Chitosan-based spray-dried respirable powders for sustained delivery of terbutaline sulfate

In this study, we describe the preparation of highly dispersible dry powders for pulmonary drug delivery that display sustained drug release characteristics. Powders were prepared by spray-drying 30% v/v aqueous ethanol formulations containing terbutaline sulfate as a model drug, chitosan as a drug release modifier and leucine as an aerosolisation enhancer. The influence of chitosan molecular weight on the drug release profile was investigated by using low, medium and high molecular weight chitosan or combinations thereof. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction, tapped density analysis, differential scanning calorimetry and thermogravitational analysis. The in vitro aerosolisation performance and drug release profile were investigated using Multi-Stage Liquid Impinger analysis and modified USP II dissolution apparatus, respectively. The powders generated were of a suitable aerodynamic size for inhalation, had low moisture content and were amorphous in nature. The powders were highly dispersible, with emitted doses of over 90% and fine particle fractions of up to 82% of the total loaded dose, and mass median aerodynamic diameters of less than 2.5microm. A sustained drug release profile was observed during dissolution testing; increasing the molecular weight of the chitosan in the formulation increased the duration of drug release. (c)2007 Elsevier B.V. All rights reserved.

Analysis of common attacks in public-key cryptosystems based on low-density parity-check codes

The security and reliability of a class of public-key cryptosystems against attacks by unauthorized parties, who had acquired partial knowledge of one or more of the private key components and/or of the message, were discussed. The standard statistical mechanical methods of dealing with diluted spin systems with replica symmetric considerations were analyzed. The dynamical transition which defined decryption success in practical situation was studied. The phase diagrams which showed the dynamical threshold as a function of the partial acquired knowledge of the private key were also presented.

Density and cross-sectional areas of axons in the olfactory tract in control subjects and Alzheimer's disease:an image analysis study

Objective. Using an image analysis system to determine whether there is loss of axons in the olfactory tract (OT) in Alzheimer’s disease (AD). Design. A retrospective neuropathological study. Patients Nine control patients and eight clinically and pathologically verified AD cases. Measurements and Results. There was a reduction in axon density in AD compared with control subjects in the central and peripheral regions of the tract. Axonal loss was mainly of axons with smaller (<2.99 µm2) myelinated cross-sectional areas. Conclusions. The data suggest significant degeneration of axons within the OT involving the smaller sized axons. Loss of axons in the OT is likely to be secondary to pathological changes originating within the parahippocampal gyrus rather than to a pathogen spreading into the brain via the olfactory pathways.

Whole body vibration treatments in postmenopausal women can improve bone mineral density:results of a stimulus focussed meta-analysis

Whole body vibration treatment is a non-pharmacological intervention intended to stimulate muscular response and increase bone mineral density, particularly for postmenopausal women. The literature related to this topic is controversial, heterogeneous, and unclear despite the prospect of a major clinical effect. The aim of this study was to identify and systematically review the literature to assess the effect of whole body vibration treatments on bone mineral density (BMD) in postmenopausal women with a specific focus on the experimental factors that influence the stimulus. Nine studies fulfilled the inclusion criteria, including 527 postmenopausal women and different vibration delivery designs. Cumulative dose, amplitudes and frequency of treatments as well as subject posture during treatment vary widely among studies. Some of the studies included an associated exercise training regime. Both randomized and controlled clinical trials were included. Whole body vibration was shown to produce significant BMD improvements on the hip and spine when compared to no intervention. Conversely, treatment associated with exercise training resulted in negligible outcomes when compared to exercise training or to placebo. Moreover, side-alternating platforms were more effective in improving BMD values than synchronous platforms and mechanical oscillations of magnitude higher than 3 g and/or frequency lower than 25 Hz were also found to be effective. Treatments with a cumulative dose over 1000 minutes in the follow-up period were correlated to positive outcomes. Our conclusion is that whole body vibration treatments in elderly women can reduce BMD decline.However, many factors (e.g. amplitude, frequency and subject posture) affect the capacity of the vibrations to propagate to the target site; the adequate level of stimulation required to produce these effects has not yet been defined. Further biomechanical analyses to predict the propagation of the vibration waves along the body and assess the stimulation levels are required.

