Investigation of a Novel Decision Support Metric for Head and Neck Adaptive Radiation Therapy Using a Real-Time In Vivo Portal Dosimetry System.

In adaptive radiation therapy of head and neck cancer, any significant anatomical changes observed are used to adapt the treatment plan to maintain target coverage without elevating the risk of xerostomia. However, the additional resources required for adaptive radiation therapy pose a challenge for broad-based implementation. It is hypothesized that a change in transit fluence is associated with volumetric change in the vicinity of the target and therefore can be used as a decision support metric for adaptive radiation therapy. This was evaluated by comparing the fluence with volumetric changes in 12 patients. Transit fluence was measured by an in vivo portal dosimetry system. Weekly cone beam computed tomography was used to determine volume change in the rectangular region of interest from condyloid process to C6. The integrated transit fluence through the region of interest on the day of the cone beam computed tomography scan was calculated with the first treatment as the baseline. The correlation between fluence change and volume change was determined. A logistic regression model was also used to associate the 5% region of interest volume reduction replanning trigger point and the fluence change. The model was assessed by a chi-square test. The area under the receiver-operating characteristic curve was also determined. A total of 46 pairs of measurements were obtained. The correlation between fluence and volumetric changes was found to be -0.776 (P value <.001). The negative correlation is attributed to the increase in the photon fluence transport resulting from the volume reduction. The chi-square of the logistic regression was found to be 17.4 (P value <.001). The area under the receiver-operating characteristic curve was found to be 0.88. Results indicate the change in transit fluence, which can be measured without consuming clinical resources or requiring additional time in the treatment room, can be used as a decision support metric for adaptive therapy.

A comparison of the effectiveness of dexmedetomidine versus propofol target-controlled infusion for sedation during fibreoptic nasotracheal intubation.

Fibreoptic intubation is a valuable modality for airway management. This study aimed to compare the effectiveness of dexmedetomidine vs target controlled propofol infusion in providing sedation during fibreoptic intubation. Forty patients with anticipated difficult airways and due to undergo tracheal intubation for elective surgery were enrolled and randomly allocated into the dexmedetomidine group (1.0 microg.kg(-1) over 10 min) (n = 20) or the propofol target controlled infusion group (n = 20). Intubating conditions and patient tolerance as graded by a scoring system were evaluated as primary outcomes. Intubation was successful in all patients. Satisfactory intubating conditions were found in both groups (19/20 in each group). The median (IOR [range]) comfort score was 2 (1-2 [1-4]) in the dexmedetomidine group and 3 (2-4 [2-5]) in the propofol group (p = 0.027), favouring the former. The dexmedetomidine group experienced fewer airway events and less heart rate response to intubation than the propofol group (p < 0.003 and p = 0.007, respectively). Both dexmedetomidine and propofol target-controlled infusion are effective for fibreoptic intubation. Dexmedetomidine allows better tolerance, more stable haemodynamic status and preserves a patent airway.

Prevalence of metabolic syndrome among patients with schizophrenia or schizoaffective disorder in Taiwan.

OBJECTIVE: Because of ethnic differences in metabolic syndrome (MS) criteria, this study aimed to investigate the MS prevalence among patients with schizophrenia or schizoaffective disorder in Taiwan. METHOD: We recruited 650 patients with schizophrenia or schizoaffective disorder from 36 psychiatric institutions. The MS prevalence was assessed based on the modified Adult Treatment Panel (ATP) III criteria for Asians. RESULTS: The overall MS prevalence was 34.9%, with 38.9% in female and 31.5% in male patients respectively. The difference of MS prevalence between our sample and the general population was marked in male patients under 40 years of age and in female patients under 50 years old. Body mass index > or =24 and age over 40 years old are two important risk factors of MS. Female and polypharmacy had marginal significance with the presence of MS. CONCLUSION: Patients with schizophrenia or schizoaffective disorder in Taiwan had a high prevalence of MS, which appeared early in their lives.

Central adiposity, regional fat distribution, and the risk of cholecystectomy in women.

