Clinical and molecular characterization of hereditary spastic paraplegia in a spanish Southern region.

INTRODUCTION: Spastic paraplegia (SPG) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations. Despite of the new molecular technologies, many patients remain yet undiagnosed. OBJECTIVE: The purpose of this study was to describe the clinical presentation and molecular characteristics of a cohort of 27 patients from 18 different families with SPG in the south of Spain. METHODS: We used a targeted next-generation sequencing (NGS) approach to study a proband from each family. RESULTS: Variants in SPG11 gene were the most common cause of SPG in our area. We made a genetic diagnosis in 52% of cases, identified 3 novel variants and reclassified one uncertain variant in SPG11 gene as pathogenic variant. We identified a patient with two truncanting mutations in SPG11 gene and late onset disease and report another missense mutation outside of motor domain of KIF1A gene in a family with pure SPG. CONCLUSION: Our study contributes to enhance the scientific knowledge of SPG. It is important to note the large group of cases (48%) that were not genetically diagnosed in our cohort. Therefore NGS approach is an efficient diagnostic tool, but it still large the number of non-diagnosed subjects, suggesting further genetic heterogeneity.

Does correlation exist between anorectal manometry and endoanal ultrasound findings in healthy subjects according to age?

BACKGROUND: different studies have demonstrated the correlation between anorectal manometry and endoanal ultrasonography data in patients with fecal incontinence, but there is no almost interest describing the same in healthy subjects according to age. AIMS: to study the possible correlation between anorectal manometry and endoanal ultrasonography data in a homogeneous group of healthy women, also according to age. MATERIAL AND METHODS: prospective observational study of a healthy subjects cohort (n=14). Homogeneous group of healthy volunteer women divided in 2 subgroups according to age. RESULTS: there was no proved correlation between the internal anal sphincter's measurement and the resting pressure in the whole sample as well as the analysis according to age. Neither there was any proved statistically significant correlation between the external anal sphincter´s thickness and the squeeze pressure, in the whole sample and by groups. CONCLUSIONS: it does not exist statistically significant correlation between the thickness of the sphincters and its function in a healthy subjects homogeneous group, neither in 2 groups according to age.

[Evaluation of the collaboration between Primary and Hospital Care in order to improve inappropriate prescription]. / Evaluación de la colaboración entre atención primaria y hospitalaria para mejorar la polimedicación inapropiada.

INTRODUCTION AND OBJECTIVES: To evaluate the implementation of a collaborative experience between Primary (PC) and Hospital Care (HC) aimed at reducing potentially inappropriate prescribing (PIP) in patients with polypharmacy. MATERIALS AND METHODS: Collaborative experience including a controlled before-after intervention study, carried out in the Donostialdea Integrated Health Organization (IHO), with Bilbao Basurto IHO as control group, Osakidetza, Basque Health Service. Participant were 227 PC physicians and physicians from 7 hospital services, and patients with 5 or more drugs meeting at least one PIP criteria. The intervention consisted of communication and knowledge between professionals, PC-HC consensus, training, identification of patients at risk, medication review, evaluation and feed-back. The collaboration process (agreements, consensus documents, training activities) and the change in the prevalence of PIP in polymedicated patients (using computerised health records) were evaluated. RESULTS: A total of 21 PIP criteria and 6 recommendation documents were agreed. An analysis was performed on 15,570 PIP from OSI Donostialdea and 24,866 from the control group. The prevalence of PIP in polymedicated patients was reduced by -4.53% (95% CI: -4.71 to -4.36, P< .0001) in comparison with the control group. The before-after differences were statistically significant across the 7 services. CONCLUSIONS: PC-HC collaboration is feasible and, along with other intervention components, reduces inappropriate polypharmacy in the context of a recently integrated healthcare organisation. The collaboration process is complex and requires continuous monitoring, policy involvement, leadership that encourages health professional participation, and intensive use of information systems.

Discovery of a small molecule insulin mimetic with antidiabetic activity in mice.

Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.

[Relation between educational level and body composition in non-institutionalized elderly: The elderly EXERNET multi-center study.] / Relación entre el nivel educativo y la composición corporal en personas mayores no institucionalizadas: proyecto multi-céntrico EXERNET.

