[Incremental impact of population dispersion on health personnel resources in Primary Care]. / Impacto incremental de la dispersión poblacional sobre los recursos de personal sanitario en Atención Primaria.

OBJECTIVE: To quantify the incremental impact that population dispersion has on the number of health personnel in Primary Care in Alto Aragón, using a reproducible method. METHOD: Descriptive observational study that compares health the number of health personnel (family medicine, pediatrics and nursing) in EAP and PA emergencies in 2019 in an unpopulated and dispersed territory such as Huesca, with the number that would correspond to it by applying population ratios per professional of hypothetical constructs with different population densities. RESULTS: Huesca, with respect to the national average, has 39% more PA health personnel. There are 239 additional professionals (112 in family medicine, 2 in pediatrics and 115 in nursing), 130 in emergencies and 109 in EAP. With the average of the five most densely populated provinces, it would reduce this staff by 49%, and with the average of the five least densely populated provinces, it would increase it by 12%. CONCLUSIONS: There is a relationship between low population density and a greater number of family medicine and PC nurses, but not with pediatrics. The powerful incremental effect that dispersion has on health care spending gives it a relevant role in the regional financing system. Comparing PC health personnel in scenarios with different population density is a useful method for quantifying the impact of dispersion.

[Myelination as a modulating factor in memory circuitry]. / La mielinización como un factor modulador de los circuitos de memoria.

INTRODUCTION: Myelin has been understood for many years as a static component that regulates the speed of electrical impulse transmission. However, multiple works defend a dynamic role dependent on experience. This has allowed the development of a new concept called myelin plasticity that contributes, together with synaptic plasticity, to the long-term changes that occur in neuronal circuits during learning and memory. Therefore, this review will address the latest published data regarding the role of myelination with memory. DEVELOPMENT: Evidence from human neuroimaging studies demonstrates that myelination can change due to activity-dependent modulation, such that learning can modify the axon myelination. Alternatively, it has also been shown that interfering with myelination, using transgenic rodent models, significantly impairs memory processes. This has important implications in alterations as severe as Alzheimer's disease, where transcriptional changes and in the phenotype of cells associated with the myelination process begin to be described. CONCLUSIONS: The new knowledge supports the concept of myelin plasticity and its implications for memory, which opens a new opportunity for the treatment of deficits that affect this cognitive function.

TITLE: La mielinización como un factor modulador de los circuitos de memoria.Introducción. La mielina se ha conceptualizado durante muchos años como un componente estático que regula la velocidad de transmisión del impulso nervioso. Sin embargo, cada vez son más los trabajos que defienden un papel dinámico y dependiente de la experiencia. Esto ha permitido el desarrollo de un nuevo concepto denominado plasticidad mielínica, que contribuye, junto con la plasticidad sináptica, a los cambios a largo plazo que se dan en los circuitos neuronales durante el aprendizaje y la memoria. Por tanto, en esta revisión se abordarán los últimos datos publicados en relación con el papel de la mielinización con la memoria. Desarrollo. La evidencia a partir de estudios de neuroimagen en humanos demuestra que la mielinización puede cambiar debido a la modulación dependiente de la actividad, de forma que los aprendizajes pueden modificar la mielinización de los axones. Alternativamente, también se ha demostrado que interferir sobre la mielinización, utilizando para ello modelos transgénicos de roedores, deteriora significativamente los procesos de memoria. Esto tiene importantes implicaciones en alteraciones tan graves como la enfermedad de Alzheimer, en la que comienzan a describirse cambios transcripcionales y en el fenotipo de las células asociadas al proceso de mielinización. Conclusiones. Los nuevos descubrimientos apoyan el concepto de plasticidad mielínica y sus implicaciones con la memoria, lo que abre una nueva oportunidad para el tratamiento de los déficits que afectan a esta función cognitiva.

High-resolution structural insights on the sugar-recognition and fusion tag properties of a versatile ß-trefoil lectin domain from the mushroom Laetiporus sulphureus.

