Dietary carbohydrate rather than protein intake drives colonic microbial fermentation during weight loss.

PURPOSE: High protein weight loss diets are effective in aiding body weight management. However, high protein and low carbohydrate intakes can alter colonic fermentation profiles in humans and may impact on colonic health. This study aims to identify the most important dietary contributors to colonic fermentation during diet-controlled weight loss. METHODS: Overweight or obese male volunteers (n = 18) consumed a body weight maintenance diet (fed at 1.5× basic metabolic rate, BMR) followed by three weight loss diets (fed at 1× BMR) for 10 days each in a cross-over design. Weight loss diets were designed as normal protein (NPWL, 15% of energy from protein, 55% from carbohydrate), normal protein enriched with free amino acids and moderate amounts of carbohydrate (NPAAWL, 15% of energy from protein, 15% from free AA, 40% from carbohydrate) or high protein containing moderate amounts of carbohydrate (HPWL, 30% of energy from protein, 40% from carbohydrate). Faecal samples collected at the end of each diet period were profiled for dietary metabolites using LC-MS/MS. RESULTS: This study shows that the NPWL diet only induced very minor changes in the faecal metabolome, whereas NPAAWL and HPWL diets decreased carbohydrate-related metabolites (butyrate, ferulic acid) and increased protein-related metabolites. Most faecal metabolites were correlated with dietary carbohydrate and not protein intake. CONCLUSION: This study demonstrates that dietary carbohydrate is the main driver of colonic fermentation in humans and that a balance between dietary carbohydrate and protein should be maintained when designing safe, effective and healthy weight loss diets.

Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens.

Eravacycline (TP-434 or 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline) is a novel fluorocycline that was evaluated for antimicrobial activity against panels of recently isolated aerobic and anaerobic Gram-negative and Gram-positive bacteria. Eravacycline showed potent broad-spectrum activity against 90% of the isolates (MIC90) in each panel at concentrations ranging from ≤0.008 to 2 µg/ml for all species panels except those of Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC90 values of 32 µg/ml for both organisms). The antibacterial activity of eravacycline was minimally affected by expression of tetracycline-specific efflux and ribosomal protection mechanisms in clinical isolates. Furthermore, eravacycline was active against multidrug-resistant bacteria, including those expressing extended-spectrum ß-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance. Eravacycline has the potential to be a promising new intravenous (i.v.)/oral antibiotic for the empirical treatment of complicated hospital/health care infections and moderate-to-severe community-acquired infections.

A randomized crossover study to assess the effect of an oat-rich diet on glycaemic control, plasma lipids and postprandial glycaemia, inflammation and oxidative stress in Type 2 diabetes.

AIMS: In the UK, lifestyle intervention is first-line management in Type 2 diabetes. It is unclear what type of diet is most efficacious for improving glycaemic control. This study investigated the effects of an oat-enriched diet on glycaemic control, postprandial glycaemia, inflammation and oxidative stress compared with standard dietary advice. METHODS: In a randomized crossover design, 27 volunteers with Type 2 diabetes, managed on diet and lifestyle only, were observed for two consecutive 8-week periods following either the oat-enriched diet or re-enforced standard dietary advice. Volunteers attended at baseline (habitual intake) and 8 and 16 weeks. Measurements included basic clinical measurements and fasted and postprandial (3-h) glucose and insulin in response to a healthy test meal. Markers of inflammation and oxidative stress, including high-sensitivity C-reactive protein, interleukin 6, interleukin 18, tumour necrosis factor-alpha, adiponectin, thiobarbituric acid reactive substances, oxygen radical antioxidant capacity, oxidized LDL and urinary isoprostanes, were also measured at fasting and in the postprandial period. RESULTS: There were no diet-related effects on glycaemic control or glycaemic or insulinaemic responses to the test meal. Total cholesterol (5.1 ± 1.0 vs. 4.9 ± 0.8 mmol/l, P = 0.019) concentrations declined following the oat-enriched diet compared with standard dietary advice. There was a postprandial decline in adiponectin concentration (P = 0.009), but no effect of dietary intervention. None of the measures of oxidative stress or inflammation were altered by the oat-enriched diet compared with standard dietary advice. CONCLUSION: The oat-enriched diet had a modest impact on lipid lowering, but did not impact on oxidative stress or inflammation in these volunteers with Type 2 diabetes.