OBJECTIVE: There is an inverse association between educational level and body composition; however this association has strongly focused in young and adults population. The aim of this study was to analyze the educational levels attained in overweight and obesity Spanish elderly and to investigate if there was a correlation between having a low educational level and the risk of having overweight, central obesity or excess fat mass during the aging process. METHODS: A representative sample of 2706 elderly (629 men and 2077 women; mean age of 72.1 ± 5.3 years) from Spain were assessed in the elderly EXERNET multi-center study between 2008 and 2009. Body composition was assessed in all subjects by bioelectrical impedance. ANCOVA was used to compare the averages between the groups. Logistic regression was used to calculate the association between educational level and the risk of having overweight, central fat or obesity. RESULTS: We observed significances between waist circumference and educational level in both sex (men 96.6 cm, women 86.3 cm); (p less than 0.05 and p less than 0.01, respective). There is an inverse association between the academic level, fat mass (29.5 kg) and percentage of body fat (40.8%) in women (p less than 0.05, p less than 0.01, respectively). No differences were observed in men. CONCLUSIONS: low educational level increases the possibility of having overweight or obesity in women and to have an increased waist circumference in both sexes.

OBJETIVO: El nivel educacional se ha relacionado inversamente con la composición corporal, sin embargo esta asociación ha sido evidenciada mayoritariamente en población joven y adulta. El objetivo del presente estudio fue evaluar la relación entre la composición corporal de las personas mayores de 65 años y su nivel educativo, y determinar si tener un nivel educativo alto puede prevenir el riesgo de padecer sobrepeso, obesidad central o exceso de grasa durante la senectud. METODOS: El estudio se realizó entre los años 2008-2009, sobre una muestra representativa de personas mayores de España (2.706; 629 varones, 2.077 mujeres; edad media 72,1 ± 5,3 años), pertenecientes al Proyecto Multi-céntrico EXERNET. La composición corporal se evaluó mediante bio-impedancia eléctrica. Se utilizó ANCOVA para determinar las diferencias entre grupos. La asociación entre el nivel educativo y el riesgo de padecer sobrepeso, obesidad central o exceso de grasa se analizó mediante regresión logística. RESULTADOS: En el perímetro de cintura, los hombres y mujeres con mayor nivel de estudios presentaron 96,6 cm y 86,3 cm, respectivamente (pmenor de 0,05 y p menor de 0,01, respectivamente). Las mujeres con menor nivel de estudios presentaron 29,5 kg de masa grasa total y 40,8% de masa grasa (p menor de 0,05 y p menor de 0,01, respectivamente). Los varones no presentaron diferencias en estas mediciones. CONCLUSIONES: Poseer un bajo nivel de estudios aumenta las posibilidades de padecer sobrepeso y obesidad en las mujeres y de tener mayor perímetro de cintura en ambos sexos.

FM19G11 reverses endothelial dysfunction in rat and human arteries through stimulation of the PI3K/Akt/eNOS pathway, independently of mTOR/HIF-1α activation.

BACKGROUND AND PURPOSE: FM19G11 up-regulates mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) and PI3K/Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved. EXPERIMENTAL APPROACH: Effects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin-resistant rats (IRR). Its effects on vasodilator responses of penile arteries (HPRAs) and corpus cavernosum (HCC) from men with vasculogenic erectile dysfunction (ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated-endothelial NOS (p-eNOS), phosphorylated-Akt (p-Akt) and HIF-1α was determined by immunodetection and cGMP by elisa. KEY RESULTS: Chronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. Ex vivo treatment with FM19G11 also significantly improved endothelium-dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p-eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p-Akt and p-eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11-induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF-1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients. CONCLUSIONS AND IMPLICATIONS: Stimulation of the PI3K/Akt/eNOS pathway by FM19G11 alleviates impaired NO-mediated endothelial vasodilatation in rat and human arteries independently of mTOR/HIF-1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED.

Inhibitors of farnesylation of Ras from a microbial natural products screening program.

Mutant ras oncogenes are associated with various human tumors such as pancreas, colon, lung, thyroid, bladder and several types of leukemia. Prenylation of Ras proteins plays a major role in cell proliferation of both normal and cancerous cells. Normal and oncogenic Ras proteins are posttranslationally modified by a farnesyl group that promotes membrane binding. Inhibitors of farnesyl protein transferase (FPTase), the enzyme that catalyzes the prenylation of Ras proteins, inhibit growth of tumor cells. In an effort to identify structurally diverse and unique inhibitors of FPTase, a program devoted to screening of natural products was initiated. This effort led to the identification of 10 different families of compounds, all of which selectively inhibit FPTase with a variety of mechanisms that are reviewed in this manuscript. These compounds originated from the fermentations of a number of microorganisms, either actinomycetes or fungi, isolated from different substrates collected in tropical and temperate areas. A chemotaxonomic discussion on the distribution of each compound among single or different types of microorganisms, either phylogenetically related or unrelated species, is included.

