Development of a mechanism and an accurate and simple mathematical model for the description of drug release: Application to a relevant example of acetazolamide-controlled release from a bio-inspired elastin-based hydrogel.

Transversality between mathematical modeling, pharmacology, and materials science is essential in order to achieve controlled-release systems with advanced properties. In this regard, the area of biomaterials provides a platform for the development of depots that are able to achieve controlled release of a drug, whereas pharmacology strives to find new therapeutic molecules and mathematical models have a connecting function, providing a rational understanding by modeling the parameters that influence the release observed. Herein we present a mechanism which, based on reasonable assumptions, explains the experimental data obtained very well. In addition, we have developed a simple and accurate "lumped" kinetics model to correctly fit the experimentally observed drug-release behavior. This lumped model allows us to have simple analytic solutions for the mass and rate of drug release as a function of time without limitations of time or mass of drug released, which represents an important step-forward in the area of in vitro drug delivery when compared to the current state of the art in mathematical modeling. As an example, we applied the mechanism and model to the release data for acetazolamide from a recombinant polymer. Both materials were selected because of a need to develop a suitable ophthalmic formulation for the treatment of glaucoma. The in vitro release model proposed herein provides a valuable predictive tool for ensuring product performance and batch-to-batch reproducibility, thus paving the way for the development of further pharmaceutical devices.

A novel short-term plasticity of intrinsic excitability in the hippocampal CA1 pyramidal cells.

Changes in neuronal activity often trigger compensatory mechanisms aimed at regulating network activity homeostatically. Here we have identified and characterized a novel form of compensatory short-term plasticity of membrane excitability, which develops early after the eye-opening period in rats (P16-19 days) but not before that developmental stage (P9-12 days old). Holding the membrane potential of CA1 neurons right below the firing threshold from 15 s to several minutes induced a potentiation of the repolarizing phase of the action potentials that contributed to a decrease in the firing rate of CA1 pyramidal neurons in vitro. Furthermore, the mechanism for inducing this plasticity required the action of intracellular Ca(2+) entering through T-type Ca(2+) channels. This increase in Ca(2+) subsequently activated the Ca(2+) sensor K(+) channel interacting protein 3, which led to the increase of an A-type K(+) current. These results suggest that Ca(2+) modulation of somatic A-current represents a new form of homeostatic regulation that provides CA1 pyramidal neurons with the ability to preserve their firing abilities in response to membrane potential variations on a scale from tens of seconds to several minutes.

Intrinsic excitability is altered by hypothyroidism in the developing hippocampal CA1 pyramidal cells.

Thyroid hormone plays an essential role in brain development, so its deficiency during a critical developmental period has been associated with profound neurological deficits, including irreversible mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the postnatal development of membrane excitability of CA1 hippocampal pyramidal cells. Current clamp recordings in the whole cell patch clamp configuration showed that the action potential of cells from hypothyroid animals presented shorter width, slower depolarization, and faster repolarization rates compared with controls both in early postnatal and pre-weanling ages. Additionally, thyroid hormone deficiency reduced the intrinsic membrane excitability as measured by the reduced number of evoked action potentials for a given depolarizing slope and by the more depolarized firing threshold observed in hypothyroid animals. Then we analyzed the fast-repolarizing A- and D-type potassium currents, as they constitute one of the major factors underlying intrinsic membrane excitability. Hypothyroid rats showed increased A-current density and a reduced isolated I(D)-like current, accompanied by parallel changes in the expression of the channels responsible for these currents in the CA1 region: Kv4.2, Kv4.3, and Kv1.2. Therefore, we suggest that the increased A-current density, subsequent to an increment in its channel expression, together with the decrease of Na(+)-currents, might help explain the functional alterations in the neuronal discharge, in the firing threshold, and in the action potential repolarization of hypothyroid pyramidal neurons.

Factores de riesgo para la presentación de complicaciones médicas en enfermos con fractura de cadera / Risk factors for the development of medical complications in patients with hip fracture

