[Intermittent theta-burst transcranial magnetic stimulation for the treatment of spasticity in patients with recurring multiple sclerosis: the results of a double-blind randomised clinical trial]. / Estimulacion magnetica transcraneal theta-burst intermitente para el tratamiento de la espasticidad en pacientes con esclerosis multiple recurrente: resultados de un ensayo clinico aleatorizado doble ciego.

AIM: It has been suggested that the repetitive transcranial magnetic stimulation could be useful as a non-pharmacological treatment for spasticity. The aim of this study was to evaluate the clinical and neurophysiological effects of high-frequency intermittent theta burst stimulation (iTBS) on lower limb spasticity in patients with relapsing multiple sclerosis in a randomized, double-blind placebo controlled trial. PATIENTS AND METHODS: Seventeen patients in the remitting phase of the disease were randomly allocated to sham or magnetic therapy group and underwent iTBS over contralateral motor cortex of the most affected leg once a day for two weeks. Each session consisted of 10 bursts containing three pulses at 50 Hz repeated at 200 ms intervals (5 Hz) every 10 s for a total of 600 stimuli. The iTBS effect was assessed by using clinical (such as the Modified Ashworth Scale) and neuro-physiological (H/M amplitude ratio and cortical silent period duration) parameters. RESULTS: Two-week iTBS over motor cortex of the most affected leg did not produce any significant clinical effect on spasticity. However, it decreases the H/M amplitude ratio and increases duration of cortical silent period but not significantly, in patients with relapsing multiple sclerosis. CONCLUSION: The stimulation protocol used in this study does not have significant therapeutic effect. Therefore, we do recommend further studies as neurophysiological changes were evident.

TITLE: Estimulacion magnetica transcraneal theta-burst intermitente para el tratamiento de la espasticidad en pacientes con esclerosis multiple recurrente: resultados de un ensayo clinico aleatorizado doble ciego.Objetivo. La estimulacion magnetica transcraneal repetitiva podria ser util como tratamiento no farmacologico para la espasticidad. El objetivo de este estudio es reevaluar el efecto clinico y los cambios neurofisiologicos que produce la estimulacion theta-burst intermitente (ETBi) sobre la espasticidad de las extremidades inferiores en pacientes con esclerosis multiple recurrente en un ensayo aleatorizado, doble ciego, controlado con placebo. Pacientes y metodos. Diecisiete pacientes en la fase remitente de la enfermedad fueron aleatoriamente asignados al grupo placebo o al grupo de tratamiento activo mediante estimulacion magnetica transcraneal repetitiva con protocolo ETBi sobre la corteza motora contralateral de la pierna mas afectada. El procedimiento consistio en 10 sesiones diarias durante dos semanas. Cada sesion consistio en 10 rafagas que contenian tres pulsos a 50 Hz repetidos a intervalos de 200 ms (5 Hz) cada 10 s para un total de 600 estimulos. El efecto de ETBi se evaluo mediante el uso de parametros clinicos (como la escala de Ashworth modificada) y neurofisiologicos (ratio de amplitud H/M y duracion del periodo cortical silente). Resultados. Dos semanas de ETBi sobre la corteza motora de la pierna mas afectada no produjeron ningun efecto clinico significativo sobre la espasticidad en pacientes con esclerosis multiple recurrente. Sin embargo, aunque de forma no significativa, se observo disminucion de la ratio de amplitud H/M y un aumento de la duracion del periodo cortical silente. Conclusion. El protocolo de estimulacion utilizado en este estudio no parece tener un efecto terapeutico significativo. Sin embargo, recomendamos estudios adicionales, ya que los cambios neurofisiologicos fueron evidentes.

B subset cells in patients with chronic granulomatous disease in a Mexican population.

INTRODUCTION: Chronic granulomatous disease (CGD) is a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH oxidase complex activity. Although the effect of CGD mainly reflects the phagocytic compartment, B cell responses are also impaired in patients with CGD. MATERIALS AND METHODS: Flow cytometric analysis was performed on peripheral blood samples from 35 CGD patients age-matched with healthy controls (HC). The target cells of our study were the naive (IgD+/CD27-), memory (IgD-/CD27+), and B1a (CD5+) cells. Immunoglobulins (Igs) were also measured. This study was performed in a Latin American cohort. RESULTS: We found significantly higher levels of naive B cells and B1a cells, but lower levels of memory B cells were found in CGD patients compared to HC. There was no significant difference of cell percentages per inheritance type. DISCUSSION: Our findings suggest that the deficiency of NADPH oxidase components can affect the differentiation of naive B cells to memory B cells. Consequently, memory cells will be low, which also influenced the expression of CD27 in memory B cells and as a result, the percentage of naive cells increases. An altered phenotype of B lymphocytes in CGD patients may contribute to the opportunistic infections and autoimmune disorders that are seen in this disease.

