The targets of information-carrying nanodomains

We recently introduced the concept of aqueous nanodomains to explain high potentization in homeopathy. These long-lived nanodomains carry excited states of at least two ranges of energy packets; one for chemical change, the other for target-information. Here we discuss how these nanodomains interact with their targets. Our assumption is that these targets are similar to nanodomains, thereby enhancing their interaction. We use a simple system involving only one enzyme reaction to model the normal, the diseased and the enhanced recovery phases. For the healthy phase, a range of initial enzyme concentrations lead to a stationary state. We adjust the initial enzyme concentration to find an 'ideal' value, for which at stationary state the enzyme cycle provides the identical substrate concentration for each of the adjoining components. We simulate the diseased phase by starting a fast isomerization between the free active enzyme and its inactive form. At the end of this phase another stationary state is reached. In the subsequent recovery phase the fast movement of the excited states in the homeopathic solution rapidly converts the inactive form of the enzyme to its electronically excited state, which then converts to active free enzyme. At the end of this phase we return to the stationary state reached at the end of the healthy phase, that is, complete recovery to health. This simple model omits many of the complexities of a live organism. However, the elements of homeopathic action at the target can be observed clearly, as shown by a number of simulations.     

Difference Newton-like methods under weak continuity conditions

We give a local convergence analysis of difference Newton-like methods for solving the nonlinear equationF(x)=0, without assuming Lipschitz continuity of the derivativeF′. The results are obtained by regarding difference Newton-like methods as inexact Newton methods.     

Evaluation of integrin molecules involved in substrate adhesion

Integrins were cross-linked to their extracellular matrix ligands using non-penetrating chemical cross-linkers. This procedure did not disturb the distribution of integrin in the adhesion structure and adhesion plaque integrin staining remained even when the cultures were extracted with ionic detergents. 80-90% of the beta 1 integrin in the cross-linked culture was extracted with RIPA buffer and the remaining 10-20% was recovered following reversal of the cross-linking. This separated two distinct integrin pools, one which can be cross-linked to substrate bound extracellular matrix and one which is not. The specificity of this procedure for cross-linking of integrins involved in substrate adhesion was demonstrated using NIH 3T3 cells which express both alpha 5 beta 1 and alpha 6 beta 1 integrins. alpha 6 was cross-linked only in cells plated on laminin whereas alpha 5 was cross-linked when fibronectin was present. Using antisera directed to the cytoplasmic domains of either alpha 5 or beta 1 integrin, it was demonstrated that these domains can be blocked in the intact cell but the blocking can be removed using ionic detergent extraction after chemical cross-linking. The extracellular matrix associated with the substrate surface but not that associated with the media exposed surface is both cross-linked and retained on the plastic dish following cross-linking.     

Theranostic Oxygen Reactive Polymers for Treatment of Traumatic Brain Injury

Traumatic brain injury (TBI) is the leading cause of disability and death in children and adults under 45, with approximately ten million new cases per year worldwide. Significant progress has been made in understanding the complex pathophysiological response to TBI; however, reducing the damage associated with the reactive oxygen species (ROS)‐dependent secondary phase of the injury remains a substantial challenge. The development of an image‐guided, Gd‐conjugated, oxygen reactive polymer (ORP) to reduce ROS levels in damaged brain tissue is reported. ORP effectively sequesters ROS while remaining biocompatible even at elevated concentrations. ORP is retained in damaged brains of controlled cortical impact (CCI) mouse models of TBI for over 24 h when injected intravenously immediately and up to 3 h post‐CCI. The polymer reduces neurodegeneration tenfold and gliosis twofold in these mouse models. ORP shows initial promise as an effective therapy for TBI and helps provide a better understanding of nanomaterial interaction with damaged brain.     

A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder that is characterized by dysmyelination of the central nervous system resulting from mutations in the proteolipid protein (PLP) gene. Mutations causing either overexpression or expression of a truncated form of PLP result in oligodendrocyte cell death because of accumulation of PLP in the endoplasmic reticulum. It has therefore been hypothesized that absence of the protein should result in a less severe phenotype. However, until now, only one patient has been described with a complete deletion of the PLP gene. We report a Dutch family with a relatively mild form of PMD, in which the disease cosegregates with a (G-to-A) mutation in the initiation codon of the PLP gene. This mutation should cause the total absence of PLP and is therefore in agreement with the hypothesis that absence of PLP leads to a mild form of PMD.     

Online Noise Estimation Using Stochastic-Gain HMM for Speech Enhancement

We propose a noise estimation algorithm for single-channel noise suppression in dynamic noisy environments. A stochastic-gain hidden Markov model (SG-HMM) is used to model the statistics of nonstationary noise with time-varying energy. The noise model is adaptive and the model parameters are estimated online from noisy observations using a recursive estimation algorithm. The parameter estimation is derived for the maximum-likelihood criterion and the algorithm is based on the recursive expectation maximization (EM) framework. The proposed method facilitates continuous adaptation to changes of both noise spectral shapes and noise energy levels, e.g., due to movement of the noise source. Using the estimated noise model, we also develop an estimator of the noise power spectral density (PSD) based on recursive averaging of estimated noise sample spectra. We demonstrate that the proposed scheme achieves more accurate estimates of the noise model and noise PSD, and as part of a speech enhancement system facilitates a lower level of residual noise.     