Objetivo. Analizar las características de los pacientes hospitalizados con fractura de cadera y su evolución clínica, así como evaluar qué factores se asocian a un mayor riesgo de complicaciones médicas durante el ingreso. Métodos. Estudio prospectivo de los enfermos mayores de 65 años ingresados con fractura de cadera en el Servicio de Traumatología del Complexo Hospitalario Xeral-Calde de Lugo durante el año 2008. Se recogieron diferentes datos clínicos analíticos relativos al estado basal de salud, las características de la fractura y las complicaciones hospitalarias. Se determinaron los factores asociados al desarrollo de la variable compuesta por aparición de complicaciones médicas mayores o fallecimiento durante el ingreso hospitalario, mediante análisis univariable y multivariable. Resultados. Se estudió a 258 pacientes, media (DE) de edad 82,2 (9,5) años, el 76% mujeres. La fractura fue osteoporótica en el 96,8% y fueron operados el 92,6% de los enfermos. El índice de Barthel medio fue 72,9 (25,7) y el de comorbilidad de Charlson medio ajustado por edad 5,2 (1,5). El 63,9% presentó alguna complicación médica mayor durante el ingreso hospitalario. Fallecieron 15 enfermos (5,8%). Las siguientes variables se asociaron al riesgo de aparición de complicaciones médicas: índice de Barthel (OR=2,21; IC del 95%, 1,1-4,25; p=0,01), edad (OR=1,09; IC del 95%, 1,02-1,12; p=0,006), hemoglobina al ingreso (OR=0,76; IC del 95%, 0,62-0,93; p=0,01). Conclusiones. Los enfermos con fractura de cadera son ancianos frágiles, con un importante grado de dependencia y comorbilidad. Es posible identificar al ingreso a aquellos con un mayor riesgo de presentar complicaciones médicas durante su estancia hospitalaria(AU)

Objective. To evaluate the clinical features and outcome of inpatients with hip fracture and to investigate the clinical variables associated with the risk of medical complications. Methods. Prospective study of hip fracture patients aged 65 or more, admitted to the Department of Orthopaedic Surgery of the Xeral-Calde Hospital, in Lugo, Spain, in 2008. The different clinical and biochemical variables as regards the baseline health status and presentation features of the hip fracture and its complications were all recorded. The factors associated with the development of medical inpatient complications, including death, were determined, using univariate and multivariate analyses. Results. A total of 258 patients were studied. The mean age was 82.2 (9.5) years, and 76% were women. The fracture was osteoporotic in 96.8%, and 92.6% were treated surgically. The mean Barthel index was 72.9 (25.7) and the age adjusted Charlson comorbidity index was 5.2 (1.5). A total of 63.9% patients had a major medical complication during their hospital stay. Mortality was 5.8%. The following variables were associated with the development of medical inpatient complications: Barthel index (OR=2.21; 95% CI, 1.1-4.25; p=0,01), age (OR=1.09; 95% CI, 1.02-1.12; p=0.006), haemoglobin at admission (OR=0.76; 95% CI, 0.62-0.93; p=0.01). Conclusions. Patients with hip fracture are fragile elderly with a high degree of functional dependence and comorbidity. Those with a high risk of developing medical inpatient complications can be identified at admission(AU)

[Risk factors for the development of medical complications in patients with hip fracture]. / Factores de riesgo para la presentación de complicaciones médicas en enfermos con fractura de cadera.

OBJECTIVE: To evaluate the clinical features and outcome of inpatients with hip fracture and to investigate the clinical variables associated with the risk of medical complications. METHODS: Prospective study of hip fracture patients aged 65 or more, admitted to the Department of Orthopaedic Surgery of the Xeral-Calde Hospital, in Lugo, Spain, in 2008. The different clinical and biochemical variables as regards the baseline health status and presentation features of the hip fracture and its complications were all recorded. The factors associated with the development of medical inpatient complications, including death, were determined, using univariate and multivariate analyses. RESULTS: A total of 258 patients were studied. The mean age was 82.2 (9.5) years, and 76% were women. The fracture was osteoporotic in 96.8%, and 92.6% were treated surgically. The mean Barthel index was 72.9 (25.7) and the age adjusted Charlson comorbidity index was 5.2 (1.5). A total of 63.9% patients had a major medical complication during their hospital stay. Mortality was 5.8%. The following variables were associated with the development of medical inpatient complications: Barthel index (OR=2.21; 95% CI, 1.1-4.25; p=0,01), age (OR=1.09; 95% CI, 1.02-1.12; p=0.006), haemoglobin at admission (OR=0.76; 95% CI, 0.62-0.93; p=0.01). CONCLUSIONS: Patients with hip fracture are fragile elderly with a high degree of functional dependence and comorbidity. Those with a high risk of developing medical inpatient complications can be identified at admission.

Role of low-voltage-activated calcium current on the firing pattern alterations induced by hypothyroidism in the rat hippocampus.