Proteomic profile of histotroph during early embryo development in mares.

There is a complex cascade involving proteins during early embryo development and maternal recognition, which is very important for maintenance of a conceptus. The aim of this study was to compare proteomic profile of uterine fluid after ovulation in pregnant and cyclic mares. In the first cycle, samples of uterine fluid of 30 cyclic mares were collected on days 7 (n = 10), 10 (n = 10) and 13 (n = 10) post ovulation and constituted the Cyclic group. In the second cycle, the same mares were bred to a fertile stallion. At days 7, 10 and 13 uterine fluid samples were collected. Immediately after sample collection, the mare's uteri were flushed, and those with an embryo recovered were assigned to the Pregnant group. Of the 30 mares flushed embryos were recovered from 6 mares on day 7, 6 on day 10 and 6 on day 13. Samples from the mares without embryo recovery were excluded from both groups. The uterine fluid samples were processed by two-dimensional electrophoresis technique followed by matrix assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry for the identification of relevant protein spots. From a total of 677 detected spots 19 were identified, 13 more abundant in Pregnant group and 6 in Cyclic group. In summary, pregnant and cyclic mares showed proteins with different abundance. Identified proteins were related to the transport of lipids through the embryo capsule, uterine motility, ATP generation, maternal immunological tolerance, cell proliferation, differentiation, metabolism and angiogenesis. Changes in the proteomic profile of uterine fluid during early embryo development in mares were related with the conceptus presence, suggesting that these alterations may be important for conceptus development and maternal recognition of pregnancy.

Ultrastructural and histological characteristics of the endometrium during early embryo development in mares.

The aim of this study was to evaluate ultrastructural and histological changes in the endometrium on days 7, 10 and 13 post-ovulation in pregnant and cyclic mares. Mares were routinely examined by transrectal palpation and ultrasonographic examination of the reproductive tract until estrus was detected. In the first cycle, endometrial biopsies from 30 cyclic mares (Cyclic group) were collected on days 7, 10 and 13 post-ovulation. In the second cycle, the same mares were bred by a fertile stallion. At days 7, 10 and 13 post-ovulation intrauterine biopsies were collected. Immediately after sample collection, the mare's uteri were flushed, and those mares with embryo recovery were assigned to the Pregnant group. From ovulation detection until day of uterine biopsy, blood samples to measure Progesterone concentrations were collected daily in cyclic and pregnant mares. A larger blood vessel caliber was observed in pregnant mares than in cyclic from day 7-13. On the 7th day of pregnancy a large loss of ciliated cells was evident in the group of pregnant mares in comparison with the Cyclic group and the superficial cells of the endometrium were more protruded, and a small amount of histotrophic material between the folds was observed. On the 10th day of pregnancy, the glandular histotrophic secretion and the secretion of luminal epithelium became more intense than the secretion of cyclic mares. On the 13th day of pregnancy, a very large amount of histotroph was observed within large glandular openings surrounded by ciliated cells. The concentrations of P4 were affected by day (P < 0.001), but were not affected by group. Changes occurred in the uterine environment thereupon the entry of the embryo into the uterus. In the stroma and in the lumen, these modifications may aid to provide the necessary nutrition for the initial development of the embryo and to promote changes at cellular structures that will interact in the embryonic signaling and future fixation, implantation and placentation.

Exploring Canine-Human Differences in Product Performance. Part II: Use of Modeling and Simulation to Explore the Impact of Formulation on Ciprofloxacin In Vivo Absorption and Dissolution in Dogs.