A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers

BACKGROUND: It has been estimated that the prevalence of carriers of a mutated mismatch repair (MMR) gene among the general population in Western countries is between 5 and 50 per 10,000. These carriers have a risk of >85% of developing colorectal carcinoma (CRC) and therefore need careful follow-up. The objective of this study was to analyze the cost-effectiveness of CRC surveillance of carriers of a mutated MMR gene. METHODS: The authors constructed a model to estimate the potential health effects (life expectancy) and healthcare costs of two strategies: 1) surveillance, with colonoscopy every 2-3 years, and 2) no CRC surveillance. Estimates of the lifetime risk of developing CRC and the stage distribution of CRC for symptomatic patients were derived from the Dutch hereditary nonpolyposis colorectal carcinoma (HNPCC) registry. The CRC stage specific relative survival rates and the effectiveness of surveillance in preventing or detecting cancer early were based on Finnish studies. The costs of surveillance and treatment were derived from recent American studies. RESULTS: The results showed that 1) surveillance of gene carriers led to an increase in life expectancy of 7 years, and 2) the costs of surveillance under a wide range of assumptions are less than the costs of no CRC surveillance. CONCLUSIONS: CRC surveillance of HNPCC gene carriers appears to be effective and considerably less costly than no CRC surveillance and therefore deserves to be supported by governmental agencies and health insurance organizations.     

Inheritance of abnormal expression of SOS-like response in xeroderma pigmentosum and hereditary cancer-prone syndromes

The time course of induction of SOS-like stress responses such as enhanced reactivation (ER) and enhanced mutagenesis (EM) has been investigated in UV-C-irradiated skin fibroblasts from a xeroderma pigmentosum (XP) family, using herpes simplex virus type 1 as a probe. Similar ER studies were performed in a Li-Fraumeni syndrome (LFS) family and in a family with a high incidence of breast, ovarian, and colon cancer. In two XP (complementation group B) patients, with a striking absence of skin tumors even at an age of >40 years, only induction of EM was observed, whereas ER was absent (XPER-). The ER- phenotype was inherited from the father, whereas cells from the mother exhibited normal expression of ER and EM. This suggests that the absence of ER is a hereditary trait that is not correlated with a repair-deficient phenotype. Abnormally high levels of ER were observed in UV-C-exposed skin fibroblasts from rive LFS patients. The inheritance of the ER response was studied in one LFS family. High levels of ER were observed only in cells derived from affected individuals carrying one mutated p53 allele, whereas cells from unaffected family members, carrying two wild-type p53 alleles, exhibited normal ER levels. This result shows that abnormally high levels of ER positively correlate with the occurrence of cancer in affected individuals from a LFS family. Interestingly, abnormally high levels of ER were observed in cells from afflicted as well as from unafflicted members of a family with a high incidence of breast, ovarian, colon, and stomach cancer. This suggests that these latter individuals have inherited a mutated, putative predisposing gene, resulting in abnormal expression of ER, but that cancer had not yet developed. The results indicate that the ER response can possibly be used as a prognostic marker to identify carriers in various hereditary cancer-prone syndromes at an early age.     

Short-lived intermediates in hemoglobin/O2 systems

By using three-dimensional computer reconstruction techniques and the production of two-dimensional unfolded maps, we analyzed the topographic organization of projections from the entorhinal cortex of the rat to the dentate gyrus. The retrograde tracers, Fast blue and Diamidino yellow, were injected at all septotemporal levels of the dentate gyrus, and the distribution of retrogradely labeled layer II cells in the entorhinal cortex was plotted by using computer-aided microscopy systems. Discrete injections of fluorescent dyes into the dentate gyrus labeled bands of layer II neurons in the entorhinal cortex that covered approximately 45% of its surface area. Injections confined to the septal half of the dentate gyrus resulted in a band that occupied the most lateral and caudomedial portions of the entorhinal cortex. Although there were subtle changes in the density of labeled cells in this region, essentially the same region of cells was labeled after any injection into the septal half of the dentate gyrus. Injections into mid-septotemporal levels of the dentate gyrus (50-75% of the distance from the septal pole) led to a distinctly different pattern of retrograde labeling. A more medial portion of the lateral entorhinal cortex and a more rostral portion of the medial entorhinal area were labeled in these cases. Another change in entorhinal labeling occurred when the injection involved the most temporal quarter of the dentate gyrus. Injections into this area led to a constrained region of entorhinal labeling that included the most medial portion of the lateral entorhinal area and the most rostral portion of the medial entorhinal area. Although the domains of cells projecting to septal, mid-septotemporal, and temporal levels of the dentate gyrus were not entirely segregated, there was relatively little overlap of the three populations of neurons. These data raise the possibility that different portions of the entorhinal-hippocampal circuit are capable of semiautonomous information processing, at least at the stage of input to the dentate gyrus.     

Long Term Behaviour of Glare

Aircraft are operated in a wide variety of environments, for periods of up to 30 years. In order to maintain safe and economical travel, it is necessary to have good knowledge of the long-term behaviour of the materials that an aircraft are built of. Over longer periods of time, one of the main threats to materials is the influence of the environment, especially that of moisture combined with temperature. The combination of materials used in Glare complicates the long-term behaviour. By investigating environmental influences on each of the different components of Glare, a basic understanding of the effects on the laminate as a whole can be obtained. In most cases, the laminated build-up has a positive effect on the environmental durability of Glare, but care needs to be taken in areas of combined moisture absorption, stress concentrations and elevated temperature.