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Enzymatic cellulose hydrolysis is an important step for the production of second-generation biofuels. The filamentous fungus Trichoderma reesei is among the most important organisms for obtaining cellulolytic enzymes. The Cel6A (CBH II) cellulase from T. ressei plays an important role in cellulose hydrolysis and acts on the non-reducing end of cellulose, in contrast to Cel7B (CBH I), which acts on the reducing end of cellulose thus releasing cellobiose. Therefore, Cel6A deficiency becomes a limiting factor in cellulose saccharification. This work attempted to use codon optimization to enhance Cel6A expression in Escherichia coli. A plasmid expression vector, pUCITD04, was designed; this vector contains: the cel6a gene, regulatory regions (the promoter and terminator T7 sequences), the OmpT signal peptide that allows the secretion of proteins into the culture medium, and a 6His tail to allow purification of the protein by affinity chromatography. The protein expression experiment using a strain of E. coli transformed with pUCITD04 resulted in a 31 kDa polypeptide being secreted into the culture medium that did not possess enzymatic activity, meanwhile, the control strain transformed with the empty plasmid did not secrete any protein fragments, indicating that a truncated Cel6A was being produced by the experimental strain. This phenomenon has been reported during the production of recombinant cellulases in E. coli. In this research, we discuss probable causes of this phenomenon, as well as the drawbacks in the production of cellulases by E. coli, directing efforts to elucidate the causes of the production of truncated cellulases by this bacterial factory. Key words: Gene construct, recombinant cellobiohydrolase, Escherichia coli.

Wild-type transthyretin (ATTRwt) amyloid deposits have been found in the ligamentum flavum of patients undergoing surgery for spinal stenosis. The relationship between ATTRwt and ligamentum flavum thickness is unclear. We used pre-operative magnetic resonance imaging (MRI) to analyze ligamentum flavum thickness in lumbar spinal stenosis patients with and without ATTRwt amyloid.We retrospectively identified 178 patients who underwent lumbar spine surgery. Ligamentum flavum thickness of 253 specimens was measured on T2-weighted axial MRI. Amyloid presence was confirmed through Congo red staining of specimens, and ATTRwt was confirmed using mass-spectrometry and gene sequencing.Twenty four of the 178 patients (13.5%) were found to have ATTRwt in the ligamentum flavum. Forty ATTRwt specimens and 213 non-ATTRwt specimens were measured. Mean ligamentum flavum thickness was 4.92 (±1.27) mm in the ATTRwt group and 4.00 (±1.21) mm in the non-ATTRwt group (p 0.01). The ligamentum flavum was thickest at L4-L5, with a thickness of 5.15 (±1.27) mm and 4.23 (±1.29) mm in the ATTRwt and non-ATTRwt group, respectively (p = 0.007). There was a significant difference in ligamentum flavum thickness between ATTRwt and non-ATTRwt case for both patients younger than 70 years (p = 0.016) and those older than 70 years (p = 0.004). ATTRwt patients had greater ligamentum flavum thickness by 0.83 mm (95% confidence interval (CI): 0.41-1.25 mm, p 0.001) when controlled for age and lumbar level.Patients with ATTRwt had thicker ligamentum flavum compared to patients without ATTRwt. Further studies are needed to investigate the pathophysiology of ATTRwt in ligamentum flavum thickening.

The term "giant cell myositis" has been used to refer to muscle diseases characterized histologically by multinucleated giant cells. Myasthenia gravis is an autoimmune neuromuscular junction disorder. The rare concurrence of giant cell myositis with myasthenia gravis has been reported; however, the clinical and histological features have varied widely. Here, we present such a case and a review of the literature. An 82-year-old woman admitted for subacute, progressive, proximal muscle weakness developed acute-onset dysphagia, dysphonia, and respiratory distress 5 days after admission. Laboratory findings were positive for acetylcholine receptor binding antibodies and striational muscle antibodies against titin. Muscle biopsy demonstrated widespread muscle fiber necrosis with multinucleated giant cells, consistent with giant cell myositis. She died despite treatment with pulse methylprednisolone and plasma exchange. A literature review of the PubMed and Scopus databases from 1944 to 2020 identified 15 additional cases of these co-existing diagnoses. We found that giant cell myositis with myasthenia gravis primarily affects female patients, is typically diagnosed in the 6-7th decades, and is characterized by the presence of thymoma. Muscle histology predominantly shows giant cell infiltrate without granulomas. The onset of myasthenia gravis symptoms may precede, follow, or coincide with symptoms of myositis. Treatment with thymectomy, anticholinesterase inhibitors, or immunosuppressive therapy may lead to favorable clinical outcomes.