PURPOSE: Whether central adiposity contributes independently of total adiposity to the risk for gall stones is inconclusive. We examined prospectively indicators of central adiposity in relation to the occurrence of gall stone disease. METHODS: We evaluated the relationship between abdominal circumference and waist to hip ratio and risk of cholecystectomy in a cohort of women who had no history of gall stone disease. As part of the Nurses' Health Study, the women reported on questionnaires their weights, heights, and waist and hip circumferences, and the occurrence of cholecystectomy. A total of 42,312 women, aged 39-66 years in 1986, who were free of prior gall stone disease, provided complete waist and hip circumference measurements in 1986. RESULTS: We documented 3197 cases of cholecystectomy during 514,283 person years of follow up. After adjusting simultaneously for regional (waist circumference or waist to hip ratio) and total adiposity (body mass index) measures as well as for other risk factors of gall stone disease, women with a height adjusted waist circumference of 36 inches or larger had a relative risk (RR) of 1.96 (95% confidence interval (CI) 1.53-2.51; p trend < 0.0001) compared with women with a height adjusted waist circumference of less than 26 inches. Waist to hip ratio was directly associated with the risk, with an RR of 1.39 (95% CI 1.16-1.66; p trend < 0.0001) for women with a waist to hip ratio of 0.86 or higher compared with women with a waist to hip ratio of less than 0.70. CONCLUSION: Abdominal circumference and waist to hip ratio were associated with an increased risk of cholecystectomy, independently of body mass index in women.

Influences of pH and hydraulic retention time on anaerobes converting beer processing wastes into hydrogen.

To convert high-solids organic wastes (3% w./w.) to high-value hydrogen, a full factorial experimental design was employed in planning the experiments for learning the effects of pH and hydraulic retention time (HRT) on the hydrogen production in a chemostat reactor using waste yeast obtained from beer processing wastes. For determining which experimental variable settings affect hydrogen production, predictive polynomial quadratic equation and response surface methodology were employed to determine and explain the conditions required for high-value hydrogen production. Experimental results indicate that a maximum hydrogen production rate of 460 mL/gVSS/d was obtained at pH = 5.8 and HRT = 32 hours. Moreover, hydrogenase targeted RT-PCR results indicate that Clostridium thermocellum and Klebsiella pneumoniae predominated.

Dietary carbohydrates and glycaemic load and the incidence of symptomatic gall stone disease in men.

BACKGROUND: Diets with a high glycaemic response exacerbate the metabolic consequences of the insulin resistance syndrome. Their effects on the incidence of gall stone disease are not clear, particularly in men. METHODS: Dietary information was collected as part of the Health Professionals Follow up Study starting in 1986 using a semiquantitative food frequency questionnaire with follow up until 1998. On biennial questionnaires participants reported new symptomatic gall stone disease, diagnosed by radiology, and whether they had undergone cholecystectomy. RESULTS: During 12 years of follow up, we documented 1810 new cases of symptomatic gall stones. After adjusting for age and other known or suspected risk factors in multivariate models, the relative risk (RR) for the highest compared with the lowest quintile of carbohydrate intake was 1.59 (95% confidence interval (CI) 1.25, 2.02; p for trend = 0.002). The RR for the highest compared with the lowest quintile of dietary glycaemic load was 1.50 (95% CI 1.20, 1.88; p for trend = 0.0008), and 1.18 for dietary glycaemic index (95% CI 1.01, 1.39; p for trend = 0.04). Independent positive associations were also seen for intakes of starch, sucrose, and fructose. CONCLUSIONS: Our findings suggest that a high intake of carbohydrate, glycaemic load, and glycaemic index increases the risk of symptomatic gall stone disease in men. These results add to the concern that low fat high carbohydrate diets may not be an optimal dietary recommendation.

Transmission electron microscopy investigation of the formation of C54-TiSi(2) phase on stressed (001)Si.

The effects of stress on the formation of C54-TiSi2 phase in Ti/(001)Si samples have been investigated by high-resolution transmission electron microscopy in conjunction with auto-correlation function (ACF) analysis. The C54-TiSi2 phase transformation temperature in tensily stressed samples was found to be lowered by about 100 degrees C than that in compressively stressed samples. The thickness of amorphous interlayers (a-interlayers) between Ti metal thin films and Si substrates was found to be thicker and thinner in the tensily and compressively stressed Si samples, respectively. Furthermore, the thicker a-interlayer was found to consist of a higher density of crystallites from the ACF analysis. With a higher density of crystallites in the a-interlayer, the grain size of C49-TiSi2 was reduced since more nucleation sites are available for the formation of C49-TiSi2. The small grain size of C49-TiSi2 in turn enhances the formation of C54-TiSi2. As a result, the phase transformation of C49- to C54-TiSi2 is enhanced by the tensile stress present in silicon substrates.

