Parkinson's disease: an update on preclinical studies of induced pluripotent stem cells.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among adults worldwide. It is characterised by the death of dopaminergic neurons in the substantia nigra pars compacta and, in some cases, presence of intracytoplasmic inclusions of α-synuclein, called Lewy bodies, a pathognomonic sign of the disease. Clinical diagnosis of PD is based on the presence of motor alterations. The treatments currently available have no neuroprotective effect. The exact causes of PD are poorly understood. Therefore, more precise preclinical models have been developed in recent years that use induced pluripotent stem cells (iPSC). In vitro studies can provide new information on PD pathogenesis and may help to identify new therapeutic targets or to develop new drugs.

[Potentially inappropriate prescribing: Usefulness of STOPP/START criteria version 2 in Catalonian elderly population]. / Prescripción potencialmente inadecuada: utilidad de los criterios STOPP/START versión 2 a nivel poblacional en Cataluña.

OBJECTIVE: To measure the prevalence of potentially inappropriate prescribing (PIP) among the elderly population in Catalonia using criteria Screening Tool of Older Person's Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) version 2. In addition, to evaluate the association between PIP and several factors (polypharmacy, gender, age and sociodemographic conditions). MATERIALS AND METHODS: Design: Retrospective cross sectional population study. SETTINGS: Primary Health Care, Catalonia, Spain. PARTICIPANTS: The study population comprised of participants 70 years old and over, who attended primary health care centres in Catalonia in 2014 (700.058 patients). MAIN ANALYSIS: 55 STOPP and 19 START criteria are applied to analyse PIP prevalence. Logistic regression models are adjusted to determine PIP association with several factors. RESULTS: The mean age is 79. 2±6.5. 58.5% being female. 38.7% of patients have 7 or more prescribed drugs, whereas 50% go to a primary care centre 10 or more times during one year. The most frequent PIP among STOPP criteria are related to nonsteroidal anti-inflammatory drug intake, antiplatelet and anticoagulants use, and benzodiazepines. According to START, the most frequent omissions are vitamin D and calcium supplements, antidepressants, and cardiovascular medications. Factors that increase PIP are: female gender, living in a nursing home, receiving home health care, polypharmacy and frequent visits to primary care centres. CONCLUSIONS: The overall prevalence of PIP is 89.6%. PPI is significantly related to certain drugs and patient's conditions. The knowledge of this association is important for the implementation of security measures for medical prescription.

Risk factors and comorbidities associated with severe aortic stenosis: A case-control study.

BACKGROUND AND OBJECTIVE: Aortic stricture (AS) is one of the most prevalent cardiovascular diseases in individuals 65 years of age or older. A number of epidemiological studies have suggested that certain cardiovascular risk factors (CRFs) and comorbidities could be associated with AS. The aim of this study was to evaluate the association between CRFs and comorbidities and severe symptomatic AS in individuals 65 years of age or older in a Spanish healthcare region. PATIENTS AND METHODS: We conducted an epidemiological case-control study from a single primary care centre. We collected information on exposure to CRFs and comorbidities and determined their association with AS, employing adjusted odds ratios (OR) and multiple logistic regression models. RESULTS: The study included 102 cases (mean age, 77.6 years) and 221 controls (mean age, 75.5 years). The CRFs significantly associated with severe symptomatic AS were hypercholesterolaemia (OR, 2.67; p < .001), tobacco use (OR, 2.60; p < .001), hypertension (OR, 2.41; p = .010) and low HDL cholesterol readings (OR, 2.20; p = .007). The comorbidities significantly associated with severe symptomatic AS were carotid stenosis (OR, 14.5; p = .017), stroke (OR, 4.14; p = .024), chronic renal failure (OR, 3.78; p < .001) and low haemoglobin levels (OR, 0.76; p < .001). CONCLUSIONS: Hypercholesterolaemia, tobacco use, arterial hypertension and low HDL cholesterol levels are the CRFs with a greater risk of severe AS. Furthermore, this disease is associated with a number of comorbidities (chronic renal failure, stroke, carotid stenosis and low haemoglobin levels), which could be markers of AS.

Parkinson's disease: An update on preclinical studies of induced pluripotent stem cells. / Enfermedad de Parkinson: actualización de estudios preclínicos con el uso de células troncales pluripotentes inducidas.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among adults worldwide. It is characterised by the death of dopaminergic neurons in the substantia nigra pars compacta and, in some cases, presence of intracytoplasmic inclusions of α-synuclein, called Lewy bodies, a pathognomonic sign of the disease. Clinical diagnosis of PD is based on the presence of motor alterations. The treatments currently available have no neuroprotective effect. The exact causes of PD are poorly understood. Therefore, more precise preclinical models have been developed in recent years that use induced pluripotent stem cells. In vitro studies can provide new information on PD pathogenesis and may help to identify new therapeutic targets or to develop new drugs.