Thyroid hormone deficiency during a critical period of development severely affects cognitive functions, resulting in profound mental retardation. Despite the importance of the disorder, the cellular mechanisms underlying these deficits remain largely unexplored. The aim of this study was to examine the effects of the absence of thyroid hormone on the development of the intrinsic properties of CA1 hippocampal pyramidal cells. These cells are known to exhibit different firing patterns during development, being classified as either regular-spiking or burst-spiking cells. Patch-clamp experiments showed that hypothyroid rats presented a larger number of regular-spiking cells at early postnatal age (P9-11). This difference in firing-pattern distribution disappeared at the pre-weanling age (P17-19), when almost every cell displayed bursting behavior in both control and hypothyroid rats. However, when studied in detail, weanling hypothyroid rats presented a smaller number of spikes per burst than did control animals. One of the major factors behind bursting behavior is sustained depolarization following an action potential. In this study, we show that action potential afterdepolarizations of hypothyroid animals registered shorter half-durations than did controls, a fact which could explain the smaller number of action potentials per burst. Additionally, the afterdepolarizations observed on both hypothyroid and control neurons were highly sensitive to low concentrations of nickel, suggesting that a low-threshold Ca(2+) current is key in the generation of spike afterdepolarizations and in the control of the bursting pattern of firing of these neurons. In agreement with this, experiments performed on dissociated hippocampal neurons have shown that this current is significantly depressed in hypothyroid animals. Therefore, we conclude that an alteration of the low-threshold calcium current is the basic factor explaining the differences observed in the firing behavior of hypothyroid animals.

Waste tyre pyrolysis: modelling of a moving bed reactor.

This paper describes the development of a new model for waste tyre pyrolysis in a moving bed reactor. This model comprises three different sub-models: a kinetic sub-model that predicts solid conversion in terms of reaction time and temperature, a heat transfer sub-model that calculates the temperature profile inside the particle and the energy flux from the surroundings to the tyre particles and, finally, a hydrodynamic model that predicts the solid flow pattern inside the reactor. These three sub-models have been integrated in order to develop a comprehensive reactor model. Experimental results were obtained in a continuous moving bed reactor and used to validate model predictions, with good approximation achieved between the experimental and simulated results. In addition, a parametric study of the model was carried out, which showed that tyre particle heating is clearly faster than average particle residence time inside the reactor. Therefore, this fast particle heating together with fast reaction kinetics enables total solid conversion to be achieved in this system in accordance with the predictive model.

Valorisation of waste tyre by pyrolysis in a moving bed reactor.

The aim of this work is to assess the behaviour of a moving bed reactor, based on a screw transporter design, in waste tyre pyrolysis under several experimental conditions. Waste tyre represents a significant problem in developed countries and it is necessary to develop new technology that could easily process big amounts of this potentially raw material. In this work, the influence of the main pyrolysis process variables (temperature, solid residence time, mass flow rate and inert gas flow) has been studied by a thorough analysis of product yields and properties. It has been found that regardless the process operational parameters, a total waste tyre devolatilisation is achieved, producing a pyrolytic carbon black with a volatile matter content under 5 wt.%. In addition, it has been proven that, in the range studied, the most influencing process variables are temperature and solid mass flow rate, mainly because both variables modify the gas residence time inside the reactor. In addition, it has been found that the modification of these variables affects to the chemical properties of the products. This fact is mainly associated to the different cracking reaction of the primary pyrolysis products.

ZD 7288 inhibits T-type calcium current in rat hippocampal pyramidal cells.

Many studies have used the channel blocker ZD 7288 to assess possible physiological and pathophysiological roles of hyperpolarization-activated cation currents (Ih). In view of the known interplay between Ih and other membrane conductances, the effects in Wistar rats of ZD 7288 on low-voltage-activated (LVA (- or T-type)) Ca2+ channels were examined in whole-cell patch-clamp recordings from CA1 pyramidal cells in the presence of TTX, TEA, 4-AP, CsCl, BaCl2 and nifedipine. ZD 7288 reduced T-type calcium channel currents and this effect was concentration dependant. ZD 7288 blocked T-type currents when applied extracellularly, but not when included in the recording pipette. Furthermore, ZD 7288 altered the steady-state voltage-dependent inactivation of T-currents. These results indicate that the blocker ZD 7288 has effects on voltage sensitive channels additional to those reported for the Ih current.

Augmentation of excitability in the hippocampus of juvenile rat.