Effects of conjugated linoleic acid plus n-3 polyunsaturated fatty acids on insulin secretion and estimated insulin sensitivity in men.

BACKGROUND/OBJECTIVES: Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested. SUBJECTS/METHODS: CLA (3 g daily) plus n-3 LC-PUFA (3 g daily) or control oil (6 g daily) was given to lean (n=12; BMI 20-26 kg/m(2)) or obese (n=10; BMI 29-35 kg/m(2)) young (20-37 years old) or lean (n=16) or obese (n=11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data. RESULTS: The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P=0.024). CONCLUSIONS: The results do not support beneficial effects of CLA/n-3 LC-PUFA for beta-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced.

The combined use of self-organizing maps and Andrews' Curves.

The use of self-organizing maps to analyze data often depends on finding effective methods to visualize the SOM's structure. In this paper we propose a new way to perform that visualization using a variant of Andrews' Curves. Also we show that the interaction between these two methods allows us to find sub-clusters within identified clusters. Perhaps more importantly, using the SOM to pre-process data by identifying gross features enables us to use Andrews' Curves on data sets which would have previously been too large for the methodology. Finally we show how a three way interaction between the human user and these two methods can be a valuable exploratory data analysis tool.

Harvesting and climate effects on organic matter characteristics in British Columbia coastal forests.

As part of investigations into the effects of harvesting old-growth forest, we characterized carbon in five organic matter pools in eight forest chronosequences of coastal British Columbia. Each chronosequence comprised stands in four seral stages from regeneration (3-8 yr) to old-growth (>250 yr), with second-growth stands mostly of harvest origin. Stands were located in two biogeoclimatic subzones with contrasting climate (wetter, slightly cooler conditions on the west coast of Vancouver Island than on the east). Carbon concentrations in fine woody debris (FWD), forest floor (LFH), fine roots from LFH, and two water-floatable fractions from 10 to 30 cm mineral soil (MIN-ROOT, 2-8 mm and MIN-FLOAT, <2 mm) showed no significant effects due to climate, seral stage, or site. There were some significant differences in N concentrations, but none related to seral stage. Carbon-13 cross-polarization with magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectra with principal component analysis of relative areas also showed little harvesting effect, but greater variation related to input of coarse woody debris (CWD) vs. roots high in tannin. Overall, there tended to be more spectral features associated with wood and lignin in the west; whereas some MIN-ROOT samples from the drier east side had aromatic intensity attributed to charcoal. The minimal effects of one harvest on organic matter are most likely due to the large legacy effect; however, more intensive management will probably result in less CWD retention, less charcoal input, and less microsite variability in these pools of poorly decomposed organic matter.

Solid-state NMR characterization of the mineral searlesite and its detection in complex synthesis mixtures.

The mineral searlesite (NaBSi(2)O(5)(OH)(2)) was synthesized and characterized by (1)H, (11)B, (23)Na, and (29)Si magic-angle spinning (MAS) NMR spectroscopy. From these spectra, the (11)B and (23)Na quadrupole coupling parameters and isotropic chemical shifts and the (29)Si chemical shift anisotropies have been precisely determined. These parameters are all consistent with the local environments obtained from the crystal structure for searlesite from X-ray diffraction, and they demonstrate that the synthetic sample has a high degree of both short- and long-range order. Furthermore, these anisotropic parameters are found to provide a unique fingerprinting of searlesite in complex mixtures where the presence of this mineral is not anticipated. This is demonstrated for product mixtures formed in attempts to incorporate boron in the structures of the layer silicates magadiite and kenyaite. These mixtures have been investigated by (11)B, (23)Na, and (29)Si MAS NMR which clearly reveal that the samples are mixtures of searlesite and magadiite/kenyaite and that searlesite production consumes all of the boron in these synthesis mixtures. However, the (29)Si MAS NMR spectra of these mixtures indicate that the presence of boron in the reaction mixtures nevertheless has an important influence on the quality of the magadiite and kenyaite layer silicates produced.