The enzymatic conversion of lignocellulosic biomass to fermentable sugars is determined by the enzymatic activity of cellulases; consequently, improving enzymatic activity has attracted great interest in the scientific community. Cocktails of commercial cellulase often have low β-glucosidase content, leading to the accumulation of cellobiose. This accumulation inhibits the activity of the cellulolytic complex and can be used to determine the enzymatic efficiency of commercial cellulase cocktails. Here, a novel codon optimized β-glucosidase gene (B-glusy) from Trichoderma reesei QM6a was cloned and expressed in three strains of Escherichia coli (E. coli). The synthetic sequence containing an open reading frame (ORF) of 1491 bp was used to encode a polypeptide of 497 amino acid residues. The β-glucosidase recombinant protein that was expressed (57 kDa of molecular weight) was purified by Ni agarose affinity chromatography and visualized by SDS-PAGE. The recombinant protein was better expressed in E. coli BL21 (DE3), and its enzymatic activity was higher at neutral pH and 30 °C (22.4 U/mg). Subsequently, the β-glucosidase was immobilized using magnetite nano-support, after which it maintained >65% of its enzymatic activity from pH 6 to 10, and was more stable than the free enzyme above 40 °C. The maximum immobilization yield had enzyme activity of 97.2%. In conclusion, β-glucosidase is efficiently expressed in the microbial strain E. coli BL21 (DE3) grown in a simplified culture medium.

Objectives We aimed to establish new cut-off values for SIRS (Systemic Inflammatory Response Syndrome) variables in the obstetric population. Methods A prospective cohort study in pregnant and postpartum women admitted with systemic infections between December 2017 and January 2019. Patients were divided into three cohorts: Group A, patients with infection but without severe maternal outcomes (SMO); Group B, patients with infection and SMO or admission to the intensive care unit (ICU); and Group C, a control group. Outcome measures were ICU admission and SMO. The relationship between SIRS criteria and SMO was expressed as the area under the receiver operating characteristics curve (AUROC), selecting the best cut-off for each SIRS criterion. Results A total of 541 obstetric patients were enrolled, including 341 with infections and 200 enrolled as the reference group (Group C). The patients with infections included 313 (91.7%) in Group A and 28 (8.2%) in Group B. There were significant differences for all SIRS variables in Group B, compared with Groups A and C, but there were no significant differences between Groups A and C. The best cut-off values were the following: temperature 38.2 °C, OR 4.1 (1.8–9.0); heart rate 120 bpm, OR 2.9 (1.2–7.4); respiratory rate 22 bpm, OR 4.1 (1.6–10.1); and leukocyte count 16,100 per mcl, OR 3.5 (1.6–7.6). Conclusions The cut-off values for SIRS variables did not differ between healthy and infected obstetric patients. However, a higher cut-off may help predict the population with a higher risk of severe maternal outcomes.