Comparison of the Effects of Endotracheal Intubation of Wistar Rats Using the Conventional Technique vs. a New Modified Technique Using a 3D Mouth-Piece.

AIMS: Endotracheal intubation in rats is challenging due to the difficult anatomical characteristics of the airway. The success rate at first attempt is low and airway damage is a common complication. We aimed to compare and evaluate the conventional intubation method with a modified procedure using an inclined plate, headlamp (700-Lumen), and 3D mouth-piece designed with a 20° curvature. Both techniques were conducted by laboratory personnel with and without previous experience in airway management of laboratory rats. MATERIAL AND METHODS: In this study, we used 36 Wistar rats of both genders. Three groups of laboratory personnel (anesthesiologists, medical students, and laboratory technicians) performed both endotracheal intubation techniques, i.e., blind intubation at supine position and endotracheal intubation at 70° supine position with a 3D mouth-piece and direct illumination of the glottis. RESULTS: The modified technique had a significantly higher success rate and shorter procedure duration. Moreover, there was no significant difference in the procedure duration between personnel with and without previous training in airway management. CONCLUSION: Previous knowledge and experience in airway management are required when performing conventional endotracheal intubation; moreover, its success rate is low. Contrastingly, using proper instruments and the 3D mouth-piece facilitated easier and quicker airway management regardless of previous experience.

QSAR and molecular docking modelling of anti-leishmanial activities of organic selenium and tellurium compounds.

Leishmaniasis affects mainly rural areas and the poorest people in the world. A computational study of the antileishmanial activity of organic selenium and tellurium compounds was performed. The 3D structures of the compounds were optimized at the wb97xd/lanl2dz level and used in the quantitative structure-activity relationship (QSAR) analysis. The antileishmanial activity was measured by L. donovani ß carbonic anhydrase inhibition (Ki) and the half-maximal inhibitory concentration (IC50) against L. infantum amastigotes. The dataset was divided into training (75%) and test sets (25%) by using a k-means clustering algorithm. For pKi prediction, model M3 with seven 3D topographic descriptors was characterized by the following statistical parameters: r 2 = 0.879, Q 2 LOO = 0.822, and Q 2 ext = 0.840. For pIC50 prediction, model M12 with six attributes was characterized by the following statistical parameters: r 2 = 0.907, Q 2 LOO = 0.824, and Q 2 ext = 0.795. Both models met all the requirements of Tropsha´s test, which implies predictions of pIC50 and pKi activities with high accuracy. Concomitantly, favourable interactions of the sulphonamide group with the Zn atom in the protein were revealed by the docking analysis.

Risk factors and comorbidities associated with severe aortic stenosis: a case-control study. / Factores de riesgo y comorbilidades asociadas a la estenosis aórtica grave: estudio de casos y controles.

BACKGROUND AND OBJECTIVE: Aortic stricture (AS) is one of the most prevalent cardiovascular diseases in individuals 65 years of age or older. A number of epidemiological studies have suggested that certain cardiovascular risk factors (CRFs) and comorbidities could be associated with AS. The aim of this study was to evaluate the association between CRFs and comorbidities and severe symptomatic AS in individuals 65 years of age or older in a Spanish healthcare region. PATIENTS AND METHODS: We conducted an epidemiological case-control study from a single primary care centre. We collected information on exposure to CRFs and comorbidities and determined their association with AS, employing adjusted odds ratios (OR) and multiple logistic regression models. RESULTS: The study included 102 cases (mean age, 77.6 years) and 221 controls (mean age, 75.5 years). The CRFs significantly associated with severe symptomatic AS were hypercholesterolaemia (OR, 2.67; p<.001), tobacco use (OR, 2.60; p<.001), hypertension (OR, 2.41; p=.010) and low HDL cholesterol readings (OR, 2.20; p=.007). The comorbidities significantly associated with severe symptomatic AS were carotid stenosis (OR, 14.5; p=.017), stroke (OR, 4.14; p=.024), chronic renal failure (OR, 3.78; p<.001) and low haemoglobin levels (OR, 0.76; p<.001). CONCLUSIONS: Hypercholesterolaemia, tobacco use, arterial hypertension and low HDL cholesterol levels are the CRFs with a greater risk of severe AS. Furthermore, this disease is associated with a number of comorbidities (chronic renal failure, stroke, carotid stenosis and low haemoglobin levels), which could be markers of AS.