This study explored the in vivo performance of three oral ciprofloxacin formulations (oral solution, fast, or slow dissolving tablets) in beagle dogs. The in vivo absorption and dissolution behaviors, estimated with in silico mechanistic models, were compared to the results previously published in human volunteers. Six normal healthy male beagle dogs (five to completion) received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by tandem mass spectrometry detection. A mechanistic absorption model was used to predict the in vivo dissolution and absorption characteristics of the oral formulations. Canine ciprofloxacin absorption was constrained to the duodenum/jejunum. This absorption window was far narrower than that seen in humans. Furthermore, while substantial within-individual variability in drug absorption was seen in human subjects, a greater magnitude of variability was observed in dogs. For three sets of data, a lag time in gastric emptying was necessary to improve the accuracy of model-generated in vivo blood level profile predictions. In addition to species-associated dissimilarities in drug solubilization due to human versus canine differences in gastrointestinal fluid compositions, the far more rapid intestinal transit time and potential segmental differences in drug absorption needed to be considered during human-canine extrapolation of oral drug and drug product performance. Through the use of mechanistic models, the data generated in the human and canine studies contributed insights into some aspects of the interspecies differences to be considered when extrapolating oral bioavailability/formulation effect data between dogs and humans.

Bioequivalence accomplishments, ongoing initiatives, and remaining challenges.

Although bioequivalence (BE) concepts date back to the late 1960s, there has been a steady evolution in the tools applied to the assessment of product comparability. Despite these advancements, we continue to face a multitude of unresolved challenges. Several of these challenges are unique to veterinary medicine due to issues such as multiple species approvals, unique dosage forms (e.g., intramammary infusion and medicated premixes), physiological challenges (e.g., limitations in blood volume and stress reactions), and the need to evaluate product equivalence for products intended to release drug over a duration of months. Thus, while in some instances, we can adopt advancements implemented by our human health counterparts but in other situations, we need to pioneer our own method for resolving these challenges. The purpose of this manuscript is to provide an update on recent advances, achievements, and ongoing initiatives associated with the assessment of product BE in veterinary medicine. This review reflects the highlights of a presentation given at the 2012 meeting of the European Association for Veterinary Pharmacology and Toxicology.

Estimating product bioequivalence for highly variable veterinary drugs.

The occurrence of drugs and drug formulations associated with large intrasubject pharmacokinetic (PK) variability has been well described in humans and is likewise encountered in veterinary medicine. The scaled average bioequivalence (SABE) approach adopted by CDER of the FDA for the determination of bioequivalence (BE) of highly variable drugs (HVD) needs to be considered when applied to veterinary dosage forms. However, because of some of the unique challenges that are encountered within the framework of veterinary medicine, variations of CDER's approach are presented. The present manuscript discusses HVD and highly variable veterinary drugs (HVVD) from the perspective of possible alternative approaches to support the assessment of product BE in veterinary medicine. Limitations in the use of 3- and 4-way crossover study designs are enumerated. In addition to a need for a statistical analysis of HVVD when using a parallel study design, the use of the secondary criteria (test-to-reference ratio), definition of σ(0) , and average BE with expanding limits are raised. A number of the details need to be finalized, from the selection of a regulatory constant to the determination of 'highly variable' in a veterinary drug product. Academicians, industrial scientists, and regulators should continue this discussion and resolve these details.

The scientific basis for establishing solubility criteria for veterinary species.

The relationship between factors influencing the in vitro and in vivo drug solubilization is highly dependent upon the physiology of the individual animal species and the physico-chemical properties of the drug. The solubilization of a drug in an aqueous medium is controlled by the strength of the interaction between a molecule of the active pharmaceutical ingredient (API) and the molecules of the solvent. In this regard, the stronger this interaction, the greater the likelihood that the drug will go into solution. Counteracting this solubilization process is the strength of the affinity of the solute for itself, or how tightly bound the compound is to its own solid state form. The stronger affinity of a solute for itself, the more difficult it will be for that molecule to go into solubility. However, solubility is not a universal value. Rather, it should be considered from the perspective of the interactions between the API in its solid form and the solution conditions such as: pH, the nature of the primary solvent, the presence of co-solvents, the presence of solubilizing additives, the ionic strength of the medium, incubation time, and temperature. Each of these factors needs to be considered when evaluating potential interspecies differences in drug solubility.

Drug solubility classification in the dog.

Similar to human drugs, oral drug delivery is a major route of drug administration in dogs. Therefore, it is important to consider how the physiological characteristics of the dog may influence the considerations that go into the classification of drug solubility. In this manuscript, we discuss the impact of body size vs. administered dose and gastric volume on the estimated gastric drug concentration that needs to be considered. However, when using a dose number (Do) paradigm, there are very few drugs for which the different methods of estimating gastric volume will alter the drug solubility classification. We also evaluate the range of pH values under which a solubility assessment should be generated and conclude that despite specific differences in the pH values of the gastrointestinal environment of people and dogs, the human pH criteria for evaluating drug solubility can be used when evaluating drug solubility of oral medications in dogs.