Objective: To determine the association between perceived discrimination and receiving adequate treatment for chronic diseases in Venezuelan migrants. Methodology: A cross-sectional study was performed. This is a secondary analysis of the ENPOVE national survey from Peru. The association between the perceived discrimination and receiving adequate treatment for chronic diseases was evaluated using a Poisson regression model, considering the adjusted effect of the multistage sampling. Results: A total of 865 migrants were evaluated (age: 36.6 ± 0.7 years and 58.2% women). Of these, 54.8% perceived discrimination, and 89.2% did not receive adequate treatment for chronic diseases. Perceived discrimination was significantly associated with a lower prevalence of receiving adequate treatment for chronic diseases (PRa = 0.49; 95%CI 0.25 – 0.97). Conclusion: This study evidenced that perceived discrimination decreases the prevalence of receiving adequate treatment for chronic diseases by approximately 50% compared with those who did not perceive discrimination. RESUMO: Objetivo: Determinar a associação entre a discriminação percebida e o recebimento de tratamento adequado para doenças crônicas em migrantes venezuelanos. Métodos: Foi realizado um estudo transversal. Esta é uma análise secundária da pesquisa nacional Venezuelan Population Residing in the Country Survey do Peru. A associação entre discriminação percebida e receber tratamento adequado para doenças crônicas foi avaliada por meio de um modelo de regressão de Poisson, considerando o efeito ajustado da amostra em múltiplos estágios. Resultados: Foram avaliados 865 migrantes (idade: 36,6 ± 0,7 anos e 58,2% mulheres). Destes, 54,8% perceberam discriminação e 89,2% não receberam tratamento para a doença crônica. A discriminação percebida foi significativamente associada à menor prevalência de receber adequado tratamento para doenças crônicas (razão de prevalência ajustada — RPa = 0,49, intervalo de confiança de 95% — IC95% 0,25 – 0,97). Conclusão: Este estudo mostrou que a discriminação percebida diminui a prevalência de receber adequado tratamento para doenças crônicas em 50%, em comparação com aqueles que não percebem a discriminação.

Summary Background Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. Methods COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0–10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov , number NCT02757352 . Findings Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. Interpretation Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Funding Eli Lilly and Company.

Wild-type transthyretin (ATTRwt) amyloid deposition has been found in the ligamentum flavum (LF) of patients undergoing spinal stenosis surgery. Our group previously reported that ATTRwt amyloid is associated with an increased lumbar ligamentum flavum thickness at symptomatic levels that required surgery. A comprehensive evaluation of LF thickness at asymptomatic levels in addition to symptomatic, treated levels has never been performed in ATTRwt patients. In this study, we compare the total LF thickness of all lumbar levels (lumbar LF burden) in ATTRwt and non-ATTRwt patients.We retrospectively identified 177 patients who underwent lumbar spine surgery. Ligamentum flavum thickness of 885 lumbar levels was measured on T2-weighted axial MRI. Amyloid presence was confirmed through Congo red staining of specimens, and subtype of ATTRwt was confirmed using mass-spectrometry and gene sequencing.Of the 177 patients, 30 (16.9%) were found to have ATTRwt in the ligamentum flavum. One hundred and fifty ATTRwt levels and 735 non-ATTRwt levels were measured by four different reviewers, with an intraclass coefficient (ICC) of 0.79. Mean ligamentum flavum thickness was 4.64 (±1.31) mm in the ATTRwt group and 3.99 (±1.45) mm in the non-ATTRwt group (p 0.001). The lumbar LF burden (sum of ligamentum flavum thickness at all lumbar levels) for ATTRwt patients was 23.22 (±4.48) mm, and for non-ATTRwt patients was 19.96 (±5.49) mm (p = 0.003) CONCLUSION: The lumbar LF burden is greater in patients with ATTRwt amyloid compared to non-ATTRwt patients. This supports prior evidence that ATTRwt amyloid deposition might be associated with increased LF thickness and lumbar stenosis. This potential association requires more research and could be an important finding, as medications have recently become available that can treat patients with ATTRwt amyloid deposition.

Background Transthyretin wild-type (ATTRwt) amyloidosis is a systemic process resulting in deposition of misfolded transthyretin protein in several different tissues throughout the body. It is known to be a cause of progressive, life-threatening cardiomyopathy and lumbar spinal stenosis and carpal tunnel syndrome. Case Description Here we present the case of a 71-year-old man who has clinical manifestations of all 3 entities over several years, providing a picture of the natural history of ATTRwt amyloidosis. This patient eventually underwent a heart transplant because of progressive cardiac amyloidosis (CA) resulting in end-stage heart failure. However, symptoms in carpal tunnel and lumbar spine manifested years before the symptoms of heart failure. ATTRwt amyloidosis may present as a clinical triad of lumbar stenosis, carpal tunnel syndrome, and heart failure. Recently developed medications have shown efficacy in slowing the progress of systemic and cardiac amyloidosis. Conclusions Knowing that extracardiac symptoms may occur first, we propose that sending ligamentum flavum and flexor tenosynovium for pathologic evaluation may be a unique opportunity to screen and treat a population of patients at risk for developing CA and heart failure.