The short-term plasticity of synaptic transmission has usually been related to neurotransmitter release-dependent processes. In this work, we describe a calcium- and release-independent augmentation of the fiber volley (FVA) that appears during stimulation of the Wistar rat commissural/Schaffer collateral afferents at 10-Hz. Among the possible mechanisms involved in this phenomenon, an increment in sodium channel density or the facilitation of recovery from inactivation does not seem to be responsible for this effect since the depolarization rate of the somatic action potentials (APs) of CA3 pyramidal cells decreases during the 10-Hz stimulation. On the other hand, an increase in the synchronization of the APs can be observed during the very first pulses of the 10-Hz tetanus. However, the major part of the FVA occurs with any increase in synchronization of AP firing. Finally, a strong increase in the firing probability, with kinetics similar to that observed with the FVA, appears at 10-Hz stimulation when APs are induced at threshold intensities. This hyperexcitability seems to be mediated by a residual depolarization that persists for more than 100 ms after the AP. The nature of this post-spike depolarization is uncertain since it persists in the absence of extracellular calcium and was not blocked by the application of phenytoin (100 microM), and this excludes the implication of either calcium or sodium-persistent currents. Additionally, the increase of the stimulation strength did not alter this depolarization, which suggests that the presumed extracellular potassium accumulation produced after the synchronic stimulation of APs is not involved in the depolarization. Interestingly, the slow post-depolarization induced by both supra- and subthreshold pulses is well fitted by a single exponential decay with similar time constants, an indication that the tail depolarization may represent passive discharge of the membrane following an incomplete repolarization of the AP.

Aspergillus pacemaker endocarditis presenting as pulmonary embolism.

Pacemaker endocarditis (PME) is a rare but severe complication of endocardial pacemaker implantation. Fungal PME is extremely uncommon. The case of a 66-year-old female patient who was diagnosed as having a pulmonary embolus based upon the patient's clinical presentation and computed tomography angiography findings is presented. Transthoracic echocardiography demonstrated a huge vegetation attached to the pacemaker wire. The pacemaker system was removed surgically during cardiovascular bypass. The vegetation was cultured, the results of which were positive for Aspergillus spp. No risk factors for Aspergillus infection were found in the patient. She was treated with liposomal amphotericin B for 3 weeks, followed by itraconazole for 40 weeks. At 1 year later, the patient remains asymptomatic.

Piomiositis pectoral por Staphylococcus aureus / Staphylococcus aureuspectoral pyomyositis

La piomiositis es una infección bacteriana espontánea de los músculos esqueléticos, que no es secundaria a una infección de tejidos contíguos (piel, huesos, etc.). Existen diversos factores predisponentes para la misma, que incluyen la diabetes mellitus, neoplasias, conectivopatías, infección por virus de la inmunodeficiencia humana, o cirugía/traumatismos previos. En un tercio de los casos no existe un factor predisponente. Dada su relativa poca frecuencia, su diagnóstico puede retrasarse si no existe un alto grado de sospecha clínica. Se presenta un caso de piomiositis de músculo pectoral mayor (AU)

Pyomyositis is a spontaneous bacterial infection of the skeletal muscles which is not secondary to infection of adjoining tissues (skin, bone, etc.) there are a number of predisposing factors including diabetes mellitus, neoplasms, connective tissue diseases, human immunodeficiency virus (HIV) infection or previous surgery/trauma. In one-third of the cases no predisposing factor is discerned. Because of its relatively low frequency, the diagnosis may be delated if there is not a high degree of clinical suspicion. We report one case of M. pectoralis major pyomyositis (AU)

[Pneumoscrotum secondary to a massive subcutaneous emphysema after expontaneous pneumothorax drainage]. / Neumoescroto secundario a enfisema subcutáneo masivo tras drenaje de un neumotórax espontáneo.

We present a case of a pneumoscrotum and pneumopenis which appeared after a trocar drainage placement for treatment of a recidivated expontaneous pneumothorax. In spite of is an entity with easy diagnosis and conservative management, maybe be confused with other more aggressive entities which treatment should be invasive.

Neumoescroto secundario a enfisema subcutáneo masivo tras drenaje de un neumotórax espontáneo / Pneumoscrotum secondary to a masive subcutaneous emphysema after expontaneous neumothorax drainage

Presentamos un caso excepcional de presentación de un neumoescroto y neumopene que apareció tras la colocación de un tubo de tórax para el drenaje de un neumotórax espontáneo recidivado. A pesar de tratarse de una entidad de fácil diagnóstico y tratamiento conservador, puede confundirse con otros cuadros más graves y cuyo tratamiento es mas invasivo

We present a case of a pneumoscrotum and pneumopenis which appeared after a trocar drainage placement for treatment of a recidivated expontaneous pneumothorax. In spite of is an entity with easy diagnosis and conservative management, maybe be confused with other more agresive entities which treatment should be invasive

Characterization of release-independent short-term depression in the juvenile rat hippocampus.