Quantification of axonal loss in Alzheimer’s disease: an image analysis study

The density of axons in the optic nerve, olfactory tract and corpus callosum was quantified in non-demented elderly subjects and in Alzheimer’s disease (AD) using an image analysis system. In each fibre tract, there was significant reduction in the density of axons in AD compared with non-demented subjects, the greatest reductions being observed in the olfactory tract and corpus callosum. Axonal loss in the optic nerve and olfactory tract was mainly of axons with smaller myelinated cross-sectional areas. In the corpus callosum, a reduction in the number of ‘thin’ and ‘thick’ fibres was observed in AD, but there was a proportionally greater loss of the ‘thick’ fibres. The data suggest significant degeneration of white matter fibre tracts in AD involving the smaller axons in the two sensory nerves and both large and small axons in the corpus callosum. Loss of axons in AD could reflect an associated white matter disorder and/or be secondary to neuronal degeneration.

The identification of pathological subtypes of Alzheimer's disease using cluster analysis

A culster analysis was performed on 78 cases of Alzheimer's disease (AD) to identify possible pathological subtypes of the disease. Data on 47 neuropathological variables, inculding features of the gross brain and the density and distribution of senile plaques (SP) and neurofibrillary tangles (NFT) were used to describe each case. Cluster analysis is a multivariate statistical method which combines together in groups, AD cases with the most similar neuropathological characteristics. The majority of cases (83%) were clustered into five such groups. The analysis suggested that an initial division of the 78 cases could be made into two major groups: (1) a large group (68%) in which the distribution of SP and NFT was restricted to a relatively small number of brain regions, and (2) a smaller group (15%) in which the lesions were more widely disseminated throughout the neocortex. Each of these groups could be subdivided on the degree of capillary amyloid angiopathy (CAA) present. In addition, those cases with a restricted development of SP/NFT and CAA could be divided further into an early and a late onset form. Familial AD cases did not cluster as a separate group but were either distributed between four of the five groups or were cases with unique combinations of pathological features not closely related to any of the groups. It was concluded that multivariate statistical methods may be of value in the classification of AD into subtypes. © 1994 Springer-Verlag.

Probabilistic principal component analysis

Principal component analysis (PCA) is a ubiquitous technique for data analysis and processing, but one which is not based upon a probability model. In this paper we demonstrate how the principal axes of a set of observed data vectors may be determined through maximum-likelihood estimation of parameters in a latent variable model closely related to factor analysis. We consider the properties of the associated likelihood function, giving an EM algorithm for estimating the principal subspace iteratively, and discuss the advantages conveyed by the definition of a probability density function for PCA.

Probabilistic principal component analysis

Principal component analysis (PCA) is a ubiquitous technique for data analysis and processing, but one which is not based upon a probability model. In this paper we demonstrate how the principal axes of a set of observed data vectors may be determined through maximum-likelihood estimation of parameters in a latent variable model closely related to factor analysis. We consider the properties of the associated likelihood function, giving an EM algorithm for estimating the principal subspace iteratively, and discuss the advantages conveyed by the definition of a probability density function for PCA.

Statistical mechanics of low-density parity-check codes

We review recent theoretical progress on the statistical mechanics of error correcting codes, focusing on low-density parity-check (LDPC) codes in general, and on Gallager and MacKay-Neal codes in particular. By exploiting the relation between LDPC codes and Ising spin systems with multispin interactions, one can carry out a statistical mechanics based analysis that determines the practical and theoretical limitations of various code constructions, corresponding to dynamical and thermodynamical transitions, respectively, as well as the behaviour of error-exponents averaged over the corresponding code ensemble as a function of channel noise. We also contrast the results obtained using methods of statistical mechanics with those derived in the information theory literature, and show how these methods can be generalized to include other channel types and related communication problems.