Editorial

Background Spatial and biological characteristics of structural frontal disconnectivity in schizophrenia remain incompletely understood. Simultaneous streamline count (SC) and fractional anisotropy (FA) analyses may yield relevant complementary information to this end. Methods Using 3T diffusion magnetic resonance imaging both SC and FA were calculated for the tracts linking lateral and medial subregions of prefrontal cortex (PFC) to cingulate, hippocampus, caudate and thalamus in 27 schizophrenia patients (14 first-episodes) and 27 controls. Relationships of these parameters with cognition, symptoms, treatment doses and illness duration were assessed where significant between-groups differences were detected. Results Patients showed lower SC and FA in the tracts linking lateral and medial PFC to thalamus (likely corresponding to anterior thalamic peduncle) and lower FA in those linking PFC to caudate (likely through internal capsule), right caudal anterior cingulate and left hippocampus (likely corresponding to hippocampal-prefrontal pathway). Moreover, patients showed greater SC values for the tracts linking medial PFC and left caudal anterior cingulate. SC and FA values for the tracts linking PFC and caudal anterior cingulate were positively related to motor speed, executive function, problem solving and completed categories in WCST. FA for the tract linking right lateral PFC and caudate was directly related to positive symptoms and FA for the tract linking left medial PFC and left thalamus was inversely related to negative symptoms. Treatment doses were not associated with SC or FA values in any tract. Illness duration was negatively associated with SC and FA in the tracts linking PFC and subcortical areas. Conclusions Widespread alterations in frontal structural connectivity of PFC can be found in schizophrenia, and are related to cognition, symptoms and illness duration.

ObjectivesTo explore the effects of tofacitinib—an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)—with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand.MethodsIn this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with pResultsIn total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were −1.55 (90% CI −2.52 to −0.58) for tofacitinib + MTX and −1.74 (−2.72 to −0.76) for tofacitinib monotherapy (both p0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy.ConclusionsThese results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage.Trial registration numberNCT01164579.

