis of the brain. One recipient of a kidney transplant lost the graft due to infection with Aspergillus fumigatus, whereas prompt initiation of therapy successfully prevented disseminated aspergillosis in the other recipients. Despite the pressure to extend the use of organs by lowering the acceptance criteria, organs should only be accepted if the cause of death of the donors is unequivocally explained.

Galectin-3 plays a role in atherosclerotic diseases, and the effect of adiponectin that protects from atherosclerotic diseases on monocytic galectin-3 was analysed. Adiponectin reduced galectin-3 mRNA, its cellular and soluble form, and this effect was impaired in T2D cells. Cellular galectin-3 was higher in monocytes of overweight than normal-weight donors and was highest in T2D cells. Cellular galectin-3 positively correlated with the BMI of the donors and negatively with soluble monocyte galectin-3. Circulating levels of total adiponectin did not correlate with cellular or soluble galectin-3 indicating that additional factors contribute to higher cellular monocytic galectin-3 in obesity and T2D.

Background CD163 is a monocyte/macrophage specific receptor whose soluble form (sCD163) is elevated in inflammatory diseases. Obesity is associated with chronic inflammation and low adiponectin, an anti-inflammatory adipokine. Adiponectin, 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR) and metformin activate the AMP-kinase that exerts anti-inflammatory effects, and the influence of adiponectin and these drugs on monocytic CD163 was analysed, and cellular and sCD163 were determined in obesity and type 2 diabetes. Materials and methods Monocytes were incubated with adiponectin, AICAR or metformin. Furthermore, monocytes and serum were obtained from type 2 diabetic patients (T2D), overweight (defined as a body mass index ≥ 25 kg m−2) and normal-weight (NW) controls. CD163 was analysed by immunoblot and sCD163 was measured by enzyme-linked immunosorbent assay in the supernatants of the monocytes and in serum. Results In monocytes, adiponectin reduced cellular and surface CD163, whereas sCD163 was not altered in the corresponding supernatants. Further, metformin and AICAR downregulated CD163. Monocytic CD163 was higher in T2D and obesity, whereas sCD163 in the supernatants was not elevated and neither correlated with serum sCD163 nor systemic adiponectin. There was a positive correlation of monocytic sCD163 with serum but not with monocytic IL-6. In the serum of obese controls and T2D patients, sCD163 was significantly higher compared to NW donors and was positively associated with systemic IL-6. Conclusions This study indicates that monocytic CD163 and systemic sCD163 are elevated in T2D and obesity. Adiponectin reduces CD163 in vitro, but additional factors related to obesity like IL-6 may be more relevant in vivo.

Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014.To assess the efficacy and safety of quinine-based agents in treating muscle cramps.On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014.Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives.Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE).We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine-theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events.There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine-vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long-term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine.

Single-nucleotide polymorphisms (SNPs) are the most common form of DNA sequence variation. There is a strong interest from both academy and industry to develop rapid, sensitive and cost effective methods for SNP detection. Here we report a novel structural concept for DNA detection based on fluorescence dequenching upon hybridization. The so-called “twin probe” consists of a central fluorene derivative as fluorophore to which two identical oligonucleotides are covalently attached. This probe architecture is applied in homogeneous hybridization assays with subsequent fluorescence spectroscopic analysis. The bioorganic hybrid structure is well suited for sequence specific DNA detection and even SNPs are identified with high efficiency. Additionally, the photophysical properties of the twin probe were investigated. The covalent attachment of two single stranded oligonucleotides leads to strong quenching of the central fluorescence dye induced by the nucleobases. The twin probe is characterized by supramolecular aggregate formation accompanied by red-shifted emission and broad fluorescence spectra.

Familial amyotrophic lateral sclerosis (ALS) with the autosomal-recessively inherited D90A CuZn-superoxide dismutase (CuZn-SOD) mutation is characterized by a stereotypic slowly progressive, distinctive phenotype and very slow central motor conduction. To determine the basis of this slowing, we assessed corticomotoneuronal function using peristimulus time histograms (PSTHs) in 8 ALS patients homozygous for the D90A CuZn-SOD mutation. The results were compared with findings in 10 patients with multiple sclerosis (MS), in which slowing of central motor conduction is common, and 11 healthy subjects. PSTHs were constructed from 3-7 different, voluntarily recruited motor units recorded in each patient from the extensor digitorum communis muscle (EDC). In D90A and MS patients, the stimulus threshold, onset latency, number of excess bins, duration, amplitude, and synchrony of the primary peak differed significantly from controls (P < 0.0004). The mean onset latency of the primary peak in D90A patients was 35.3 ms, compared to 23.6 ms for MS patients and 19.3 ms for normal subjects (P < 0.0001). In the D90A patients, the onset latencies of the primary peak had a bimodal distribution, whereas in MS the distribution showed a continuum. Loss of synchrony was similar in D90A and MS patients, but the threshold, number of excess bins, and duration differed significantly (P < 0.0057), which suggests that either axonal loss or demyelination can result in delayed and desynchronized primary peaks. We propose that conduction slowing in the D90A homozygotes results from selective loss of fast-conducting large pyramidal cells with preservation of slow-conducting mono- or polysynaptic corticomotoneuronal connections.