Comparative Study of Capillary Filtration Coefficient (Kfc) Determination by a Manual and Automatic Perfusion System. Step by Step Technique Review.

The purpose of calculating the capillary filtration coefficient is to experimentally evaluate edema formation in models of pulmonary ischemia-reperfusion injury. For many years, the obtaining of this coefficient implies a series of manual maneuvers during ex-vivo reperfusion of pulmonary arterial pressure, venous pressure and weight, as well as the calculation of the Kfc formula. Through automation, the calculation of capillary filtration coefficient could be easier and more efficient. To describe an automatic method designed in our laboratory to calculating the capillary filtration coefficient and compare with traditional determination of capillary filtration coefficient as gold standard method. An automatic three valve perfusion system was constructed, commanded by a mastery module connected to a graphical user interface. To test its accuracy, cardiopulmonary blocks of Wistar rats were harvested and distributed in manual (n=8) and automated (n=8) capillary filtration coefficient determination groups. Physiological parameters as pulmonary arterial pressure, pulmonary venous pressure, weight and capillary filtration coefficient were obtained. Results: Capillary filtration coefficient, pulmonary arterial pressure, venous arterial pressure shown no statistical significance difference between the groups. The automated perfusion system for obtaining Kfc was standardized and validated, giving reliable results without biases and making the process more efficient in terms of time and personal staff.

Correction: Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system.

The original version of this Article omitted the author Margarita Parada-kusz from the Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.

Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system.

Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor α (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARα resulted in increased KLF4+ goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased Reg3g, reduced luminal bacterial detection, and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARα signaling is critical to the global development of the intestinal immune system.

Theoretical analysis of C-F bond cleavage mediated by cob[I]alamin-based structures.

In the present work, C-F bond cleavage mediated by the super-reduced form of cobalamin (i.e., CoICbl) was theoretically studied at the ONIOM(BP86/6-311++G(d,p):PM6) + SMD level of theory. Dispersion effects were introduced by employing Grimme's empirical dispersion at the ONIOM(BP86-D/6-311++G(d,p):PM6) + SMD level. In the first stage of the study, cobalamin was characterized in terms of the coordination number of the central cobalt atom. The ONIOM(BP86/6-311++G(d,p):PM6) results showed that the base-off form of the system is slightly more stable than its base-on counterpart (ΔE = E base-off - E base-on ~ -2 kcal/mol). The inclusion of dispersive forces in the description of the system stabilizes the base-on form, which becomes as stable as its base-off counterpart. Moreover, in the latter case, the energy barrier separating both structures was found to be negligible, with a computed value of 1.02 kcal/mol. In the second stage of the work, the reaction CoICbl + CH3F → MeCbl + F- was studied considering the base-off and the base-on forms of CoICbl. The reaction that occurs in the presence of the base-on form of CoICbl was found to be kinetically more favorable (ΔE ≠ = 13.7 kcal/mol) than that occurring in the presence of the base-off form (ΔE ≠ = 41.2 kcal/mol). Further reaction-force analyses of the processes showed that the energy barrier to C-F bond cleavage arises largely due to structural rearrangements when the reaction occurs on the base-on form of the CoICbl complex, but is mainly due to electronic rearrangements when the reaction takes place on the base-off form of the complex. The latter behavior emerges from differences in the synchronicity of the bond strengthening/weakening processes along the reaction path; the base-on mode of CoICbl is able to decrease the synchronicity of the chemical events. This work gives new molecular-level insights into the role of Cbl-based systems in the cleavage of C-F bonds. These insights have potential implications for research into processes for degrading fluorine-containing pollutants.

Effects of Sildenafil and Tadalafil on Edema and Reactive Oxygen Species Production in an Experimental Model of Lung Ischemia-Reperfusion Injury.