Background: Philadelphia-like (Ph-like) subtype occurs in 15-20% of children patients diagnosed with precursor B cell (PCB) acute lymphoblastic leukemia (ALL). It is characterized by alterations in kinases and their receptors, affecting signaling pathways such as Jak2-Stat5, class Abl and Ras. It is particularly frequent (35%) in Hispano-Latino high risk PCB-ALL patients, residing in the USA. In Mexico, based on our ethnicity and the poor response to treatment of PCB-ALL pediatric patients, the Ph-like subtype could be frequent. However, this entity is widely variable and the diagnosis is based on genomic methods. In our country the incidence of leukemia is high, 78.1/1,000,000, and 83% of these cases are ALL. Therefore, it is important to detect Ph-like patients using diagnostic methods accessible to Institutions that treat patients with leukemia in our country. Aims: To develop an algorithm adapted to our local capacity for the diagnosis of Ph-like ALL children in Mexico. To determine the frequency of Ph-like patients in two Pediatric Institutions in our country Hypothesis: Ph-like ALL frequency in Mexican children will be higher than that reported in Hispano-Latino PCB-ALL patients. Methods, study design and laboratory studies: Bone marrow samples from 119 PCB-ALL patients (18≤ years old) at diagnosis were studied. Samples were collected at the Instituto Nacional de Pediatría and the Hospital Infantil de México Federico Gómez in Mexico City. Patients with recurrent gene fusions, ETV6-RUNX1, TCF3-PBX1,KMT2A-var and BCR-ABL1, were excluded. The Ph-like status of each patient was determined using molecular and biochemical methods. We analyzed a gene expression signature conformed by the genes: CRLF2, TSPN7, IGJ, PON2, SEMA6A and BMPR1B (q-RT-PCR), and detected the P2RY8-CRLF2 deletion (RT-PCR) in all patients. In those patients with overexpression of CRLF2, but negative to P2RY8-CRLF2, the IGH-CRLF2 rearrangement (FISH) was examined. The positive cases to P2RY8-CRLF2, without overexpression of CRLF2, were analyzed looking for minor subclones (FISH) with the deletion. IKZF1 deletions (nested RT-PCR) were analyzed in all patients. The biochemical studies included CRLF2 protein expression, phosphoflow analysis of Jak2-Stat5, class Abl and Ras targets (flow cytometry). All these assays were performed whenever the cell sample allowed it. Patients with two or more of the following characteristics were considered as Ph-like cases: with overexpression of 50% or more of the expression signature, positive to P2RY8-CRLF2 or IGH-CRLF2, alteration of one or more signaling pathways, with IKZF1 deletions. Results: In 50% (n=74) of patients CRLF2 overexpression was detected, within them 15% were positive to P2RY8-CRLF2 deletion, 17% to IGH-CRLF2 rearrangement, and 18% had an unidentified CRLF2 alteration that cause the overexpression. Within the 50% of cases without CRLF2 overexpression, 18% were positive to the P2RY8-CRLF2 rearrangement. IKZF1 deletion was evaluated in 55 patients and 72% were positive. Results obtained revealed a high frequency of CRLF2 and IKZF1. In 68 patients the gene expression profile was evaluated, 60% presented overexpression of 50% or more genes. The biochemical analysis revealed that 67% (n=42) of patients were positive to CRLF2 protein, 29% (n=21) had abnormal Jak2/Stat5 activation, 34% (n=32) presented abnormal Abl activation, and in 43% (n=7) abnormal Ras activation was detected. Not all the CRLF2 protein positive patients presented Jak2-Stat5 pathway activation (2%). Patients with more than one abnormal pathway were detected (18% with Jak2-Stat5/Abl or Abl/Ras, n=21). Based on our algorithm of analysis, 53% of the analyzed patients present genetic and biochemical characteristics of the Ph-like subtype. Conclusions: The combined methods contributed to identify Ph-like patients, the results demonstrate that the frequency of PCB-ALL children with Ph-like characteristics in Mexican patients is higher compared to other populations. This study demonstrates high frequency of CRLF2 alterations and IKZF1 deletions in PCB-ALL in Mexican population. In our experience, analysis of the pathway activation assays and the identification of CRLF2 and IKZF1 alterations are required to detect Ph-like patients. These results could be useful to stratify the childhood PCB-ALL patients in our country. Acknowledgments: CONACYT: PDCPN-2004/248591; Cátedra 2038. Disclosures No relevant conflicts of interest to declare.

Motor preparation for execution of both simple and choice reaction time tasks (SRT and CRT) involves enhancement of corticospinal excitability (CE). However, motor preparation also implies changes in inhibitory control that have thus far been much less studied. Short-interval intracortical inhibition (SICI) has been shown to decrease before CE increases. Therefore we reasoned that, if SICI contributes to inhibitory control of voluntary movement during the preparatory phase, it would be larger in CRT than in SRT because of the need to keep the movement unreleased until the uncertainty resolves on which task is required. We measured changes in SICI and in CE at different time points preceding motor reaction in normal subjects. Single-pulse transcranial magnetic stimulation (spTMS) and paired-pulse transcranial magnetic stimulation (ppTMS) produced time-dependent changes in both SRT and CRT, with shortening when applied close to the presentation of the imperative signal (“early”) and lengthening when applied near the expected reaction (“late”). In addition, at all stimulation time points, reaction time was shorter with ppTMS than that with spTMS, but there was no consistent association between the amount of SICI and reaction time changes. At early stimulation time points, CE was reduced in CRT but not in SRT. However, SICI in CRT was not different from SICI in SRT. At late stimulation time points, SICI decreased just before enhancement of CE. Our findings indicate that inhibitory circuits other than SICI are responsible for setting the level of CE at earlier parts of the reaction time period. Although the decrease in SICI may contribute to the increase in CE at the last part of the premotor period, the two phenomena are not dependent on each other.