Drug solubility classification in the bovine.

Currently, the basis for solubility test conditions and the corresponding solubility criteria is derived from the tremendous wealth of information developed to support human pharmaceutical product development and regulation. However, there are several critical differences between the gastrointestinal tract of ruminants and monogastric species that can affect the conditions and criteria to be applied to the classification of drug solubility in cattle. These include the pH of the stomach, the volume of the stomach, the types of oral formulations, and the definition of 'highest dose'. These points are discussed below and alternative perspectives for consideration with regard to possible modification of solubility criteria for ruminants are presented.

Piomiosistis como complicación de la varicela. A propósito de un caso / Pyomiositis as a complication of varicella. A case report

La varicela es la enfermedad exantemática más frecuente en la infancia. Generalmente es benigna y autolimitada. Están descritas complicaciones que requieren tratamiento hospitalario y que están asociadas a una alta morbimortalidad. La piomiositis o infección aguda del músculo estriado es, aunque infrecuente, una de las posibles complicaciones musculoesqueléticas de la varicela. Presentamos el caso de un niño que durante la convalecencia de dicha enfermedad presentó como complicación una celulitis del miembro inferior y, posteriormente, una piomiositis del músculo gastrocnemio (AU)

Varicella is the most common exanthematic disease in childhood. It is usually benign and self-limited. Some complications that require hospital treatment and are associated with high morbidity and mortality are reported. Pyomyositis or acute infection of the striated muscle is, although rare, one of the musculoskeletal possible complications of varicella. We present the case of a child that, while convalescing from that disease, presented lower limb cellulites, and later a pyomyositis of the gastrocnemius muscle (AU)

Litiasis biliar en el lactante. A propósito de un caso / Gallstones in the infant. A case report

Hasta hace poco, la litiasis biliar en el niño se consideraba una enfermedad infrecuente. El número de casos diagnosticados ha aumentado mucho en los últimos años y esto se debe, principalmente, al uso de la ecografía como técnica de estudio ante todo cuadro de dolor abdominal recurrente o inespecífico. La litiasis biliar sintomática en lactantes cursa como un cuadro de molestias abdominales inespecíficas, por lo que es obligado tenerlo presente en el diagnóstico diferencial de todo lactante con evolución desfavorable a pesar del tratamiento de otras patologías más frecuentes (AU)

Until recently gallstones in baby was considered a rare disease. The number of diagnosed cases has risen much in recent years, this is mainly due the ultrasound as technique to study all recurrent abdominal pain or unspecific. The symptomatic gallstones in infant presents a table of nonspecific abdominal discomfort and it is bound to have it in the differential diagnosis of any infant with unfavorable evolution despite treatment of other diseases more frequently (AU)

Current challenges facing the determination of product bioequivalence in veterinary medicine.

Despite the pharmacological and statistical advances that have occurred since the early days of bioequivalence assessments, there remain many unresolved issues associated with the bioequivalence evaluation of human and veterinary pharmaceuticals. While many of these issues are common to both human and veterinary medicine, there are also challenges specific to veterinary drug products. Examples of complex problems that remain to be resolved include the assessment of drugs associated with complex kinetics (e.g., sustained release formulations that produce multiple peaks), the evaluation of intramammary formulations, uncertainty associated with conditions under which specific enantiomers of metabolites need to be factored into the bioequivalence evaluation, the study design for products and active pharmaceutical ingredients that exhibit highly variable kinetics, equivalence of biomass products, methods for evaluating topical formulations or formulations with very long duration of release, the evaluation of products where destructive sampling is necessary (e.g., aquaculture products), and the evaluation of bioequivalence for Type A medicated articles. This manuscript highlights many of the unresolved challenges currently impacting the evaluation of product bioequivalence in veterinary medicine, and provides a summary of the associated scientific complexities with each of these issues.

Novedades normativas en materia de incapacidad temporal / New regulations regarding temporary disability

En este artículo ofrecemos una revisión de los cambios normativos más recientes que afectan al sistema español de la Seguridad Social en materia de protección en incapacidades laborales (especialmente Incapacidad Temporal), pues es importante que los médicos generales conozcan cómo estos cambios pueden influir en su actividad profesional diaria (AU)

In this article we offer a review of the most recent regulatory changes affecting the Spanish Social Security System regarding working disability protection (especially Temporary Disability). The general practitioners must know how these changes can influence their diary professional activity (AU)