In this work, we analyzed at high resolution the sugar-binding mode of the recombinant N-terminal ricin-B domain of the hemolytic protein LSLa (LSL(150)) from the mushroom Laetiporus sulphureus and also provide functional in vitro evidence suggesting that, together with its putative receptor-binding role, this module may also increase the solubility of its membrane pore-forming partner. We first demonstrate that recombinant LSL(150) behaves as an autonomous folding unit and an active lectin. We have determined its crystal structure at 1.47 Å resolution and also that of the [LSL(150):(lactose)ß, γ)] binary complex at 1.67 Å resolution. This complex reveals two lactose molecules bound to the ß and γ sites of LSL(150), respectively. Isothermal titration calorimetry indicates that LSL(150) binds two lactoses in solution with highly different affinities. Also, we test the working hypothesis that LSL(150) exhibits in vivo properties typical of solubility tags. With this aim, we have fused an engineered version of LSL(150) (LSL(t)) to the N-terminal end of various recombinant proteins. All the designed LSL(150)-tagged fusion proteins were successfully produced at high yield, and furthermore, the target proteins were purified by a straightforward affinity procedure on agarose-based matrices due to the excellent properties of LSL(150) as an affinity tag. An optimized protocol for target protein purification was devised, which involved removal of the LSL(150) tag through in-column cleavage of the fusion proteins with His(6)-tagged TEV endoprotease. These results permitted to set up a novel, lectin-based system for production and purification of recombinant proteins in E. coli cells with attractive biotechnological applications.

[Implementation of a new referral model for the musculoskeletal care pathway: Does it improve healthcare outcomes?] / Implantación de un nuevo modelo organizativo en la atención al proceso musculoesquelético: ¿mejora la capacidad de resolución de los procesos?

OBJECTIVE: To evaluate the impact of an organisational change in the musculoskeletal referral pathway in our health management area (HMA) by identifying changes in the ability to improve healthcare outcomes by facilitating referral to the most suitable specialty. DESIGN: This prospective descriptive study aimed to evaluate referral trends from primary care services (PCS) and hospital care (PHS) to musculoskeletal services from 2012 to 2018. MATERIALS AND METHODS: We included all patients who were referred to any of the 3 musculoskeletal services from our HMA catchment area, without specifying sample size. The variables studied were PCS, PHS, service of origin and destination. We used the SPSS programme for the statistical analysis and obtained absolute frequency data. RESULTS: The total number of referrals from PCS increased from 25,575 in 2012 to 24,871 in 2018. PHS referrals decreased from 17,207 in 2012 to 9,803 in 2018. With regards to PCS referrals, the service most increasing the number of referrals to the musculoskeletal team was the Rehabilitation Service, from 8.2% in 2012 to 47% in 2018. Regarding PHSs referrals by specialty, the service that most reduced the number of referrals to the musculoskeletal team was the Traumatology Service, from 10,587 in 2012 to 3,911 in 2018. CONCLUSIONS: The redesign of the musculoskeletal referral pathway improved healthcare outcomes by improving the quality of the referral process. In this organisational change, the Rehabilitation Service took the leadership from the point of view of healthcare and management of the musculoskeletal process, collaborating in the improvement of the healthcare outcomes of these processes.

[Antineoplastic oral agents and drug-nutrient interactions: a sistematic review]. / Interacción de los antineoplásicos orales con los alimentos: revisión sistemática.

INTRODUCTION: Studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. OBJECTIVES: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. METHODS: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. RESULTS: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drug-food interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. DISCUSSION: Currently, the clinical importance of drug-food interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDA bioequivalence dictamen.

[Retroperitoneal fibrosis secondary to gastric neoplasia]. / Fibrosis retroperitoneal secundaria a neoplasia gástrica.

The retroperitoneal fibrosis is a very little frequent pathology that habitually includes the abdominal aorta and ureters. Two thirds of cases the etiology is idiopathic and in a third it is secondary to other causes as drugs, generalized infections or diseases and tumors which are considered to be responsible from 8 to 10%. The most frequent is colorectal adenocarcinoma, being anecdotal the gastric location with six described cases to date. We present a case of a patient with gastric cancer and secondary retroperitoneal fibrosis of difficult diagnosis and handling.