The building block folding model and the kinetics of protein folding.

Here we show that qualitatively, the building blocks folding model accounts for three-state versus the two-state protein folding. Additionally, it is consistent with the faster versus slower folding rates of the two-state proteins. Specifically, we illustrate that the building blocks size, their mode of associations in the native structure, the number of ways they can combinatorially assemble, their population times and the way they are split in the iterative, step-by-step structural dissection which yields the anatomy trees, explain a broad range of folding rates. We further show that proteins with similar general topologies may have different folding pathways, and hence different folding rates. On the other hand, the effect of mutations resembles that of changes in conditions, shifting the population times and hence the energy landscapes. Hence, together with the secondary structure type and the extent of local versus non-local interactions, a coherent, consistent rationale for folding kinetics can be outlined, in agreement with experimental results. Given the native structure of a protein, these guidelines enable a qualitative prediction of the folding kinetics. We further describe these in the context of the protein folding energy landscape. Quantitatively, in principle, the diffusion-collision model for the building block association can be used. However, the folding rates of the building blocks and traps in their formation and association, need to be considered.

Thermodynamic differences among homologous thermophilic and mesophilic proteins.

Here, we analyze the thermodynamic parameters and their correlations in families containing homologous thermophilic and mesophilic proteins which show reversible two-state folding <--> unfolding transitions between the native and the denatured states. For the proteins in these families, the melting temperatures correlate with the maximal protein stability change (between the native and the denatured states) as well as with the enthalpic and entropic changes at the melting temperature. In contrast, the heat capacity change is uncorrelated with the melting temperature. These and additional results illustrate that higher melting temperatures are largely obtained via an upshift and broadening of the protein stability curves. Both thermophilic and mesophilic proteins are maximally stable around room temperature. However, the maximal stabilities of thermophilic proteins are considerably greater than those of their mesophilic homologues. At the living temperatures of their respective source organisms, homologous thermophilic and mesophilic proteins have similar stabilities. The protein stability at the living temperature of the source organism does not correlate with the living temperature of the protein. We tie thermodynamic observations to microscopics via the hydrophobic effect and a two-state model of the water structure. We conclude that, to achieve higher stability and greater resistance to high and low temperatures, specific interactions, particularly electrostatic, should be engineered into the protein. The effect of these specific interactions is largely reflected in an increased enthalpy change at the melting temperature.

Structured disorder and conformational selection.

Traditionally, molecular disorder has been viewed as local or global instability. Molecules or regions displaying disorder have been considered inherently unstructured. The term has been routinely applied to cases for which no atomic coordinates can be derived from crystallized molecules. Yet, even when it appears that the molecules are disordered, prevailing conformations exist, with population times higher than those of all alternate conformations. Disordered molecules are the outcome of rugged energy landscapes away from the native state around the bottom of the funnel. Ruggedness has a biological function, creating a distribution of structured conformers that bind via conformational selection, driving association and multimolecular complex formation, whether chain-linked in folding or unlinked in binding. We classify disordered molecules into two types. The first type possesses a hydrophobic core. Here, even if the native conformation is unstable, it still has a large enough population time, enabling its experimental detection. In the second type, no such hydrophobic core exists. Hence, the native conformations of molecules belonging to this category have shorter population times, hindering their experimental detection. Although there is a continuum of distribution of hydrophobic cores in proteins, an empirical, statistically based hydrophobicity function may be used as a guideline for distinguishing the two disordered molecule types. Furthermore, the two types relate to steps in the protein folding reaction. With respect to protein design, this leads us to propose that engineering-optimized specific electrostatic interactions to avoid electrostatic repulsion would reduce the type I disordered state, driving the molten globule (MG) --> native (N) state. In contrast, for overcoming the type II disordered state, in addition to specific interactions, a stronger hydrophobic core is also indicated, leading to the denatured --> MG --> N state.

Collection efficiency and capacity of three samplers for acidic and basic gases.

This paper compares the collection efficiency and capacity of a coated porous metal disk with those of a silica gel tube and an impinger at the acid or basic aerosol concentration of two times the permissible exposure limitation (Taiwan IOSH, Institute of Occupational Safety and Health), relative humidity of 80 +/- 5%, and temperature of 30 +/- 3 degrees C in the laboratory. Using 5% sodium carbonate/glycerin coating, the collection efficiencies of the porous metal disk for nitric acid, hydrogen chloride, and hydrogen fluoride are found to be higher than those of the silica gel tube and the impinger when the sampling time is less than 3.0 h. The gas collection capacity of the porous metal disk coated with 5% sodium carbonate is calculated to be 3.9, 5.8, and >2.5 mg for nitric acid, hydrogen chloride, and hydrogen fluoride, respectively. For ammonia, the porous metal disk coated using 4% citric acid performs slightly better than the impinger, and the corresponding capacity is slightly greater than 33.6 mg.