Solid-state NMR detection, characterization, and quantification of the multiple aluminum environments in US-Y catalysts by (27)Al MAS and MQMAS experiments at very high field.

The detection of all of the aluminum present in steamed zeolite H-Y catalysts by (27)Al MAS NMR at 14.4 T (600 MHz for (1)H) and 18.8T (800 MHz for (1)H) is reported. Further, it is shown that it is possible by (27)Al MAS and MQMAS NMR measurements to clearly identify four separate aluminum environments which are characteristic of these materials and to unambiguously assign their coordinations. Average chemical shift and quadrupolar coupling parameters are used to accurately simulate the (27)Al MAS NMR spectra at 9.4 T (400 MHz for (1)H), 14.4 T (600 MHz for (1)H) and 18.8 T (800 MHz for (1)H) in terms of these four aluminum environments. In addition, these average chemical shift and quadrupolar coupling parameters are used to calculate peak positions in the (27)Al MQMAS isotropic dimension that are in good agreement with the experimental data acquired at 9.4 and 18.8 T.

Quantitative NMR imaging study of the mechanism of drug release from swelling hydroxypropylmethylcellulose tablets.

NMR imaging has been used to study the release behavior of two model drugs, triflupromazine-HCl and 5-fluorouracil, from swelling hydroxypropylmethylcellulose (HPMC) tablets. Preliminary experiments were performed on equilibrium mixtures of drug, polymer and water to determine how properties such as NMR relaxation parameters and self-diffusion were affected by the drug and polymer concentrations. The tablet swelling was restricted to one dimension and distributions of the water and model drugs were obtained by 1H and 19F imaging, respectively. The HPMC distribution at each time in the swelling process was determined indirectly from its effect on the relaxation parameters of the water and the drugs. In the one-dimensional swelling tablet, distributions of drug and polymer were compared to determine what factors influenced the release of drug from the swelling tablet. The distributions for triflupromazine-HCl and HPMC paralleled each other and the drug was only released at the eroding edge of the tablet where the HPMC concentration dropped below 10%. In contrast, 5-fluorouracil was released much more rapidly from the tablet and appeared to escape by diffusion from regions as high as 30% HPMC. An empirical measure of the rate of tablet edge movement can be obtained from plots of the edge position as a function of the square root of time. For HPMC, the rate of tablet expansion was determined in this way to be (2.4+/-0.8)x10(-6) cm(2) s(-1). The self-diffusion of triflupromazine-HCl in equilibrated mixtures of similar composition to the eroding tablet edge is approximately 3x10(-6) cm(2) s(-1) while the self-diffusion coefficient of 5-fluorouracil remained higher than this value until the HPMC concentration reached about 30%. This comparison of 'diffusion' properties may be useful in predicting the mechanism of drug release from other swelling hydrophilic matrix systems.

NMR imaging investigations of drug delivery devices using a flow-through USP dissolution apparatus.

A system for performing NMR imaging experiments on drug delivery devices within a flow-through dissolution apparatus, USP Apparatus 4, has been developed. The system was used to image the physical changes that occur in solid dosage forms during dissolution in the flow-through apparatus. Simultaneous cumulative drug release measurements were also made. The NMR images obtained under these conditions and the drug release data provide a better understanding of the processes involved in the release of drugs from drug delivery systems based on diffusion, dissolution and osmosis mechanisms.

Kernel and nonlinear canonical correlation analysis.

We review a neural implementation of the statistical technique of Canonical Correlation Analysis (CCA) and extend it to nonlinear CCA. We then derive the method of kernel-based CCA and compare these two methods on real and artificial data sets before using both on the Blind Separation of Sources.