Pain assessment in individuals with dementia and communication problems in Spain. A systematic review. / Valoración del dolor en personas con demencia y problemas de comunicación en España. Revisión sistemática.

BACKGROUND AND OBJECTIVE: Pain assessment in individuals with advanced dementia and communication problems continue to be underdiagnosed and undertreated due to the difficulty in performing this assessment. This review explores and synthesises how pain in individuals with advanced dementia and communication problems are being assessed in the context of Spanish healthcare. MATERIALS AND METHODS: A systematic review of the literature was conducted following the PRISMA criteria. We reviewed the databases of PubMed, Web of Science, Cinahl, Scopus, Dialnet and Cuitatge up to December 2017. Four independent reviewers identified studies that included instruments to assess pain in individuals with dementia and communication problems in the Spanish healthcare context. We performed a narrative synthesis of the included articles. RESULTS: After applying the inclusion criteria, 10 studies were included. Of these, 4 were methodological studies validating Spanish versions of scales (Abbey, Algoplus, Doloplus and PAINAD-Sp), and 1 was on the development of the original EDAD scale. We also identified 3 studies conducted in Spain that used a translation of the PAINAD, 1 study that used a Spanish translation of Doloplus2 and 1 publication that included the use in Spain of a scale not validated for this patient profile (Pain-VAS). CONCLUSIONS: There are currently several instruments validated in Spanish to assess pain in individuals with advanced dementia and communication problems (Abbey, Algoplus, Doloplus y PAINAD-Sp). However, these instruments have still not been widely used in research, and their psychometric properties could be improved.

The Akt kinase signals directly to endothelial nitric oxide synthase.

Endothelial nitric oxide synthase (eNOS) is an important modulator of angiogenesis and vascular tone [1]. It is stimulated by treatment of endothelial cells in a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent fashion by insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) [2] [3] and is activated by phosphorylation at Ser1177 in the sequence RIRTQS(1177)F (in the single-letter amino acid code) [4]. The protein kinase Akt is an important downstream target of PI 3-kinase [5] [6], regulating VEGF-stimulated endothelial cell survival [7]. Akt phosphorylates substrates within a defined motif [8], which is present in the sequence surrounding Ser1177 in eNOS. Both Akt [5] [6] and eNOS [9] are localized to, and activated at, the plasma membrane. We found that purified Akt phosphorylated cardiac eNOS at Ser1177, resulting in activation of eNOS. Phosphorylation at this site was stimulated by treatment of bovine aortic endothelial cells (BAECs) with VEGF or IGF-1, and Akt was activated in parallel. Preincubation with wortmannin, an inhibitor of Akt signalling, reduced VEGF- or IGF-1-induced Akt activity and eNOS phosphorylation. Akt was detected in immunoprecipitates of eNOS from BAECs, and eNOS in immunoprecipitates of Akt, indicating that the two enzymes associate in vivo. It is thus apparent that Akt directly activates eNOS in endothelial cells. These results strongly suggest that Akt has an important role in the regulation of normal angiogenesis and raise the possibility that the enhanced activity of this kinase that occurs in carcinomas may contribute to tumor vascularization and survival.

Affective alterations in patients with Cushing's syndrome in remission are associated with decreased BDNF and cortisone levels.