Fluconazole disk diffusion test with methylene blue- and glucose-enriched Mueller-Hinton agar for determining susceptibility of Candida species.

A 25-microg fluconazole disk diffusion test using a Mueller-Hinton agar plate containing 2% glucose and 5 microg of methylene blue/ml (GM-MH) was compared to the macrodilution reference method for 210 Candida species. The GM-MH agar plate was read at 24 h. The predictive values of disks with susceptible, intermediate, and resistant results on the GM-MH agar plate at 24 h were 97.1, 56.3, and 76.5%, respectively.

Protein folding and function: the N-terminal fragment in adenylate kinase.

Three-dimensional protein folds range from simple to highly complex architectures. In complex folds, some building block fragments are more important for correct protein folding than others. Such fragments are typically buried in the protein core and mediate interactions between other fragments. Here we present an automated, surface area-based algorithm that is able to indicate which, among all local elements of the structure, is critical for the formation of the native fold, and apply it to structurally well-characterized proteins. In particular, we focus on adenylate kinase. The fragment containing the phosphate binding, P-loop (the "giant anion hole") flanked by a beta-strand and an alpha-helix near the N-terminus, is identified as a critical building block. This building block shows a high degree of sequence and structural conservation in all adenylate kinases. The results of our molecular dynamics simulations are consistent with this identification. In its absence, the protein flips to a stable, non-native state. In this misfolded conformation, the other local elements of the structure are in their native-like conformations; however, their association is non-native. Furthermore, this element is critically important for the function of the enzyme, coupling folding, and function.

A proposed structural model for amyloid fibril elongation: domain swapping forms an interdigitating beta-structure polymer.

We propose a model illustrating how proteins, which differ in their overall sequences and structures, can form the propagating, twisted beta-sheet conformations, characteristic of amyloids. Some cases of amyloid formation can be explained through a "domain swapping" event, where the swapped segment is either a beta-hairpin or an unstable conformation which can partially unfold and assume a beta-hairpin structure. As in domain swapping, here the swapped beta-hairpin is at the edge of the structure, has few (if any) salt bridges and hydrogen bonds connecting it to the remainder of the structure and variable extents of buried non-polar surface areas. Additionally, in both cases the swapped piece constitutes a transient "building block" of the structure, with a high population time. Whereas in domain swapping the swapped fragment has been shown to be an alpha-helix, loop, strand or an entire domain, but so far not a beta-hairpin, despite the large number of cases in which it was already detected, here swapping may involve such a structural motif. We show how the swapping of beta-hairpins would form an interdigitated, twisted beta-sheet conformation, explaining the remarkable high stability of the protofibril in vitro. Such a swapping mechanism is attractive as it involves a universal mechanism in proteins, critical for their function, namely hinge-bending motions. Our proposal is consistent with structural superpositioning of mutational variants. While the overall r.m.s.d.s of the wild-type and mutants are small, the proposed hinge-bending region consistently shows larger deviations. These larger deviations illustrate that this region is more prone to respond to the mutational changes, regardless of their location in the sequence or in the structure. Nevertheless, above all, we stress that this proposition is hypothetical, since it is based on assumptions lacking definitive experimental support.

Molecular dynamics simulation of Escherichia coli dihydrofolate reductase and its protein fragments: relative stabilities in experiment and simulations.

We have carried out molecular dynamics simulations of the native dihydrofolate reductase from Escherichia coli and several of its folded protein fragments at standard temperature. The simulations have shown fragments 1--36, 37--88, and 89--159 to be unstable, with a C(alpha)RMSD (C(alpha) root mean squared deviation) >5 A after 3.0 nsec of simulation. The unfolding of fragment 1--36 was immediate, whereas fragments 37--88 and 89--159 gradually unfolded because of the presence of the beta-sheet core structure. In the absence of residues 1--36, the two distinct domains comprising fragment 39--159 associated with each other, resulting in a stable conformation. This conformation retained most of its native structural elements. We have further simulated fragments derived from computational protein cutting. These were also found to be unstable, with the exception of fragment 104--159. In the absence of alpha(4), the loose loop region of residues 120--127 exhibited a beta-strand-like behavior, associating itself with the beta-sheet core of the protein fragment. The current study suggests that the folding of dihydrofolate reductase involves cooperative folding of distinct domains which otherwise would have been unstable as independent folded units in solution. Finally, the critical role of residues 1--36 in allowing the two distinct domains of fragment 104--159 to fold into the final native conformation is discussed.