Imagining motor actions is enough to enhance cortical motor excitability. However, the fact that execution of the motor task has to be inhibited should have a correlate on the extent of cortical excitability enhancement. Therefore, we examined the possible differences between real and motor imagery of simple reaction time tasks (SRT) in the facilitation of the motor-evoked potential (MEP) to transcranial magnetic stimulation (TMS) and in the reduction of short-interval intracortical inhibition (SICI) taking place before the movement onset. Thirteen healthy volunteers were requested to perform visual real or imaginary SRT tasks (rSRT and iSRT) with their dominant hand. For rSRT, subjects had to perform a rapid isometric squeeze as soon as possible after the imperative signal. For iSRT they had to imagine the same movement without actually doing it. Electromyographic (EMG) signals were recorded from the first dorsal interosseus (FDI) muscle. The mean EMG onset was calculated for each subject in rSRT trials. Single-and paired-pulse TMS (at an interstimulus interval of 2.5 ms) were applied at rest and at time intervals of -25, -50, -75, -100 and -125 ms before the expected real (rSRT) mean EMG onset. In rSRT there was a significant increase of MEP to single-pulseTMS at the intervals of -50 and -25 ms, and in iSRT at -50 ms in comparison to the rest condition. % SICI changes were significantly reduced at the intervals of -75, -50 and -25 ms, before EMG the onset in rSRT and at -50 and -25 in iSRT (P < 0.05) in comparison to % SICI changes at rest. The differences between MEPs to spTMS and MEP to ppTMS were significantly larger at rest, -125 and -100 ms intervals in rSRT, and at all intervals in iSRT. Imagining to move causes an increase in corticospinal excitability and a decrease in intracortical inhibition that follow a temporal profile similar to those observed with real movements. However, complete removal of SICI happened only in rSRT at the shortest intervals before the EMG onset. Such action may delineate new tool in motor rehabilitation of patients who have limitation to move.

Single-pulse transcranial magnetic stimulation (TMS) of the human motor cortex evokes simple muscle jerks whose physiological significance is unclear. Indeed, in subjects performing a motor task, there is uncertainty as to whether TMS-evoked outputs reflect the ongoing behavior or, alternatively, a disrupted motor plan. Considering force direction and magnitude to reflect qualitative and quantitative features of the motor plan respectively, we studied the relationships between voluntary forces and those evoked by TMS. In five healthy adults, we recorded the isometric forces acting a hand joint and the electromyographic activity in the first dorsal interosseous (FDI) muscle. Responses obtained at rest were highly invariant. Evoked responses obtained while subjects generated static and dynamic contractions were highly codirectional with the voluntary forces. Such directional relationships were independent of stimulation intensity, stimulated cortical volume, or magnitude of voluntary force exerted. Dynamic force generation was associated with a marked increase in the magnitude of the evoked force that was linearly related to the rate of force generation. The timing of central conduction was different depending on functional role of the target muscle, as either agonist or joint fixator. These results indicate that the architecture of motor plans remain grossly undisrupted by cortical stimulation applied during voluntary motor behavior. The significant magnitude modulation of responses during dynamic force generation suggests an essential role of the corticospinal system in the specification of force changes. Finally, the corticospinal activation depends on the functional role assumed by the target muscle, either postural or agonist.

Presentation of Case A 58-year-old right-handed woman was admitted to the hospital because of multiple cranial neuropathies. The patient had been well until two days earlier, when she began to have difficulty swallowing food while having dinner at home. During the next two or three hours, diplopia developed, with marked dysarthria to the point of losing the power of speech. She was taken to another hospital, where attempted magnetic resonance imaging (MRI) and angiographic studies could not be performed because of her inability to cooperate. Approximately 24 hours after her admission there, her condition was unimproved, and she was transferred . . .

During simultaneous generation of static and dynamic forces, motor cortical signals only predict the dynamic components, suggesting a key role in the coding of force changes. However, such a role is obscured by uncertainties regarding the representation of dynamic force signals in corticospinal outputs. We used transcranial magnetic stimulation (TMS) of the motor cortex in humans during a task that dissociated the direction of instantaneous net force and that of force derivative. The direction of TMS-evoked force outputs was closely associated with that of the force derivative, and had no relationship with that of the net force generated simultaneously, even though the magnitude of the instantaneous net force largely exceeded that of the force derivative. This observation supports the hypothesis that during dynamic force generation, the motor cortex and the corticospinal system assume a pivotal role in coding the direction of force changes, through selective recruitment of spinal motoneurons.