A statistical-mechanical analysis of coded CDMA with regular LDPC codes

We analyze, using the replica method of statistical mechanics, the theoretical performance of coded code-division multiple-access (CDMA) systems in which regular low-density parity-check (LDPC) codes are used for channel coding.

Statistical mechanics of broadcast channels using low-density parity-check codes

We investigate the use of Gallager's low-density parity-check (LDPC) codes in a degraded broadcast channel, one of the fundamental models in network information theory. Combining linear codes is a standard technique in practical network communication schemes and is known to provide better performance than simple time sharing methods when algebraic codes are used. The statistical physics based analysis shows that the practical performance of the suggested method, achieved by employing the belief propagation algorithm, is superior to that of LDPC based time sharing codes while the best performance, when received transmissions are optimally decoded, is bounded by the time sharing limit.

Statistical mechanics analysis of LDPC coding in MIMO Gaussian channels

Using analytical methods of statistical mechanics, we analyse the typical behaviour of a multiple-input multiple-output (MIMO) Gaussian channel with binary inputs under low-density parity-check (LDPC) network coding and joint decoding. The saddle point equations for the replica symmetric solution are found in particular realizations of this channel, including a small and large number of transmitters and receivers. In particular, we examine the cases of a single transmitter, a single receiver and symmetric and asymmetric interference. Both dynamical and thermodynamical transitions from the ferromagnetic solution of perfect decoding to a non-ferromagnetic solution are identified for the cases considered, marking the practical and theoretical limits of the system under the current coding scheme. Numerical results are provided, showing the typical level of improvement/deterioration achieved with respect to the single transmitter/receiver result, for the various cases. © 2007 IOP Publishing Ltd.

Quantifying the pathology of neurodegenerative disorders:Quantitative measurements, sampling strategies and data analysis

The use of quantitative methods has become increasingly important in the study of neurodegenerative disease. Disorders such as Alzheimer's disease (AD) are characterized by the formation of discrete, microscopic, pathological lesions which play an important role in pathological diagnosis. This article reviews the advantages and limitations of the different methods of quantifying the abundance of pathological lesions in histological sections, including estimates of density, frequency, coverage, and the use of semiquantitative scores. The major sampling methods by which these quantitative measures can be obtained from histological sections, including plot or quadrat sampling, transect sampling, and point-quarter sampling, are also described. In addition, the data analysis methods commonly used to analyse quantitative data in neuropathology, including analyses of variance (ANOVA) and principal components analysis (PCA), are discussed. These methods are illustrated with reference to particular problems in the pathological diagnosis of AD and dementia with Lewy bodies (DLB).

Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID):A study using α-internexin immunohistochemistry and principal components analysis (PCA)

Ten cases of neuronal intermediate filament inclusion disease (NIFID) were studied quantitatively. The α-internexin positive neurofilament inclusions (NI) were most abundant in the motor cortex and CA sectors of the hippocampus. The densities of the NI and the swollen achromatic neurons (SN) were similar in laminae II/III and V/VI but glial cell density was greater in V/VI. The density of the NI was positively correlated with the SN and the glial cells. Principal components analysis (PCA) suggested that PC1 was associated with variation in neuronal loss in the frontal/temporal lobes and PC2 with neuronal loss in the frontal lobe and NI density in the parahippocampal gyrus. The data suggest: 1) frontal and temporal lobe degeneration in NIFID is associated with the widespread formation of NI and SN, 2) NI and SN affect cortical laminae II/III and V/VI, 3) the NI and SN affect closely related neuronal populations, and 4) variations in neuronal loss and in the density of NI were the most important sources of pathological heterogeneity. © Springer-Verlag 2005.

Differences in the density and spatial distribution of florid and diffuse plaques in variant Creutzfeldt-Jakob disease (vCJD)

Objective: To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently. Material: Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD. Method: The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis. Results: The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters. Conclusion: The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.