[Clinical experience in the treatment of motor fluctuations in Parkinson's disease. Delphi consensus of a group of experts in movement disorders]. / Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.

INTRODUCTION: Motor fluctuations are one of the most common complications of Parkinson's disease and their treatment is still a complex matter. Therefore, from the Neurology Movement Disorders Group we present our clinical experience in the treatment of these complications, with the intention of it being useful in decision-making in daily clinical practice. DEVELOPMENT: Nineteen questions were developed based on a literature review and an open survey answered by members of this group. These issues were discussed in two phases, using the Delphi methodology. Considering the results of the survey, levodopa dose adjustment and dopamine agonists are the option with the best efficacy/tolerability ratio in the treatment of motor fluctuations. Rotigotine is useful in the motor fluctuations associated with gastroparesis, and intermittent subcutaneous apomorphine has positive effects in patients with unpredictable off periods. The most relevant adverse effect associated with dopamine agonists is impulse control disorder. Catechol-O-methyltransferase inhibitors are useful in the initial stages of motor fluctuations, especially in wearing off. Monoamine oxidase inhibitors are generally drugs that are well-tolerated and useful in motor fluctuations. If these measures are not effective, second-line treatments should be indicated on a case-by-case basis. CONCLUSION: The clinical profile of patients with Parkinson's disease is paramount in deciding the most appropriate therapy for the treatment of motor fluctuations.

TITLE: Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.Introducción. Las fluctuaciones motoras son una de las complicaciones más frecuentes en la enfermedad de Parkinson y su tratamiento sigue siendo complejo. Por ello, desde el Grupo de Trastornos del Movimiento de la Asociación Madrileña de Neurología presentamos nuestra experiencia clínica en el tratamiento de estas complicaciones, con la intención de que sea de utilidad en la toma de decisiones en la práctica clínica diaria. Desarrollo. Se elaboraron 19 preguntas a partir de una revisión bibliográfica y una encuesta abierta respondida por los miembros de dicho grupo. Dichas cuestiones se debatieron en dos fases, utilizando la metodología Delphi. Considerando los resultados de la encuesta, el ajuste de la dosis de levodopa y los agonistas dopaminérgicos son la opción con mejor relación eficacia/tolerabilidad en el tratamiento de las fluctuaciones motoras. La rotigotina es útil en las fluctuaciones motoras asociadas a gastroparesia, y la apomorfina subcutánea intermitente, en pacientes con off impredecible. El efecto adverso más relevante asociado a los agonistas dopaminérgicos es el trastorno del control de impulsos. Los inhibidores de la catecol-O-metiltransferasa son útiles en las fluctuaciones motoras de inicio, especialmente en el wearing off. Los inhibidores de la monoaminooxidasa son fármacos, en general, bien tolerados y útiles en las fluctuaciones motoras. En caso de que estas medidas no resulten eficaces, se deben indicar terapias de segunda línea de manera individualizada. Conclusión. El perfil clínico del paciente con enfermedad de Parkinson es primordial para decidir la terapia más adecuada en el tratamiento de las fluctuaciones motoras.

Choroidal haemangioma and photodynamic therapy. Anatomical and functional response of patients with choroidal hemangioma treated with photodynamic therapy. / Hemangioma coroideo y terapia fotodinámica. Respuesta anatómica y funcional de los pacientes con hemangioma coroideo tratados con terapia fotodinámica.

OBJECTIVE: To study the effectiveness and limitations of photodynamic therapy (PDT) as treatment of choice in patients with symptomatic circumscribed choroidal haemangioma. METHODS: A retrospective study was conducted on 16 patients (13 men and 3 women, with mean age of 54.88 years) with circumscribed choroidal haemangioma, who attended our centre and were treated with PDT in the last 7 years. RESULTS: All patients had circumscribed choroidal haemangioma, which caused a decrease in visual acuity (VA) secondary to the presence of intraretinal microcystic oedema or neurosensory detachment. The mean initial VA was 0.23, and the final mean VA after performing PDT was 0.38 (all the VA were measured in decimal scale). It should be noted that patients needed a mean of 1.69 PDT sessions. Three of the patients needed rescue treatment with trans-pupillary thermotherapy, intravitreal injection of anti-vascular endothelial growth factor (ranibizumab, aflibercept) or a dexamethasone intravitreal implant (Ozurdex®). The indication for a change of treatment was the persistence of intraretinal microcystic oedema and/or neurosensory detachment (or incomplete resolution) after 3 PDT sessions. As overall results, 62.5% of patients evolved into anatomical and functional (increase in AV or stability) resolution. CONCLUSIONS: PDT is a straight forward and fast procedure, with a good anatomical and functional response, causing minimal damage to adjacent vessels.