OBJECTIVE: Affective alterations and poorer quality of life often persist in patients with Cushing's syndrome (CS) in remission. Brain-derived neurotrophic factor (BDNF) regulates the hypothalamic-pituitary-adrenal axis (HPA) and is highly expressed in brain areas controlling mood and response to stress. Our aims were to assess affective alterations after long-term remission of CS and evaluate whether they are associated with serum BDNF, salivary cortisol (SalF) and/or cortisone (SalE) concentrations. SUBJECTS AND METHODS: Thirty-six CS patients in remission (32 females/4 males; mean age (±s.d.), 48.8 ± 11.8 years; median duration of remission, 72 months) and 36 gender-, age- and BMI-matched controls were included. Beck Depression Inventory-II (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), Positive Affect Negative Affect Scale (PANAS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS) and EuroQoL and CushingQoL questionnaires were completed and measured to evaluate anxiety, depression, stress perception and quality of life (QoL) respectively. Salivary cortisol was measured using liquid chromatography/tandem mass spectrometry (LC/TMS). BDNF was measured in serum using an ELISA. RESULTS: Remitted CS patients showed worse scores in all questionnaires than controls: STAI (P < 0.001), BDI (P < 0.001), CES-D (P < 0.001), PANAS (P < 0.01), PSS (P < 0.01) and EuroQoL (P < 0.01). A decrease in BDNF was observed in CS vs controls (P = 0.038), and low BDNF was associated with more anxiety (r = -0.247, P = 0.037), depression (r = -0.249, P = 0.035), stress (r = -0.277, P = 0.019) and affective balance (r = 0.243, P = 0.04). Morning salivary cortisone was inversely associated with trait anxiety (r = -0.377, P = 0.040) and depressed affect (r = -0.392, P = 0.032) in CS patients. Delay to diagnosis was associated with depressive symptoms (BDI-II: r = 0.398, P = 0.036 and CES-D: r = 0.449, P = 0.017) and CushingQoL scoring (r = -0.460, P < 0.01). CONCLUSIONS: Low BDNF levels are associated with affective alterations in 'cured' CS patients, including depression, anxiety and impaired stress perception. Elevated levels of SalE might also be related to poor affective status in these patients.

Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents.

Nitric oxide synthases (NOSs) play a crucial role in the control of blood flow, memory formation, and the immune response. These proteins can be structurally divided into oxygenase and reductase domains. The reductase domain shares a high degree of sequence homology with P450 reductase, which is thought to be the major enzyme responsible for the one-electron reduction of foreign compounds, including bioreductive antitumor agents currently undergoing clinical trials. In view of the structural similarities between NOS and P450 reductase, we investigated the capacity of NOS to reduce the hypoxic cytotoxin tirapazamine, the antitumor agent doxorubicin, and also the redox cycling compound menadione. All three isoforms exhibited high levels of activity toward these compounds. In the case of doxorubicin and menadione, the activity of NOS II was 5-10-fold higher than the other enzymes, whereas with tirapazamine, the activities were broadly similar. NOS-mediated metabolism of tirapazamine resulted in a large increase in plasmid DNA strand breaks, demonstrating that the reduction was a bioactivation process. In addition, tirapazamine inhibited NOS activity. Because nitric oxide is implicated in maintaining tumor vascular homeostasis, it is conceivable that tirapazamine could potentiate its own toxicity by increasing the degree of hypoxia. This study suggests that the NOSs could play a key role in the therapeutic effects of tirapazamine, particularly because NOS activity is markedly increased in several human tumors. In addition, the presence of NOS in the heart indicates that these enzymes may contribute to the cardiotoxicity of redox cycling drugs, such as doxorubicin.

Reconstitution of hepatitis B surface antigen proteins into phospholipid vesicles.

Hepatitis B surface antigen (HBsAg), devoid of 75% of its total lipids has been reconstituted with several phospholipids by the detergent dialysis method, using the non-ionic detergent beta-D-octyl glucoside. Upon reconstitution with both neutral and acidic phospholipids, HBsAg particles had the same morphology and, as indicated by trypsin hydrolysis, the topology of the surface proteins was maintained. However, only negatively charged phospholipids were able to completely revert the conformational changes which had been induced by removal of the lipids. The helical content, as indicated by CD techniques, and the antigenic activity, as measured by binding to polyclonal antibodies, of HBsAg reconstituted with acidic phospholipids were practically identical to those of the native antigen. Cholesterol had no effect on the antigenic activity recovered by reconstitution with any of the phospholipids.

Antigenicity of hepatitis B surface antigen proteins reconstituted with phospholipids.