BACKGROUND: Lung ischemia-reperfusion injury is characterized by formation of reactive oxygen species and cellular swelling leading to pulmonary edema and primary graft dysfunction. Phosphodiesterase 5 inhibitors could ameliorate lung ischemia-reperfusion injury by interfering in many molecular pathways. The aim of this work was to evaluate and compare the effects of sildenafil and tadalafil on edema and reactive oxygen species formation in an ex vivo nonhuman animal model of lung ischemia-reperfusion injury. METHODS: Thirty-two Wistar rats were distributed, treated, perfused and the cardiopulmonary blocks were managed as follows: control group: immediate excision and reperfusion without pretreatment; ischemia reperfusion group: treatment with dimethylsulfoxide 0.9% and excision 1 hour later; sildenafil group: treatment with sildenafil (0.7 mg/kg) and excision 1 hour later; and tadalafil group: treatment with tadalafil (0.15 mg/kg) and excision 2 hours later. All cardiopulmonary blocks except control group were preserved for 8 hours and then reperfused. Pulmonary arterial pressure, pulmonary venous pressure, and capillary filtration coefficient were measured. Reactive oxygen species were measured. RESULTS: Edema was similar between control and sildenafil groups, but significantly greater in the ischemia-reperfusion (P ≤ .04) and tadalafil (P ≤ .003) groups compared with the sildenafil group. The malondialdehyde levels were significantly lower in the sildenafil (P ≤ .001) and tadalafil (P ≤ .001) groups than the ischemia-reperfusion group. CONCLUSIONS: Administration of sildenafil, but not tadalafil, decreased edema in lung ischemia-reperfusion injury. Both drugs decreased reactive oxygen species formation in a lung ischemia-reperfusion injury model.

Primary Spinal Epidural Lymphoma As a Cause of Spontaneous Spinal Anterior Syndrome: A Case Report and Literature Review.

Background Primary spinal epidural lymphoma (PSEL) is one of the rarest categories of tumors. Spinal cord compression is an uncommon primary manifestation and requires to be treated with surgery for the purpose of diagnosis and decompression. Case Presentation A 45-year-old man presented with a new onset thoracic pain and progress to an anterior spinal syndrome with hypoesthesia and loss of thermalgesia. Magnetic resonance image showed a paravertebral mass that produces medullary compression at T3. The patient was taken up to surgery, where the pathology examination showed a diffuse large B-cell lymphoma. Conclusions PSEL is a pathological entity, which must be considered on a middle-aged man who began with radicular compression, and the treatment of choice is decompression and biopsy. The specific management has not been established yet, but the literature suggests chemotherapy and radiotherapy; however, the outcome is unclear.

Cardiac complications during pregnancy are better predicted with the modified WHO risk score.

BACKGROUND/OBJECTIVE: Several risk scores (RSs) have been used to stratify risk of cardiac complications (CCs) in pregnant patients with heart disease. We aimed to compare and contrast the accuracy of several RSs for predicting CC in this population. METHODS: Prospective inclusion of all consecutive pregnant patients with heart disease, and follow-up until 6 months postpartum. CCs were defined as primary if admission was required due to heart failure, arrhythmia or thromboembolic events, and secondary if the decline in NYHA class compared with baseline was >2 or urgent invasive cardiac procedures were needed. The discriminatory power of each RS was assessed by the area-under-the receiver-operating characteristic (ROC) curve (AUC). RESULTS: 179 patients, mean age: 32 years, accounted for 13.4% of CC (primary 11.7%, secondary 1.7%); the main diagnosis was congenital heart disease (CHD) in 68% followed by valvulopathies in 16%, arrhythmia in 7% and myocardiopathies in 5%. 22% (n=40) were classified as mWHO=1, 59% (n=105) mWHO=2 including subgroup 2-3, 14% (n=26) mWHO=3 and 4%(n=7) mWHO=4; 1 patient was unclassifiable. mWHO showed a better AUC (0.763) than CARPREG (0.67). For the CHD population, ZAHARA RS showed an AUC of 0.74, and Khairy an AUC of 0.632. CONCLUSIONS: mWHO was better at predicting CC than CARPREG; mWHO was also better at predicting CC than the specific CHD RS in the CHD subgroup. PRACTICE: There are an increasing number of pregnant women with HD. IMPLICATIONS: Improved prediction of CC risk during pregnancy can provide better preconception assessment in women with HD.

Survey of the knowledge and management of transient ischemic attacks among primary care physicians and nurses.

INTRODUCTION: Transient ischaemic attack (TIA) patients often report that Primary Care physicians (PCPs) and nurses are their main medical contacts after onset of symptoms in our health area. There are few studies on the knowledge and management of TIA among Community and Family Medicine professionals. MATERIAL AND METHODS: Our aim was to study the current knowledge and practice in the management of TIA patients among Primary Care physicians and nurses. A cross-sectional survey with seven questions about TIA was conducted among 640 PCPs and nurses from Primary Care centres in our health area. RESULTS: In total, 285 (46.7% PCPs) took participate in the study. Of these, 239 (83.9%) participants knew the duration of a TIA. However only 40 (14%) recognised all clinical symptoms. An urgent neuroimaging was preferred by 67%. Only 42.5% agreed that an urgent cervical duplex would be useful in these patients. Transcranial Doppler was recognised by only 35.4%. A majority (78.2%) of participants agreed that TIA patients must be admitted to hospital. PCPs had the best knowledge of TIA (odds ratio [OR] 2.138; 95% CI 1.124-4.067; P = 0.021) but there were no differences between physicians and nurses on the management of these patients. Nurses from rural Primary Care centers had the worst level of knowledge (OR 0.410; 95% CI 0.189-0.891; P = 0.024). CONCLUSION: TIA was well recognized as a medical emergency. However, knowledge of clinical symptoms of TIA must be improved.