Background The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS). Methods We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center. Results We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later. Conclusions The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.

Short-interval intracortical inhibition (SICI) decreases during voluntary contraction of the target muscle. It is unknown whether this effect also occurs with postural contractions. We have compared the effects of voluntary and postural contractions on SICI in the soleus (SOL) muscle. We applied transcranial magnetic stimuli (TMS) in subjects under three tasks: sitting at rest (Rest), sitting while activating the SOL muscle (Voluntary), or standing quietly (Postural). In control trials, we applied suprathreshold TMS to obtain unconditioned motor-evoked potentials (MEPs). In test trials, the same TMS was preceded by a subthreshold TMS at different interstimulus intervals (ISIs), to obtain a conditioned MEP. SICI and intracortical facilitation (ICF) were expressed as the decrease or increase in MEP size relative to unconditioned MEPs. There was significant effect of task in mean SICI or mean ICF in SOL. Mean SICI in SOL was 52% in Rest and decreased to 21% in Voluntary and 15% in Postural. Mean ICF in SOL was 132% and decreased to 113% in Voluntary and to 108% in Postural. Mean SICI in SOL was not different in Voluntary and Postural tasks. There was no effect of task in mean SICI or mean ICF in TA. Our results indicate that decrease of SICI with muscle contraction occurs to a similar extent with tonic voluntary and postural activation, suggesting that those contractions require a similar type of cortical involvement. However, it cannot be excluded that some part of the SICI reduction with muscle contraction depends on changes in segmental excitability.

We describe a patient with long-standing pyoderma gangrenosum unresponsive to therapy. The patient had concomitant cryoglobulinemia and hepatitis C. When the hepatitis C was treated with interferon alfa-2a his pyoderma gangrenosum resolved. Whether this was from the interferon alfa or spontaneous resolution is not known.

Alpha-synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in alpha-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human alpha-synuclein, alpha-synuclein A30P, and alpha-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15x endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of alpha-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like alpha-synuclein inclusions could be identified. Biochemical analysis demonstrated alpha-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human alpha-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.

Severe neurologic complications following treatment with cyclosporine are uncommon. They tend to occur during the first month of treatment and disappear after withdrawal or reduction of the dose of the drug. We report the case of a man who underwent a liver transplantation and subsequently developed severe central nervous system toxicity. After two years receiving cyclosporine, he presented with a brachial monoparesis and a complex visual disturbance. Symptoms slowly worsened during four months. On admission, he had confusion and seizures. Multiple areas of T2 prolongation, located in cerebral white matter, were seen on magnetic resonance imaging (MRI). Symptoms partially improved after cyclosporine withdrawal, but brain lesions shown on MRI persisted in serial imaging studies after two years of follow-up. We discuss the mechanisms that have been proposed to explain this clinical picture. Severe cyclosporine-associated neurotoxicity can also occur after chronic administration, even with serum levels in therapeutic range.

Introducción: en el año 2006 existían en el mundo alrededor de 690 millones de personas mayores de 60 años. En los países desarrollados, más del 20 % de la población era de la tercera edad, como consecuencia de un aumento de la esperanza de vida y disminución de la natalidad. Objetivo: caracterizar la adherencia terapéutica antihipertensiva en pacientes mayores de 60 años. Método: se realizó un estudio descriptivo transversal sobre adherencia terapéutica antihipertensiva en el adulto mayor, en el policlínico “Omar Ranedo Pubillones” durante el año 2007. Se eligieron 43 pacientes de una muestra de 344. Resultados: la prescripción de fármacos hipotensores resultó adecuada en el 86,6 % de los pacientes estudiados. Los principales errores de prescripción se deben a intervalos terapéuticos inferiores, así como, dosis superiores a las recomendadas. Un tercio de los pacientes tenían conocimiento deficiente sobre HTA y, el 48,3 % no cumplen con el tratamiento indicado por el facultativo. Conclusiones: en la mayoría de los pacientes incluidos en la investigación existe una adherencia inadecuada al tratamiento antihipertensivo, lo que determinará a corto, mediano y largo plazo un incremento de la morbimortalidad por enfermedades cardiovasculares, cerebrovasculares, y su consiguiente impacto social.