Hepatitis B surface antigen (HBsAg) has been reconstituted with different phospholipid classes. All epitopes defined by a panel of monoclonal antibodies which recognize both group- and subtype-specific antigenic determinants showed specificity for acidic phospholipids. Electrostatic interactions between HBsAg proteins and acidic phospholipids are partly responsible for the complete recovery of the antigenic properties. In addition to the nature of the polar head group, the fatty acid composition of the phospholipid also influenced the recovery of the antigenic activity. Negatively charged phospholipids must bear at least one unsaturated fatty acid in order to be effective in recovering full antigenic activity of HBsAg. The results reported herein support the conclusion that the antigenic activity is dependent on the physical state of the phospholipid moiety. The appropriate membrane fluidity is required for optimum conformation but, once this conformation is established, additional interactions imparted by the various phospholipids give a difference in the patterns of antigenicity. The analysis of binding of the monoclonal antibodies allowed the classification of the epitopes into two groups according to their dependence on the lipid moiety. Of all the antigenic determinants only those close to the lipid-protein interface would change upon direct interaction with the phospholipids. The rest would depend on the correct protein conformation determined by the appropriate phospholipid composition.

Cloning, expression, purification, and characterization of the major core protein (p26) from equine infectious anemia virus.

The gene coding for the major core protein (p26) of the lentivirus equine infectious anemia virus (EIAV) was cloned from EIAV infected serum, expressed in E. coli, and the resultant protein purified to electrophoretic homogeneity. The protein was expressed in a soluble form and was purified by conventional protein separation methods. When analyzed by SDS-PAGE, under both reducing and non-reducing conditions, the purified protein migrated as a 26 kDa monomer. Recombinant p26 (rp26), therefore, does not contain any intermolecular disulfide bond. Gel filtration chromatography also indicated that the protein occurs as a monomer in solution. Labeling of free sulphydryl groups with [1-14C]iodoacetamide suggests that none of the three cysteine residues of rp26 is involved in intramolecular disulfide bonds. The circular dichroism spectrum of rp26 was consistent with the following assignment of secondary structure elements: 51% a-helix, 15% beta-turn, and 34% aperiodic. Fluorescencespectroscopy revealed that the three tryptophan residues in rp26 occupy two different environments. These data support the conclusion that the recombinant protein is folded into an ordered and probably native conformation. Immunoblotting and enzyme immunoassay with EIAV infected sera demonstrated that recombinant p26 protein may be useful for diagnostic purposes.

Selective destabilization of acidic phospholipid bilayers performed by the hepatitis B virus fusion peptide.

A peptide corresponding to the N-terminal region of the S protein of hepatitis B virus (Met-Glu-Asn-Ile-Thr-Ser-Gly-Phe-Leu-Gly-Pro-Leu-Leu-Val-Leu-Gln) has been previously demonstrated to perform aggregation and destabilization of acidic liposome bilayers and to adopt a highly stable beta-sheet conformation in the presence of phospholipids. The changes in the lipid moiety produced by this peptide have been followed by fluorescence depolarization and electron microscopy. The later was employed to determine the size and shape of the peptide-vesicle complexes, showing the presence of highly aggregated and fused structures only when negatively charged liposomes were employed. 1,6-Diphenyl-1,3,5-hexatriene depolarization measurements showed that the interaction of the peptide with both negatively charged and zwitterionic liposomes was accompanied by a substantial reduction of the transition amplitude without affecting the temperature of the gel-to-liquid crystalline phase transition. These data are indicative of the peptide insertion inside the bilayer of both types of liposomes affecting the acyl chain order, though only the interaction with acidic phospholipids leads to aggregation and fusion. This preferential destabilization of the peptide towards negatively charged phospholipids can be ascribed to the electrostatic interactions between the peptide and the polar head groups, as monitored by 1-(4-(trimethylammoniumphenyl)-6-phenyl-1,3, 5-hexatriene fluorescence depolarization analysis.

Thermal stability of hepatitis B surface antigen S proteins.