[Prevalence study of iodine deficiency in a 6-year-old school population]. / Estudio de prevalencia de la deficiencia de yodo en una población escolarizada de 6 años.

INTRODUCTION: Iodine is a dietary element, a deficiency of which leads to complications grouped with the name Iodine Deficiency Disorders (IDD). The intake of foods rich in iodine is the only route of iodine administration. Iodine is considered to deficient when its concentration is less than 100 microg/L in urine, thus increasing the possibility of IDD. AIM: To determine the prevalence of iodine deficiency in 6-year-old school children in the region of Lleida. METHODS: A randomised cross-sectional study of 6-year-old school children in the area of Lleida was selected. After the acceptance, a questionnaire had to be filled in and a urine sample was collected to determine the urinary iodine. RESULTS: A total of 328 subjects were included (5 without urine sample), 46.8% boys, 54.27% in public schools, 17.2% immigrants and 40.95% had lunch at school. The majority (62.42%) ate fish twice or more a week, 60.98% used iodised salt and 90.65% drank milk daily. The iodine mean was 234.4 microg/l (SD=133.7). Only 9.29% (6.12-12.45%) had iodine deficiency which was associated to the type of school the children attended (private or public), immigrant origin, iodised salt, fish and milk nutrition. CONCLUSIONS: The prevalence of iodine deficiency in Lleida is lower than in previous publications, shown by the good nutrition parameters. The shortage of iodine is higher in immigrant boys, although better nutrition measures could be taken to improve their situation.

Differentiation and homing of IgA-secreting cells.

Most antibody-secreting cells (ASCs) in mucosal tissues produce immunoglobulin A (IgA), the most abundant immunoglobulin in the body and the main class of antibody found in secretions. IgA-ASCs differentiate in the mucosal-associated lymphoid tissues and are usually considered as a homogeneous population of cells. However, IgA-ASCs that travel to the small intestine have unique characteristics in terms of their migratory requirements. These IgA-ASCs require the homing molecules alpha4beta7 and CCR9 to interact with their ligands, mucosal addressin cell adhesion molecule-1 and CCL25, which are constitutively expressed in the small intestine. Indeed, recent work has shown that IgA-ASCs specific for the small bowel are generated under different conditions as compared with IgA-ASCs in other mucosal compartments. Moreover, the mechanisms inducing IgA class switching may also vary according to the tissue where IgA-ASCs differentiate. Here we describe the mechanisms involved in the differentiation of IgA-ASCs in mucosal compartments, in particular those involved in the generation of gut-homing IgA-ASCs.

Cyclosporine preconditions dendritic cells during differentiation and reduces IL-2 and IL-12 production following activation: a potential tolerogenic effect.

The mode of action of cyclosporine (CsA) has been ascribed to its capacity to inhibit IL-2 and IFNgamma production by T cells, two cytokines implicated in allograft rejection. Recently, it has been reported that upon activation, dendritic cells (DCs) exhibit transient production of IL-2, a property that appears to be related to their capacity to initiate immune responses. On the other hand, DCs can generate signals determining Th1/Th2 polarizing effects, an effect that can drastically influence the outcome of organ transplant. The purpose of the present study was to investigate the effect of CsA on cytokine production by immature and mature DCs. DC precursors from mouse bone marrow were induced to differentiate by incubation with GM-CSF for 5 days followed by activation with LPS for 4 hours. CsA was added at different times during this process. Our results show that when CsA is added during the differentiation period following activation with LPS, IL-2 and IL-12 secretion are significantly reduced without affecting the evolution of the DC. Conversely, CsA had no effect when added during the LPS activation period. These results show that CsA affects DCs before they receive the final activation stimulus, preconditioning them to antigen stimulation. This preconditioning of DCs by calcineurin-inhibiting drugs conceptually integrates the mode of action of CsA with the tolerogenic and T-cell polarization function ascribed to DCs. These results may be especially meaningful for the future design of immunosuppressive protocols.