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The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson’s disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.

Mio-Pliocene hypabyssal rocks of the Combia event in the Amaga basin (NW Andes-Colombia), contain a deformational record of the activity of the Cauca-Romeral fault system, and the interaction of terranes within the Choco and northern Andean blocks. Previous paleomagnetic studies interpreted coherent counterclockwise rotations and noncoherent modes of rotation about horizontal axes for the Combia intrusives. However, rotations were determined from in-situ paleomagnetic directions and the existing data set is small. In order to better understand the deformational features of these rocks, we collected new paleomagnetic, structural, petrographic and magnetic fabric data from well exposed hypabyssal rocks of the Combia event. The magnetizations of these rocks are controlled by a low-coercivity ferromagnetic phase. Samples respond well to alternatingfield demagnetization isolating a magnetization component of moderate coercivity. These rocks do not have ductile deformation features. Anisotropy of magnetic susceptibility and morphotectonic analysis indicate that rotation about horizontal axes is consistently to the south-east, suggesting the need to apply a structural correction to the paleomagnetic data. The relationships between magnetic foliations and host-rock bedding planes indicate tectonic activity initiated before ~10 Ma. We present a mean paleomagnetic direction (declination D = 342.8°, inclination I = 12.1°, 95% confidence interval α95 = 12.5°, precision parameter k = 8.6, number of specimens n = 18) that incorporates structural corrections. The dispersion S = 27° of site means cannot be explained by secular variation alone, but it indicates a counterclockwise rotation of 14.8° ± 12.7° relative to stable South America. Paleomagnetic data within a block bounded by the Sabanalarga and Cascajosa faults forms a more coherent data set (D = 336.5°, I = 17.4°, α95 = 11.7°, k = 12.5, n = 14), which differs from sites west of the Sabanalarga fault and shows a rotation about a vertical axis of 20.2° ± 10.7°. Deformation in the Amaga basin may be tentatively explained by the obduction of the Canas Gordas terrane over the northwestern margin of the northern Andean block. However, it can also be related to the local effects of the Cauca-Romeral fault system.

The aim of this study is to analyse the percentage of hypovitaminosis D, as well as its relationship with the various parameters of calcium-phosphate metabolism. A case control study was conducted on 366 patients, divided into two groups: Group 1: 127 non-stone-forming patients, and Group 2: 239 calcium stone forming. A study was performed on calcium-phosphate metabolism and urinary lithogenic factors. The percentage of vitamin D deficiency (25-OH-vitamin D levels

The aim of this study is to assess the presence of substantia nigra (SN) hypoechogenicity in a cohort of Friedreich's ataxia (FRDA) patients and its possible association with restless syndrome (RLS). Fourteen genetically confirmed FRDA patients and 14 sex- and age-matched healthy controls underwent transcranial sonography examination to evaluate the area of echogenicity of the SN. Both groups were clinically assessed with the essential and additional diagnostic criteria for RLS established by the International RLS Study Group. Ataxia was evaluated using the Scale for the Assessment and Rating of Ataxia. We did not find significant differences between the mean sum area of SN echogenicity in FRDA patients and in controls. Only one patient in the FDRA group and two control subjects showed SN hypoechogenicity. Two out of the 14 FDRA patients and one of the controls fulfilled diagnostic criteria for RLS. The areas of SN echogenicity in the two FRDA patients with RLS were the lowest found in this group. We conclude that our data do not support the notion that SN hypoechogenicity is related to FRDA itself, although it might be associated with RLS.

Calcium lithiasis is the most frequently diagnosed renal lithiasis and is associated with a high percentage of patients with metabolic disorders, such as hypercalciuria, hypocitraturia, and hyperoxaluria. The present study included 50 patients with recurrent calcium lithiasis. We conducted a random urine test during nocturnal fasting and a 24-h urine test, and examined calcium, oxalate, and citrate. A study of the linear correlation between the metabolites was performed, and the receiver operator characteristic (ROC) curves were analyzed in the random urine samples to determine the cutoff values for hypercalciuria (excretion greater than 200 mg), hyperoxaluria (excretion greater than 40 mg), and hypocitraturia (excretion less than 320 mg) in the 24-h urine. Linear relationships were observed between the calcium levels in the random and 24-h urine samples (R = 0.717, p = 0.0001), the oxalate levels in the random and 24-h urine samples (R = 0.838, p = 0.0001), and the citrate levels in the random and 24-h urine samples (R = 0.799, p = 0.0001). After obtaining the ROC curves, we observed that more than 10.15 mg/dl of random calcium and more than 16.45 mg/l of random oxalate were indicative of hypercalciuria and hyperoxaluria, respectively, in the 24-h urine. In addition, we found that the presence of less than 183 mg/l of random citrate was indicative of the presence of hypocitraturia in the 24-h urine. Using the proposed values, screening for hypercalciuria, hyperoxaluria, and hypocitraturia can be performed with a random urine sample during fasting with an overall sensitivity greater than 86 %.