[The evaluation of the efficacy of a multidisciplinary treatment in a group of obese patients with a BMI > or = 35 and a change in lung function]. / Valoración de la eficacia de un tratamiento multidisciplinario en un grupo de pacientes obesos con IMC > o = 35 y alteración de la función pulmonar.

OBJECTIVE: To assess the efficacy of an interdisciplinary protocol for treating obesity in a group of patients with BMI > or = 35 and with altered respiratory function that was not necessarily related to obesity or not. PATIENTS AND METHOD: Forty obese individuals between 18 and 60 years of age with altered respiratory function were enrolled. Spirometric values, plethysmograph volumes, arterial blood gases, and nighttime respiratory polygraphs were recorded. Following psychological and nutritional evaluation, the patients commenced year-long treatment for obesity involving a personalized diet and psychological counseling. Follow-up was weekly and individualized at first; in later sessions, patients were grouped. Lung function tests were repeated after loss of 5 kg. Sleep polygraphy was repeated after loss of 10 kg. RESULTS: Weight loss over 15 kg was achieved by 48.6% of the patients. Respiratory function variables: FVC, FEV1, RV, ERV, PaO2 and SatO2 after treatment changed significantly from initial levels. Significant differences were also seen in the severity of sleep apnea and pressures needed for continuous positive airway pressure. Uric acid, glucose and triglyceride blood levels became normal in 89%, 61% and 50% of the patients, respectively, after weight loss. No characteristic psychological profile was identified for severe obesity, although levels of anxiety, eating behavior, marital adjustment and perception of body image were aspects that were fundamentally altered. CONCLUSIONS: In the difficult group of obese patients with BMI > or = 35, interdisciplinary treatment has proven effective for achieving substantial weight loss, while improving respiratory function and severity of sleep disorder. This therapy, which is at present viable for few centers, deserves consideration in the interest of benefiting the increasing number of obese patients.

[Painful bilateral lumbar radiculoplexopathy associated with Epstein-Barr virus infection]. / Radiculoplexopathie lombaire douloureuse bilatérale associée à une infection par le virus d'Epstein-Barr.

We report a case of polyneuropathy caused by primary Epstein Barr virus (EBV) infection in a 57-year-old patient. The primary EBV infection was confirmed by serology tests and EBNA (Epstein-Barr nuclear antigen) seroconversion. The main clinical sign was a highly painful subacute, bilateral lumbar radiculoplexopathy with amyotrophy which responded to corticosteroids and complement treatment within a few months. The association of left facial paralysis, neurophysiological signs of polyradiculopathy and elevated protein levels in the cerebrospinal fluid demonstrate the variability of peripheral neurological involvement in the same subject with EBV infection. This case also demonstrates the poorly limits of dysimmune polyneuropathies, including lumbar radiculoplexopathy which can be considered as an exceptional variant.

Relación entre el nivel educativo y la composición corporal en personas mayores no institucionalizadas: proyecto multi-céntrico Exernet / Relation between educational level and body composition in non-institutionalized elderly: the elderly EXERNET multi-center study

Fundamentos: El nivel educacional se ha relacionado inversamente con la composición corporal, sin embargo esta asociación ha sido evidenciada mayoritariamente en población joven y adulta. El objetivo del presente estudio fue evaluar la relación entre la composición corporal de las personas mayores de 65 años y su nivel educativo, y determinar si tener un nivel educativo alto puede prevenir el riesgo de padecer sobrepeso, obesidad central o exceso de grasa durante la senectud. Métodos: El estudio se realizó entre los años 2008-2009, sobre una muestra representativa de personas mayores de España (n= 2,706; 629 varones, 2,077 mujeres; edad media 72,1 ± 5,3 años), pertenecientes al Proyecto Multi-céntrico EXERNET. La composición corporal se evaluó mediante bio-impedancia eléctrica. Se utilizó ANCOVA para determinar las diferencias entre grupos. La asociación entre el nivel educativo y el riesgo de padecer sobrepeso, obesidad central o exceso de grasa se analizó mediante regresión logística. Resultados: En el perímetro de cintura, los hombres y mujeres con mayor nivel de estudios presentaron 96,6 cm y 86,3 cm, respectivamente (p<0,05 y p<0,01, respectivamente). Las mujeres con menor nivel de estudios presentaron 29,5 kg de masa grasa total y 40,8% de masa grasa (p<0,05 y p<0,01, respectivamente). Los varones no presentaron diferencias en estas mediciones. Conclusiones: Poseer un bajo nivel de estudios aumenta las posibilidades de padecer sobrepeso y obesidad en las mujeres y de tener mayor perímetro de cintura en ambos sexos (AU)