Retrospective multicentre observational study on clinical management and treatment of different types of status epilepticus in clinical practice. / Estudio observacional multicéntrico retrospectivo sobre el manejo clínico y terapéutico de los diferentes tipos de estatus epiléptico en la práctica clínica.

INTRODUCTION: Status epilepticus (SE) is a neurological emergency associated with significant mortality and morbidity. We analyse characteristics of this entity in our population. METHODS: Data from electronic medical records of adults diagnosed with SE were collected retrospectively from 5 hospitals over 4 years. RESULTS: Data reflected 84 episodes of SE in 77 patients with a mean age of 60.3 years. Of this sample, 52.4% had a previous history of epilepsy. Status classification: 47.6% tonic-clonic, 21.4% complex partial, 17.9% partial motor, 6% partial simple, 3.6% myoclonic, and 3.6% subtle SE. Based on the duration of the episode, SE was defined in this study as early stage (up to 30min) in 13.1%, established (30-120min) in 20.2%, refractory (more than 120min) in 41.7%, and super-refractory (episodes continuing or recurring after more than 24h of anaesthesia) in 13.1%. Ten patients (11.9%) died when treatment failed to control SE. The cumulative percentage of success achieved was 8.3% with the first treatment, 27.3% for the second, 48.7% for the third, 58.2% for the fourth, 70.1% for the fifth, 80.8% for the sixth, 83.2% for the seventh, and 84.4% for the eighth. CONCLUSIONS: In our study, we found that SE did not respond to treatment within 2h in approximately half the cases and 11.9% of the patients died without achieving seizure control, regardless of the type of status. Half the patients responded by the third treatment but some patients needed as many as 8 treatments to resolve seizures. Using large registers permitting analysis of the different types and stages of SE is warranted.

(+)-and (-)-Phenazocine enantiomers: Evaluation of their dual opioid agonist/σ1 antagonist properties and antinociceptive effects.

cis-N-Substituted N-normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity σ1 receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis-N-2-phenylethyl N-normetazocine (phenazocine) enantiomers showed mixed opioid/σ1 receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of σ1 pharmacological profile in the antinociceptive effects of (+)- and (-)-phenazocine. Therefore, the present study was designed to ascertain this component by in vitro and in vivo studies. In particular, we tested the σ1 affinity of both enantiomers by a predictive binding assay in absence or presence of phenytoin (DPH). Our results showed that DPH (1 mM) did not increase the σ1 receptor affinity of (+)-and (-)-phenazocine (Ki = 3.8 ± 0.4 nM, Ki = 85 ± 2.0 nM, respectively) suggesting a σ1 antagonist profile of both enantiomers. This σ1 antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ1 receptor agonist PRE-084, was able to unmask their σ1 antagonistic component associated with the opioid activity. The σ1 antagonistic component of (+)- and (-)-phenazocine may justify their analgesic activity and it suggests that they may constitute useful lead compounds to develop new ligands with this dual activity.

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin.

Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.

Dexamethasone intravitreal implants for diabetic macular edema refractory to ranibizumab monotherapy or combination therapy.

OBJECTIVE: To determine the effectiveness and local safety of dexamethasone intravitreal implants as a treatment in diabetic macular edema (DME) refractory to intravitreal injections of ranibizumab monotherapy or combination therapy. METHODS: A retrospective study conducted on patients with DME refractory to ranibizumab monotherapy or combined with other treatments treated with dexamethasone intravitreal implants. The parameters analyzed were visual acuity (VA) by ETDRS (Early Treatment Diabetic Retinopathy Study) charts and foveal thickness by spectral-domain optical coherence tomography (SD-OCT) before the treatment, 2 months after treatment, and at the end of the follow-up. RESULTS: A total of 14 eyes of 14 patients were included, with a mean age of 64 years (SD: 9.5; range 41-78) and a mean follow-up of 7.6 months. The mean VA improved from 53 letters to 59 letters at 2 months (P=.03), and 57 at the end of the follow-up period (P=.3). The mean foveal thickness decreased from 502 µ to 304 µ at 2 months (P=.001), and 376 µ at the end of the follow-up period (P=.009). Further treatment with intravitreal dexamethasone was required in 43% of the patients, and 21% had increased intraocular pressure, which was controlled with topical medication. CONCLUSIONS: Intravitreal dexamethasone implant is an effective and locally safe treatment for the management of DME refractory to ranibizumab monotherapy or combined with other treatments.

Cancer-testis antigens and immunotherapy in the light of cancer complexity.