Dexamethasone effects on cerebral protein synthesis prior to and following hypoxia-ischemia in immature rat.

We hypothesized that the neuroprotection against cerebral hypoxic-ischemic damage observed with dexamethasone treatment in immature rats is related to a change in cerebral protein synthesis. Six-day-old Wistar rats were injected with either vehicle (10 ml/kg) or dexamethasone (0.1 mg/kg) 24 h prior to cerebral hypoxia-ischemia. Local cerebral protein synthesis (incorporation of 14C-leucine into proteins) was measured in 7-day-old rats during normoxia, during hypoxia-ischemia, and after hypoxia-ischemia which was produced with right carotid artery ligation and 2-h exposure to 8% O2. In normoxic controls, cerebral protein synthesis was similar in dexamethasone and vehicle-treated animals. During hypoxia-ischemia, local cerebral protein synthesis decreased markedly (p < 0.0001) in ischemic regions ipsilateral to the occlusion, irrespective of treatment. After hypoxia-ischemia, protein synthesis declined even further in vehicle-treated animals. Reductions in protein synthesis were substantially more severe in vehicle- than dexamethasone-treated animals, particularly after hypoxia-ischemia (p < 0.0001). Thus, neuroprotection with dexamethasone is not related to a reduction in basal levels of cerebral protein synthesis, but is associated with an improved protein synthesis during and following hypoxia-ischemia.

A neural implementation of canonical correlation analysis.

We derive a new method of performing Canonical Correlation Analysis with Artificial Neural Networks. We demonstrate the network's capabilities on artificial data and then compare its effectiveness with that of a standard statistical method on real data. We demonstrate the capabilities of the network in two situations where standard statistical techniques are not effective: where we have correlations stretching over three data sets and where the maximum nonlinear correlation is greater than any linear correlation. The network is also applied to Becker's (Network: Computation in Neural Systems, 1996, 7:7-31) random dot stereogram data and shown to be extremely effective at detecting shift information.

Modelling multiple-cause structure using rectification constraints.

We present an artificial neural network which self-organizes in an unsupervised manner to form a sparse distributed representation of the underlying causes in data sets. This coding is achieved by introducing several rectification constraints to a PCA network, based on our prior beliefs about the data. Through experimentation we investigate the relative performance of these rectifications on the weights and/or outputs of the network. We find that use of an exponential function on the output to the network is most reliable in discovering all the causes in data sets even when the input data are strongly corrupted by random noise. Preprocessing our inputs to achieve unit variance on each is very effective in helping us to discover all underlying causes when the power on each cause is variable. Our resulting network methodologies are straightforward yet extremely robust over many trials.

Use of NMR imaging in the optimization of a compression-coated regulated release system.

Nuclear magnetic resonance (NMR) imaging is routinely used to detect the protons of mobile water molecules within samples. In this investigation, this non-destructive, non-invasive technique was used to determine the cause for faster than predicted drug release from a dissolution-based regulated-release tablet. The NMR images of tablets, from two different formulations, taken at various intervals of time while immersed in static USP dissolution medium showed that the tablet with faster than predicted drug release had a porous coating. The porous coat exposed more of the core surface area to the dissolution medium than desired and this caused an increase in the rate of dissolution of the core. The data presented in this paper demonstrate the usefulness of NMR imaging in solid dosage form development.

Complications in investigations of the swelling of hydrogel matrices due to the presence of trapped gas.

In recent studies, NMR imaging has been used to investigate the swelling of hydroxypropylmethylcellulose (HPMC) tablets and to determine polymer concentration distributions in the swollen matrix. The total amount of polymer in the system was computed from these distributions and was up to 35% greater than the known weight of HPMC in the tablet. This deviation was traced to the presence of air bubbles in the swollen matrix which occupied a significant volume previously assumed to be occupied by polymer and water. When the air in the tablet was removed by vacuum, the swollen gel contained no evidence of air bubbles and the calculated total polymer weights from the HPMC distributions were equal to the amount of HPMC in the tablet.