Thermal stability of hepatitis B surface antigen (HBsAg) has been studied by analyzing alterations in the native secondary structure and the antigenic activity. After heating for 19 h, circular dichrosim showed a cooperative transition with a midpoint at 49 degrees C. The conformational changes induced by temperature reduced the helical content of HBsAg S proteins from 49% at 23 degrees C to 26% at 60 degrees C and abolished the antigenic activity, as measured by binding to polyclonal antibodies. Furthermore, the six different antigenic determinants recognized by our panel of monoclonal antibodies were also shown to be dependent on the native structure of HBsAg proteins. Hence, it can be inferred that these epitopes are conformation-dependent. Binding of monoclonal antibodies to HBsAg protected the native structure of the corresponding antigenic determinant from thermal denaturation. In fact, binding of one of the monoclonals tested resulted not only in protection of the corresponding epitope, but also in a consistent increase of antibody binding with increasing temperature. Such an increase in antibody binding occurred simultaneously with an increase in the fluidity of surface lipid regions, as monitored by fluorescence depolarization of 1-(trimethylammoniophenyl)-6-phenyl-1,3,5-hexatriene. This correlation, along with the observation that lipids play an important role in maintaining the structure and antigenic activity of HBsAg (Gavilanes et al. (1990) Biochem. J. 265, 857-864), allow to speculate the certain epitopes of HBsAg which are close to the lipid-protein interface, are dependent on the fluidity of the surface lipid regions. Thus, any change in the physical state of the lipids could confer a different degree of exposure to the antigenic determinants.

[Benign concentric annular macular dystrophy]. / Distrofia macular anular benigna.

CLINICAL CASES: Two cases of benign concentric macular dystrophy are described. In one case, ophthalmologic examination, fluorescein angiogram and visual field measurement were performed. The presence of a juxtafoveal fibrosis in the other patient, indicate that choroidal neovascularization may be associated with this type of macular dystrophy. DISCUSSION: Benign concentric macular dystrophy is an entity with well-defined ophthalmoscopic and angiographic characteristics. Usually the prognosis is good. Rarely, choroidal neovascularization can be associated with this macular dystrophy.

[Acute intoxication with sustained-release lithium carbonate tablets. A propos of a case]. / Intoxicación aguda por comprimidos de liberación sostenida de carbonato de litio. A propósito de un caso clínico.

OBJECTIVE: To describe the case of a patient who ingested 50 sustained release lithium carbonate 400 mg tablets, and reached a late peak concentration above 3 mEq/L. CASE REPORT: A 32-year-old male with bipolar mood disorder ingested 50 sustained-release lithium carbonate tablets. Upon admission to the emergency room, a gastric wash was performed,from which several tablet remnants were obtained, as well as an intestinal lavage using activated carbon. PHYSICAL EXAMINATION: good general status, no fever, blood pressure 160/90 mm Hg, no edemas. Neurologic, pulmonary, and cardiac examinations were normal. CBC and the chemistry panel were normal. The patient's psychopathological examination suggested a stable status with no apparent manifestations arising from a decompensated mood disorder. Five hours after his massive lithium ingestion the drug's plasma levels were 0.75 mEq/L. At 22 hours post-ingestion a chemistry panel was obtained, which showed serum creatinin at 1.38 mg/dL and a lithium plasma concentration of 3.15 mEq/L. A hemodyalisis trial was attempted for 4 hours. At 73 hours post-ingestion, lithium plasma levels were 0.6 mEq/L, that is, within therapeutic range. The patient was hemodynamically stable and serial blood tests were normal; he was discharged. COMMENT: Acute lithium intoxication with plasma levels above 3 mEq/l can be fatal or result in irreversible neurologicsequelae in almost one third of cases, with persistent cerebellar dysfunction in association with dementia of variable degree, andrenal, blood, and liver disturbances. Sustained-release tablets may prolong absorption and delay peak plasma concentrations. In such cases, therefore, it is recommended that drug plasma concentrations be monitored during 48-72 hours post-ingestion.

[Pharmaceutical care of patients with rheumatoid and psoriatic arthritis receiving etanercept]. / Atención farmacéutica a pacientes con artritis reumatoide y psoriásica en tratamiento con etanercept.