The ability of immunotherapy to evoke successful antitumor immune responses has been well documented over the past decade. Despite abundant preclinical data, it is only with the recent approval by the Food and Drug Administration (FDA) of the drugs such as sipuleucel-T and ipilimumab that immunotherapy is finally being recognized as a viable alternative to traditional therapies for treatment of various cancers. Despite the ability of immunotherapy to elicit successful antitumor immune responses, its efficacy is hindered by several factors. Among these are the paucity of tumor-associated antigens (TAA) that can be used as effective targets and the systemic toxicities that often lead to treatment interruption. Indeed, such adverse effects, which can be immunological and/or parenchymal, can be particularly severe and even fatal to some patients. A family of TAA called cancer-testis antigens (CTA) has been identified and their encoding genes have been extensively investigated. CTA expression has been demonstrated in a variety of human cancer tissues, and at least 19 CTA have been found to elicit humoral and/or cellular immune responses in cancer patients. Here we discuss how CTA and immunotherapy will most likely play a major role in the cure of cancer in the light of cancer complexity.

Sperm protein 17 is an oncofetal antigen: a lesson from a murine model.

Sperm protein 17 (Sp17) was originally identified in the flagellum of spermatozoa and subsequently included in the subfamily of tumor-associated antigens known as cancer-testes antigens (CTA). Sp17 has been associated with the motility and migratory capacity in tumor cells, representing a link between gene expression patterns in germinal and tumor cells of different histological origins. Here we review the relevance of Sp17 expression in the mouse embryo and cancerous tissues, and present additional data demonstrating Sp17 complex expression pattern in this murine model. The expression of Sp17 in embryonic as well as adult neoplastic cells, but not normal tissues, suggests this protein should be considered an "oncofetal antigen." Further investigations are necessary to elucidate the mechanisms and functional significance of Sp17 aberrant expression in human adult cells and its implication in the pathobiology of cancer.

Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors.

RATIONALE: Sigma-1 (σ1) receptor inhibition ameliorates neuropathic pain by inhibiting central sensitization. However, it is unknown whether σ1 receptor inhibition also decreases inflammatory hyperalgesia, or whether peripheral σ1 receptors are involved in this process. OBJECTIVE: The purpose of this study was to determine the role of σ1 receptors in carrageenan-induced inflammatory hyperalgesia, particularly at the inflammation site. RESULTS: The subcutaneous (s.c.) administration of the selective σ1 antagonists BD-1063 and S1RA to wild-type mice dose-dependently and fully reversed inflammatory mechanical (paw pressure) and thermal (radiant heat) hyperalgesia. These antihyperalgesic effects were abolished by the s.c. administration of the σ1 agonist PRE-084 and also by the intraplantar (i.pl.) administration of this compound in the inflamed paw, suggesting that blockade of peripheral σ1 receptors in the inflamed site is involved in the antihyperalgesic effects induced by σ1 antagonists. In fact, the i.pl. administration of σ1 antagonists in the inflamed paw (but not in the contralateral paw) was sufficient to completely reverse inflammatory hyperalgesia. σ1 knockout (σ1-KO) mice did not develop mechanical hyperalgesia but developed thermal hypersensitivity; however, the s.c. administration of BD-1063 or S1RA had no effect on thermal hyperalgesia in σ1-KO mice, supporting on-target mechanisms for the effects of both drugs. The antiedematous effects of σ1 inhibition do not account for the decreased hyperalgesia, since carrageenan-induced edema was unaffected by σ1 knockout or systemic σ1 pharmacological antagonism. CONCLUSIONS: σ1 receptors play a major role in inflammatory hyperalgesia. Targeting σ1 receptors in the inflamed tissue may be useful for the treatment of inflammatory pain.

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.

BACKGROUND AND PURPOSE: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314. EXPERIMENTAL APPROACH: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed. KEY RESULTS: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314. CONCLUSIONS AND IMPLICATIONS: Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.

Preoperative study of the inner segment/outer segment junction of photoreceptors by spectral-domain optical coherence tomography as a prognostic factor in patients with epiretinal membranes.

OBJECTIVE: To demonstrate whether the preoperative integrity of the inner segment/outer segment (IS/OS) junction of photoreceptors studied by spectral-domain optical coherence tomography (SD-OCT) is a prognostic factor in epiretinal membrane surgery. METHODS: We retrospectively studied patients with an idiopathic epiretinal membrane who underwent a 23-gauge vitrectomy to remove this membrane. Best-corrected visual acuity (BCVA) and SD-OCT scans were examined before and 6 months after the surgery. We studied the retinal microstructure, especially the IS/OS junction of the photoreceptors, and evaluated the intergroup differences between patients with an intact layer and those with an irregular or disrupted layer. We applied both the Wilcoxon and Mann-Whitney tests for statistical analysis. RESULTS: In total, 51 eyes from 51 enrolled patients were examined in this study. The postoperative BCVA was significantly better for eyes that had an intact IS/OS junction than for eyes that had an irregular or disrupted IS/OS junction, as preoperatively observed with SD-OCT scans (P < 0.001). We also observed an important association between disrupted IS/OS junctions and the presence of cystic macular edema (P < 0.01). CONCLUSION: The presence of an intact IS/OS junction on the preoperative SD-OCT scan was an important predictor of better visual recovery after epiretinal membrane surgery.

Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1.

Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF-1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch-targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels.

Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes.

Multiple myeloma is a deadly hematopoietic malignancy. Despite therapeutic advances such as autologous stem cell transplantation and novel chemotherapeutics, multiple myeloma remains incurable. Multiple myeloma cell localization in the bone marrow and the cross-talk with the bone niche trigger dramatic alterations in the bone marrow microenvironment critical for tumor progression, resistance to therapies and osteolytic bone destruction. It does not surprise that the molecular bases of such fatal interaction are under examination as source of novel potential pharmacological targets. Among these, the Notch family of receptors and ligands has gained growing interest in the recent years because of their early deregulation in multiple myeloma and their ability to affect multiple features of the disease, including tumor cell growth, drug resistance, angiogenesis and bone lesions. This review will explore the evidences of Notch deregulation in multiple myeloma, the state of the art of the currently known roles of its signaling in the fatal interaction between multiple myeloma cells, extracellular matrix and cells in the bone marrow stroma. Finally, we will present recent findings concerning the arguments for or against a therapy addressed to Notch signaling inhibition in the cure of multiple myeloma.

[Utility and validity of indicators from the Nursing Outcomes Classification as a support tool for diagnosing Ineffective Self Health Management in patients with chronic conditions in primary health care]. / Utilidad y validez de un instrumento basado en indicadores de la Nursing Outcomes Classification como ayuda al diagnóstico de pacientes crónicos de At.

BACKGROUND: Self-care and management of therapeutic regime (drugs adherence, preventive behaviours and development of healthy life-styles) are key components for managing chronic diseases. Nursing has standardized languages which describe many of these situations, such as the diagnosis "Ineffective Self Health Management" (ISHM) or many of the Nursing Outcomes Classification (NOC) indicators. The aims of this study were to determine the interobserver reliability of a NOC-based instrument for assessment and aid in diagnosis of the ISHM in patients with chronic conditions in Primary Health Care, to determine its diagnostic validity and to describe the prevalence of patients with this problem. METHODS: Cross-sectional validation study developed in the provinces of Málaga, Cádiz and Almería from 2006 to 2009. Each patient was assessed by 3 independent observers: the first two observers evaluated scoring of the NOC indicators and the third one acted as the "gold-standard". RESULTS: Two hundred and twenty-eight patients were included, 37.7% of them with more than one chronic condition. NOC indicators showed a high interobserver reliability (ICC>0,70) and a consistency (Cronbach's alpha: 0.81). With a cut-point of 10.5, sensitivity was 61% and specificity 85%, and the area under the curve was 0.81 (CI95%: 0.77 to 0.85). The prevalence of patients with ISHM was 36% (CI 95%: 34 to 40). CONCLUSIONS: The use of NOC indicators allows evaluation of management of the therapeutic regime in people with chronic conditions with a satisfactory validity and it provides new approaches for dealing with this problem.

A therapeutic dose of FK506 does not affect collagen turnover pathways in healthy human gingival fibroblasts.

We previously demonstrated that a high dose of tacrolimus (1 mumol/L) induced expression of matrix metalloproteinase (MMP) proteins in human cultured gingival fibroblasts, suggesting a molecular mechanism maintaining gingival collagen homeostasis in tacrolimus-treated patients. Herein we have analyzed whether the effect on collagen turnover might be influenced by a therapeutic tacrolimus dose. Human gingival fibroblasts were incubated for 72 hours with 10 nmol/L, 100 nmol/L, and 1 mumol/L tacrolimus, or left untreated (CT). Collagen type I and III (COL-I, COL-III), lysyl hydroxylase 2b (LH2b), MMP-1 and -2, tissue inhibitor of MMP-1 and transforming growth factor-beta1 (TGF-beta1) mRNA levels were assayed by reverse-transcriptase polymerase chain reaction, collagen protein levels by dot blot, and MMP activity by sodium dodecyl sulfate zymography. Tacrolimus did not affect COL-I, COL-III, or MMP gene expression, while LH2b and TGF-beta1 tended to be down-regulated after 1 mumol/L FK506. Conversely, protein levels of MMP-1 (P = NS) and MMP-2 (P < .05 vs CT, 10 nmol/L, 100 nmol/L) were up-regulated after 1 mumol/L tacrolimus. Our findings confirmed that a high dose of tacrolimus does not induce interstitial collagen overexpression by gingival fibroblasts and induces up-regulation of MMPs protein levels. Interestingly, at doses corresponding to whole blood trough levels, tacrolimus did not exert any evident effect on collagen turnover pathways, suggesting that tacrolimus is likely to not affect collagen homeostasis in the gingival connective tissue compartment of FK506-immunosuppressed subjects. This effect did not seem to be dose-dependent.