Short-term depression strongly influences neuronal activity in cerebral circuits and contributes to low-pass temporal filtering of information. In this work, we show that synaptic depression evoked by stimulation of commissural-Schaffer collateral afferents at 10 Hz is associated with a reduction of the fibre volley. This depression of action potentials is also evident in the absence of extracellular Ca(2+), which underlies its release-independent nature. In addition, this reduction of the excitability is independent of failures in action potential propagation since increasing the distance between the stimulus and recording electrodes does not alter this effect. Whole-cell recordings show that tetanic stimulation at supraminimal intensity induces action potential failures preceded by changes in the repolarization rate of the action potentials leading the membrane potential to hyperpolarized values. This activity-dependent hyperpolarization was blocked by ouabain, an indication of the important role of the Na(+)-K(+)-ATPase in this process. Then again, an alteration of the firing threshold was observed when action potentials were elicited either by somatic current injection or by synaptic stimulation, which indicates that this mechanism could alter the EPSP-spike coupling in these cells. The results suggest that these factors act together to reduce gradually the safety factor for action potential generation and to produce failures in action potential initiation; in fact, experiments made at twice the supraminimal intensity show a dramatic decrease in the rate of these failures. Taken together, the results suggest the existence of a release-independent component of short-term depression that is related to failures in action potential initiation.

Tos crónica como forma de presentación de una endocarditis bacteriana subaguda / Chronic cough as presentation of subacute bacterial endocarditis

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Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats.

Thyroid hormone deficiency during a critical period of development profoundly affects cognitive functions such as attention, learning, and memory, but the synaptic alterations underlying these deficits remain unexplored. The present study examines the effect of congenital hypothyroidism on long-term synaptic plasticity. This plasticity is believed to be essential for learning and memory and for activity-dependent regulation of synapse formation in the developing brain. We found that the neonatal expression of long-term potentiation (LTP), long-term depression (LTD), depotentiation, and de-depression in hippocampal slices from hypothyroid animals was similar to that of controls. To examine the postnatal development of these plasticities, we used slices from neonatal (2-3 weeks) and adult (7-8 weeks) rats. This work demonstrates that the ability to express all these forms of synaptic plasticity is reduced in an age-dependent manner in control rats. LTP and depotentiation are also downregulated in adult hypothyroid rats, but we have found that de-depression is not affected during maturation. In addition, these animals express LTD at ages at which controls fail to induce it. In contrast, input/output experiments have shown greater levels of basal synaptic efficacy in hypothyroid adults, and this effect is probably related to the higher probability of release observed by paired-pulse experiments. Nevertheless, these effects appear to be unrelated to the differences observed in long-term synaptic plasticity, as no correlation was found between basal synaptic efficacy and the degree of LTD and de-depression. Furthermore, the NMDA-receptor antagonist amino-phosphonopentanoic acid (APV) completely blocked LTD, which suggests a postsynaptic locus of this alteration. Because LTD has been associated with novelty acquisition, we suggest that the greater LTD observed in adult hypothyroid rats might be related to the hyperactivity of these animals. However, other possibilities such as a retarded maturation of synaptic plasticity must be taken into account.

La tomografía computarizada en el diagnóstico del tromboembolismo pulmonar / The computed tomography scan in the diagnosis of pulmonary thromboembolism

El tromboembolismo pulmonar (TEP) es una patología muy frecuente, considerándose la causa prevenible más frecuente de muerte hospitalaria. Las estrategias diagnósticas tradicionales incluyen en la mayoría de las ocasiones una gammagrafía pulmonar de ventilación/perfusión (V/Q), combinada en general con distintas pruebas diagnósticas no invasivas, como realización de eco-doppler de extremidades inferiores, determinación de dímero D, etc. La tomografía computarizada (TC) torácica está cada vez más implantada en el diagnóstico de esta enfermedad. Los trabajos publicados muestran que la TC es una técnica útil, presentando un porcentaje de exploraciones inconcluyentes mucho menor que la gammagrafía de V/Q, y una concordancia interobservador más alta. La principal crítica que recibe es una sensibilidad relativamente baja para detectar el TEP exclusivamente subsegmentario. Sin embargo, se han presentado ya varios trabajos que evalúan la evolución de los pacientes a los que se retira (o no se inicia) la anticoagulación en base a una TC negativa, y los resultados demuestran que esta exploración tiene un elevado valor predictivo negativo, que la hace equivalente a otras estrategias diagnósticas aceptadas en la enfermedad. Como valor adicional, la TC puede ofrecer información útil para el diagnóstico en pacientes en que se sospecha un TEP, pero que tienen otra enfermedad. Este trabajo revisa la literatura sobre el tema, con el fin de ofrecer una perspectiva sobre la utilidad de la TC en la valoración del paciente con sospecha de TEP (AU)