Background: There is an inverse association between educational level and body composition; however this association has strongly focused in young and adults population. The aim of this study was to analyze the educational levels attained in overweight and obesity Spanish elderly and to investigate if there was a correlation between having a low educational level and the risk of having overweight, central obesity or excess fat mass during the aging process. Methods: A representative sample of 2706 elderly (629 men and 2077 women; mean age of 72.1 ± 5.3 years) from Spain were assessed in the elderly EXERNET multi-center study between 2008 and 2009. Body composition was assessed in all subjects by bioelectrical impedance. ANCOVA was used to compare the averages between the groups. Logistic regression was used to calculate the association between educational level and the risk of having overweight, central fat or obesity. Results: We observed significances between waist circumference and educational level in both sex (men 96.6 cm, women 86.3 cm); (p<0.05 and p<0.01, respective). There is an inverse association between the academic level, fat mass (29.5 kg) and percentage of body fat (40.8%) in women (p<0.05, p<0.01, respectively). No differences were observed in men. Conclusions: A low educational level increases the possibility of having overweight or obesity in women and to have an increased waist circumference in both sexes (AU)

Anorgasmia masculina como síntoma inicial de mielitis transversa / Male anorgasmia as initial symptom of transverse myelitis

No disponible

Contribución de los estudios neurofisiológicos seriados en el síndrome de Guillain-Barré atípico / Contribution of serial neurophysiological studies in atypical Guillain-Barré syndrome

No disponible

Attenuating pregnane X receptor (PXR) activation: a molecular modelling approach.

Recent studies have demonstrated that the pregnane X receptor (PXR) is a key regulator of cytochromes P450 3A (e.g. CYP3A4 in human) gene expression. As a result, activation of PXR may lead to CYP3A4 protein over-expression. Because induction of CYP3A4 could result in clinically important drug drug interactions, there has been a great interest in reducing the possibility of PXR activation by drug candidates in drug-discovery programmes. In order to provide structural insight for attenuating drug candidate-mediated PXR activation, we used a docking approach to study the structure activity relationship for PXR activators. Based on our docking models, it is proposed that introducing polar groups to the end of an activator should reduce its human PXR (hPXR) activity via destabilizing interactions in the hydrophobic areas of the PXR ligand-binding pocket. A number of analogues that incorporate these structural features then were designed and synthesized, and they exhibited significantly lower hPXR activation in a transactivation assay and decreased CYP3A4 induction in a human hepatocytes-based assay. In addition, an example in which attenuating hPXR activation was achieved by sterically destabilizing the helices 11 and 12 of the receptor is presented.

Comparison of genotypic and phenotypic techniques for assessing the variability of the fungus Epicoccum nigrum.

AIMS: The diversity within a collection of worldwide isolates of Epicoccum nigrum has been studied using several phenotypic approaches. In addition, the abilities of phenotypic and genotypic techniques for the differentiation of a set of isolates are compared. METHODS AND RESULTS: The methodology used include the study of isozymes (acetyl esterase and alkaline phosphatase), HPLC profile of metabolites and antibiotic activities against a panel of bacteria, yeasts and filamentous fungi, and cytotoxicity against three mammalian cell lines. Two procedures for assessing the relationships within a collection of isolates, using a combination of the techniques, were evaluated, comparing the advantages and disadvantages of each method. CONCLUSIONS: The results showed that each individual technique allows differentiation of the isolates studied to some degree and that the information provided by each technique could be considered as complementary. Genotypic techniques were more powerful than the phenotypic ones to discriminate among the strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This work evaluates the predictive value of several phenotypic techniques on a collection of fungal isolates, and compares the results obtained with genotypic techniques performed on the same strains.

[Paraganglioma of the cauda equina]. / Paraganglioma de la cauda equina.

The case of a 36 year old woman with a paraganglioma of the cauda equina was studied. This localization is rare and special emphasis is made concerning the peculiarities of presentation, aggravating factors of the clinical manifestations and neuroradiologic findings. A review of the 66 paragangliomas of the cauda equina published to date is carried out. This entity deals with a tumor in the adult, with slight male predominance and a clinical presentation not differing from that of other lesions occupying the space of the cauda equina. The most frequent initial symptom is low back pain with or without sciatic irradiation. Total resection of the tumor may cure the patient.