OBJECTIVE: To evaluate a pharmaceutical care protocol for patients with rheumatoid arthritis (RA) or psoriatic arthritis who begin treatment with etanercept with the objective of identifying potential medication-related problems and implementing therapeutic measures to improve the way this drug is used. METHOD: An observational, prospective, 3-month study of patients with RA receiving etanercept therapy from March to December 2003 was conducted and a pharmaceutical care protocol was set up. During the first visit, a pharmacotherapeutic record was initiated for each patient, including socio-demographic data, personal history, diagnosis, DMARDs (disease-modifying anti-rheumatic drugs) previously received, and concomitant therapies for other underlying conditions. Patients were briefed on dosage, administration route, and potential adverse events both orally and in writing. Correct drug administration and preservation were verified during the second visit, where potential adverse effects were identified, treatment adherence was confirmed, and, if needed, potential drug interactions with other ongoing medications were disclosed. During the third visit, adherence was assessed, adverse events were recorded, and patients evaluated their response to treatment. RESULTS: Fifty patients were included, 40 with a diagnosis of rheumatoid arthritis (80%) and 10 diagnosed with psoriatic arthritis (20%). In all, 72% had received previous treatment with methotrexate (MTX), 40% with leflunomide, 20% with infliximab, 56% with corticoids, 2% with analgesics, 56% with NSAIDs, and 30% with other DMARDs. CONCLUSIONS: No significant drug interactions were found. Regarding adherence to treatment, 7.7% of patients skipped one or more doses, with travelling being the most common reason. Adverse events reported included: injection site reaction (27%), headache (7.7%) and nausea (7.7%). At 3 months after treatment onset, a reduction of MTX doses was seen in 18% of patients, of leflunomide dosage in 8%, of corticoids in 18%, of analgesic usage in 6%, and of NSAIDs in 8% of patients. In agreement with these results, 92% of patients reported having experienced improvment.

White matter alterations in the brains of patients with active, remitted, and cured cushing syndrome: a DTI study.

BACKGROUND AND PURPOSE: Cushing syndrome appears after chronic exposure to elevated glucocorticoid levels. Cortisol excess may alter white matter microstructure. Our purpose was to study WM changes in patients with Cushing syndrome compared with controls by using DTI and the influence of hypercortisolism. MATERIALS AND METHODS: Thirty-five patients with Cushing syndrome and 35 healthy controls, matched for age, education, and sex, were analyzed through DTI (tract-based spatial statistics) for fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity (general linear model, family-wise error, and threshold-free cluster enhancement corrections, P < .05). Furthermore, the influence of hypercortisolism on WM DTI changes was studied by comparing 4 subgroups: 8 patients with Cushing syndrome with active hypercortisolism, 7 with Cushing syndrome with medication-remitted cortisol, 20 surgically cured, and 35 controls. Cardiovascular risk factors were used as covariates. In addition, correlations were analyzed among DTI values, concomitant 24-hour urinary free cortisol levels, and disease duration. RESULTS: There were widespread alterations (reduced fractional anisotropy, and increased mean diffusivity, axial diffusivity, and radial diffusivity values; P < .05) in patients with Cushing syndrome compared with controls, independent of the cardiovascular risk factors present. Both active and cured Cushing syndrome subgroups showed similar changes compared with controls. Patients with medically remitted Cushing syndrome also had reduced fractional anisotropy and increased mean diffusivity and radial diffusivity values, compared with controls. No correlations were found between DTI maps and 24-hour urinary free cortisol levels or with disease duration. CONCLUSIONS: Diffuse WM alterations in patients with Cushing syndrome suggest underlying loss of WM integrity and demyelination. Once present, they seem to be independent of concomitant hypercortisolism, persisting after remission/cure.

Identification of novel cellular proteins that bind to the LC8 dynein light chain using a pepscan technique.

Dynein is a minus end-directed microtubule motor that serves multiple cellular functions. We have performed a fine mapping of the 8 kDa dynein light chain (LC8) binding sites throughout the development of a library of consecutive synthetic dodecapeptides covering the amino acid sequences of the various proteins known to interact with this dynein member according to the yeast two hybrid system. Two different consensus sequences were identified: GIQVD present in nNOS, in DNA cytosine methyl transferase and also in GKAP, where it is present twice in the protein sequence. The other LC8 binding motif is KSTQT, present in Bim, dynein heavy chain, Kid-1, protein 4 and also in swallow. Interestingly, this KSTQT motif is also present in several viruses known to associate with microtubules during retrograde transport from the plasma membrane to the nucleus during viral infection.