Measurement of cryoprotective solvent penetration into intact organ tissues using high-field NMR microimaging.

Existing methods are not able to monitor accurately the penetration of cryoprotective solvents (CPS) into intact tissues. In this study, NMR imaging is shown to be a noninvasive nondestructive way to measure penetration rates and effective diffusion coefficients of Me2SO into samples of rat kidney and rat liver tissues. This new method is unique in that the measurements obtained are not averaged over the entire tissue volume but may be made at any site in the tissue. Measurements of penetration rates yield values which are similar to literature values, and the effective diffusion coefficients fall within the expected range. The images also suggest an explanation of why CPSs fail to completely protect organs from freezing damage.

Stochastic ICA contrast maximisation using OJA's nonlinear PCA algorithm.

Independent Component Analysis (ICA) is an important extension of linear Principal Component Analysis (PCA). PCA performs a data transformation to provide independence to second order, that is, decorrelation. ICA transforms data to provide approximate independence up to and beyond second order yielding transformed data with fully factorable probability densities. The linear ICA transformation has been applied to the classical statistical signal-processing problem of Blind Separation of Sources (BSS), that is, separating unknown original source signals from a mixture whose mode of mixing is undetermined. In this paper it is shown that Oja's Nonlinear PCA algorithm performs a general stochastic online adaptive ICA. This analysis is corroborated with three simulations. The first separates unknown mixtures of original natural images, which have sub-Gaussian densities, the second separates linear mixtures of natural speech whose densities are super-Gaussian. Finally unknown mixtures of original images, which have both sub- and super-Gaussian densities are separated.

1D and 2D solid state NMR investigations of the framework structure of As-synthesized AlPO4-14.

The framework structure of As-synthesized AlPO4-14 has been investigated with a combination of different one-dimensional 27Al and 31P solid state NMR techniques and 27Al/31P double resonance methods. The results are found to be fully consistent with the assumed structural model. 27Al MAS and DOR experiments at three different magnetic field strengths together with simulations show the presence of two tetrahedral sites, one pentacoordinated and one octahedral aluminum site. The 27Al quadrupolar coupling constants and the 31P isotropic chemical shifts of the tetrahedral sites correlate well with tetrahedral shear-strain parameters and mean P-O-Al bond angles, respectively. These correlations allow one to assign all of the NMR resonances to specific T-sites in the proposed framework structure. The assignments are then further confirmed by the application of three different two-dimensional heteronuclear correlation methods (i.e., 27Al-->31P TEDOR, CP, and INEPT) which reveal the connectivities between AlOx and PO4 polyhedra. The two-dimensional INEPT experiment is applied here for the first time in the solid state.

Magnetic resonance imaging evaluation of photodynamic therapy-induced hemorrhagic necrosis in the murine M1 tumor model.

Proton magnetic resonance imaging (MRI) and histological methods were used to evaluate photodynamic therapy (PDT)-induced hemorrhagic necrosis in the murine M1 tumor within 72 h of treatment of male DBA/2 mice. The effects of three photosensitizing drugs were investigated: Photofrin (n = 4), Zn (II) phthalocyanine (n = 7) and benzoporphyrin derivative monoacid ring A (n = 11). As noted in previous studies of PDT using MRI, MRI makes possible serial, noninvasive, in vivo observation of tissue response to PDT. Our serial study of MRI and histological data confirms that tumors responded in the same way to PDT treatment using the three photosensitizing drugs: vascular damage followed by hemorrhagic necrosis. Most importantly and unlike previous MRI studies of PDT, we used a very high field magnet that enhanced the effect of magnetic susceptibility on image signal when blood is processed by the body after PDT-induced hemorrhagic necrosis. This last finding demonstrates the utility of high field magnets and the importance of localized, serial experiments in future magnetic resonance studies of PDT.