Transient, highly populated, building blocks folding model.

Protein folding is a hierarchical event, in which transiently formed local structural elements assemble to yield the native conformation. In principle, multiple paths glide down the energy landscape, but, in practice, only a few of the paths are highly traveled. Here, the literature is reviewed in this light, and, particularly, a hierarchical, building block protein-folding model is presented, putting it in the context of a broad range of experimental and theoretical results published over the past few years. The model is based on two premises: First, although the local building block elements may be unstable, they nevertheless have higher population times than all alternate conformations; and, second, protein folding progresses through a combinatorial assembly of these elements. Through the binding of the most favorable building block conformers, there is a redistribution of the conformers in solution, propagating the protein-folding reaction. We describe the algorithm, and illustrate its usefulness, then we focus on its utility in assigning simple vs complex folding pathways, on chaperonin-assisted folding, on its relevance to domain-swapping processes, and on its relevance and relationship to disconnectivity graphs and tree diagrams. Considering protein folding as initiating from local transient structural elements is consistent with available experimental and theoretical results. Here, we have shown that, early in the folding process, sequential interactions are likely to take place, even if the final native fold is a complex, nonsequential one. Such a route is favorable kinetically and entropically. Through the construction of anatomy trees, the model enables derivation of the major folding pathways and their bumps, and qualitatively explains the kinetics of protein folding.

Clinical characteristic of parenteral iron supplementation in hemodialysis patients receiving erythropoietin therapy.

BACKGROUND: Iron deficiency constitutes the major cause of erythropoietin hyporesponse in uremic patients receiving erythropoietin therapy; therefore, iron supplementation is necessary for these patients. Recent data suggested that intravenous iron supply is a preferable route for iron supplementation. However, it remains unclear whether a single large dose or multiple small doses are a better way of administering an intravenous iron supply. METHODS: To determine the effect of different dosing schedules of intravenous iron therapy on the hematocrit level, we randomly assigned 18 patients to 3 groups. The first group of patients (n = 6) received a single dose of 800 mg intravenous fesin (ferric saccharate). The second group of patients (n = 6) received 400 mg intravenous fesin once weekly for 2 successive weeks. The third group of patients (n = 6) received 120 mg of intravenous fesin for 7 successive hemodialysis sessions. EPO was given at a fixed dose for all individuals in the study period. RESULTS: The results showed that all 3 groups of patients had a progressive increase in hematocrit (Hct) level following intravenous iron therapy. Serum ferritin levels increased rapidly following iron therapy and then declined gradually in all 3 groups. But no statistical significance could be found among the 3 groups because of the small patient number. Also, no differences were observed in Hct or serum ferritin levels among these 3 groups of patients at all stages. CONCLUSION: In this study, we found that a large single dose as well as small multiple doses of parenteral iron therapy had similar effects in correcting the iron deficiency in hemodialysis patients treated with erythropoietin. To save manpower and costs, we recommend the large single dosing schedule.

Anatomy of protein structures: visualizing how a one-dimensional protein chain folds into a three-dimensional shape.

Here, we depict the anatomy of protein structures in terms of the protein folding process. Via an iterative, top-down dissecting procedure, tertiary structures are spliced down to reveal their anatomy: first, to produce domains (defined by visual three-dimensional inspection criteria); then, hydrophobic folding units (HFU); and, at the end of a multilevel process, a set of building blocks. The resulting anatomy tree organization not only clearly depicts the organization of a one-dimensional polypeptide chain in three-dimensional space but also straightforwardly describes the most likely folding pathway(s). Comparison of the tree with the formation of the hydrophobic folding units through combinatorial assembly of the building blocks illustrates how the chain folds in a sequential or a complex folding pathway. Further, the tree points to the kinetics of the folding, whether the chain is a fast or a slow folder, and the probability of misfolding. Our ability to successfully dissect the protein into an anatomy tree illustrates that protein folding is a hierarchical process and further validates a building blocks protein folding model.