On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.

The enzyme catalysing the reduction of adenosine 5'-phosphosulfate (AdoPS) to sulfite in higher plants, AdoPS reductase, is considered to be the key enzyme of assimilatory sulfate reduction. In order to address its reaction mechanism, the APR2 isoform of this enzyme from Arabidopsis thaliana was overexpressed in Escherichia coli and purified to homogeneity. Incubation of the enzyme with [35S]AdoPS at 4 degrees C resulted in radioactive labelling of the protein. Analysis of APR2 tryptic peptides revealed 35SO2-3 bound to Cys248, the only Cys conserved between AdoPS and prokaryotic phosphoadenosine 5'-phosphosulfate reductases. Consistent with this result, radioactivity could be released from the protein by incubation with thiols, inorganic sulfide and sulfite. The intermediate remained stable, however, after incubation with sulfate, oxidized glutathione or AdoPS. Because truncated APR2, missing the thioredoxin-like C-terminal part, could be labelled even at 37 degrees C, and because this intermediate was more stable than the complete protein, we conclude that the thioredoxin-like domain was required to release the bound SO2-3 from the intermediate. Taken together, these results demonstrate for the first time the binding of 35SO2-3 from [35S]AdoPS to AdoPS reductase and its subsequent release, and thus contribute to our understanding of the molecular mechanism of AdoPS reduction in plants.

We report a patient who developed a focal myopathy with prominent contractures of his thigh muscles induced by chronic heroin injection. Muscle biopsy and magnetic resonance imaging (MRI) were indicative of a fibrotic and inflammatory process. Treatment with steroids, D-penicillamine, and physical therapy led to full functional recovery within 6 months. Sequential electromyographic (EMG) studies and muscle biopsies showed evidence of regenerating muscle fibers and absence of inflammatory cells. We conclude that heroin-induced focal myopathy is reversible and that combination therapy with D-penicillamine and steroids may be useful.

Complex fasciculations are common in patients with amyotrophic lateral sclerosis (ALS). Combined fasciculations, defined as a complex fasciculation consisting of two or more components that occur independently but also in combination with another component, also occur in ALS. To test the hypothesis that combined fasciculations originate at the supraspinal level, we analyzed 2681 fasciculation potentials from 17 patients with definite or probable ALS by the El Escorial criteria. Results were compared with 304 fasciculation potentials recorded from 6 patients with Kennedy's disease, in which the upper motoneurons are spared. The mean firing frequency of the fasciculations was 24.4 +/- 25.6 per minute in ALS, significantly higher than the 2.9 +/- 3.4 per minute found in Kennedy's disease (P < 0.0001). In ALS, the mean combination ratio (the number of times that a combined fasciculation occurred divided by the total number of fasciculations) was 4.6 +/- 8.3% (range 0-33). Fourteen of 17 ALS patients had combined fasciculations, but only one combined fasciculation was found in a patient with Kennedy's disease. Combined fasciculations are distinctive in ALS, and we hypothesize that they are triggered by a supraspinal mechanism reflecting dysfunction of descending motor pathways.

We used peristimulus time histograms (PSTHs) to estimate characteristics of the composite excitatory postsynaptic potentials (EPSPs) generated at the anterior horn cell by a descending cortical volley induced by subthreshold transcranial magnetic stimuli in 11 normal subjects, 9 patients with DNA-confirmed Kennedy's disease, and 10 patients with amyotrophic lateral sclerosis (ALS). In Kennedy's disease the mean of the estimated EPSP amplitude (3.5 +/- 1.6 mV), as well as the means of duration (4.1 +/- 1.3 ms) and onset latency (20.4 +/- 2.7 ms) of the primary peak of 35 different motor units were not significantly different from normal subjects, in whom corresponding values of 49 motor units measured 2.9 +/- 1.6 mV (EPSP amplitude), 3.5 +/- 1.4 ms (duration) and 19.3 +/- 2.8 ms (onset latency). In 48 motor units of patients with ALS the mean of the estimated EPSP amplitude, duration, and latency measured 2.7 +/- 1.8 mV, 7.8 +/- 5.7 ms, and 24.0 +/- 6.5 ms, respectively, differing significantly from normal subjects and patients with Kennedy's disease. The normal cortically induced EPSP in Kennedy's disease is very different from the range of EPSP abnormalities in ALS, indicating that lower motor neuron disease per se does not result in an abnormal cortically induced EPSP derived from PSTHs. The normal findings in Kennedy's disease support our previous suggestions that the EPSP abnormalities in ALS are supraspinal in origin.

Background Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials. Objectives To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND. Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information. Selection criteria We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy. Data collection and analysis All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction. Main results Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small studies showed a statistically nonsignificant result for the amino acid L-threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps. Authors' conclusions There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed.

We describe a case of a 65-year old patient diagnosed with amyotrophic lateral sclerosis. The clinical findings, with symmetric, predominantly proximal wasting and weakness of both arms (especially of the infra-, supraspinatus and deltoideus) leading to severe functional disability and contrasting with preserved independent ambulation and sparing of bulbar muscles, were consistent with the proposed criteria of the so-called flail arm syndrome. Based on our case we characterize the clinical features of flail arm syndrome and review the literature.