We confront a practical cutting stock problem from a production plant of plastic rolls. The problem is a variant of the well-known one dimensional cutting stock, with particular constraints and optimization criteria defined by the experts of the company. We start by giving a problem formulation in which optimization criteria have been considered in linear hierarchy according to expert preferences, and then propose a heuristic solution based on a GRASP algorithm. The generation phase of this algorithm solves a simplified version which is rather similar to the conventional one dimensional cutting stock. To do that, we propose a Sequential Heuristic Randomized Procedure (SHRP). Then in the repairing phase, the solution of the simplified problem is transformed into a solution to the real problem. For experimental study we have chosen a set of problem instances of com-mon use to compare SHRP with another recent approach. Also, we show by means of examples, how our approach works over instances taken from the real production process, MEC-FEDER Grant TIN2007-67466-C02-01 and by contract CN-05-127 of the University of Oviedo and the company ERVISA, and by FICYT under grant BP04-021

The antitumoral effect of cisplatin [cis-diamminodichloroplatinum(II)] in mammals is related to its binding to DNA components. However, there is a lack of specific chemical methods to selectively detect those adducts formed in vivo at low concentrations. In this work, a new sensitive and selective method of determining cisplatin-DNA adducts based on the use of element-selective mass spectrometry is proposed, and the method is then applied to detect cisplatin adducts induced in vivo in somatic cells of Drosophila melanogaster. The bioanalytical strategy proposed here allows the determination of the most important DNA adduct formed between adjacent guanine units of the same DNA strand with cisplatin, and it is based on the coupling of capillary liquid chromatography (cap-LC) to inductively coupled plasma mass spectrometry (ICP-MS). This set-up allows the simultaneous monitoring of the Pt (from the drug) and P (from the DNA components) present in these adducts, once they have been cleaved by enzymatic hydrolysis of the DNA samples. Using this instrumental set-up, the adducts of cisplatin formed in vivo when D. melanogaster flies are exposed to different cisplatin concentrations can be detected and their concentration determined. The results obtained show a direct correlation between the concentration of cisplatin adducts, the induced genotoxic damage (measured as DNA strand breaks using the Comet assay) and the cisplatin concentration. [figure: see text] The work illustrates the complementary use of bioanalytical and biological information to study cisplatin interactions with DNA is vivo at biologically relevant concentrations of the drug.

This work compares seven regression algorithms implemented in artificial neural networks (ANNs) supported by 14 power-quality features, which are based in higher-order statistics. Combining time and frequency domain estimators to deal with non-stationary measurement sequences, the final goal of the system is the implementation in the future smart grid to guarantee compatibility between all equipment connected. The principal results are based in spectral kurtosis measurements, which easily adapt to the impulsive nature of the power quality events. These results verify that the proposed technique is capable of offering interesting results for power quality (PQ) disturbance classification. The best results are obtained using radial basis networks, generalized regression, and multilayer perceptron, mainly due to the non-linear nature of data.

Guillain–Barre syndrome (GBS) is an acute demyelinating inflammatory polyradiculoneuropathy characterised by rapidly progressing predominantly motor impairment and areflexia. Studies in patients and animals have provided convincing evidence that GBS is caused by an aberrant autoimmune response that damages peripheral nerves [1]. GBS rarely develops in patients who suffer from other autoimmune conditions, such as idiopathic thrombocytopenic purpura (ITP), which suggests a shared immune response [2–11]. Rituximab is a monoclonal antibody particularly efficacious in the treatment of several haematological cancers, which has also been used for the treatment of some autoimmune conditions [12]. Here we report on a patient with ITP who developed a typical GBS after treatment with rituximab. This 86-year-old man, with the antecedents of arterial hypertension, chronic obstructive lung disease and atrial fibrillation, consulted in December, 2008, due to purpuric lesions in the lower limbs. He was diagnosed as ITP. His platelet count was 5,000/mm. He received intravenous immunoglobulins (ivIG) 1 mg/kg/day for 2 days plus a descending treatment with oral prednisone (beginning with 1 mg/kg/day) for 1 month. His platelet count after this treatment was 250,000. In January, 2009, he was admitted again because his blood sample showed 10,000 platelets. He was treated with oral prednisone 1 mg/kg/day for 16 consecutive days. This treatment was stopped due to persistent thrombocytopenia (20,000 platelets). IvIG 1 g/kg/day for 2 days and intravenous rituximab (750 mg once a week for 4 weeks) were administered. His platelet count before the last rituximab dose (27 February 2009) was 121,000. Thirty-nine days after the last dose of rituximab (8 April 2009) he developed an acutely ascending progressive tetraparesis. On admission, two days after the beginning of the clinical picture, symmetric weakness, 4/5 in the upper extremities and 3/5 in lower extremities, and universal arreflexia were found. Plantar responses were flexor. Sensory examination was normal and sphincters were not affected. Platelet count was 192,000/mm. A lumbar tap was performed on admission. Glucose levels were normal, there were no cells and protein concentration was 57 mg/dl. The remaining routine laboratory determinations, including tumor markers and a complete autoimmune profile, were normal. With the presumptive diagnosis of Guillain–Barre syndrome, treatment with ivIG 0.4 g/kg/day for 5 days was given. An electrophysiological study, performed six days after the beginning of the symptoms, disclosed slowing of motor conduction velocities (MCV) in all studied nerves. MCV were markedly delayed (\32 m/s) in peroneal and tibial nerves, and slightly slowed in median and ulnar nerves (46 and 49 m/s, respectively). Motor distal latencies (MDL) were clearly prolonged in tibial and medial nerves and within normal limits in peroneal and ulnar nerves. F waves could not be obtained in right peroneal nerve, right posterior tibial nerve and right median nerve, and were delayed in right ulnar nerve. There was attenuation of distal compound muscle R. Jaso C. Valero Services of Internal Medicine, University Hospital Marques de Valdecilla, Santander, Spain