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.

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.

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.

A systematic study of the vibrational free energies of polypeptides in folded and random states.

Molecular vibrations, especially low frequency motions, may be used as an indication of the rigidity or the flatness of the protein folding energy landscape. We have studied the vibrational properties of native folded as well as random coil structures of more than 60 polypeptides. The picture we obtain allows us to perceive how and why the energy landscape progressively rigidifies while still allowing potential flexibility. Compared with random coil structures, both alpha-helices and beta-hairpins are vibrationally more flexible. The vibrational properties of loop structures are similar to those of the corresponding random coil structures. Inclusion of an alpha-helix tends to rigidify peptides and so-called building blocks of the structure, whereas the addition of a beta-structure has less effect. When small building blocks coalesce to form larger domains, the protein rigidifies. However, some folded native conformations are still found to be vibrationally more flexible than random coil structures, for example, beta(2)-microglobulin and the SH3 domain. Vibrational free energy contributes significantly to the thermodynamics of protein folding and affects the distribution of the conformational substates. We found a weak correlation between the vibrational folding energy and the protein size, consistent with both previous experimental estimates and theoretical partition of the heat capacity change in protein folding.

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.

Correction of a migrated Tenckhoff peritoneal dialysis catheter using a Lunderquist guidewire: report of two cases.

Two chronic ambulatory peritoneal dialysis (CAPD) patients who experienced from ultrafiltration failure resulting from malposition of a Tenckhoff catheter were treated. Conservative management such as changing body position, saline infusion, and enemas had been tried, but had failed. To avoid surgical intervention, we attempted to correct the malposition using a 120-cm-long Lunderquist guidewire (Nycomed, NY) with a 15-cm-long soft and flexible tip at its distal end. Under fluoroscopy, we successfully repositioned these two migrated Tenckhoff catheters using a Lunderquist guidewire. To the best of our knowledge, this is the first report of using a Lunderquist guidewire to correct a malfunctioning Tenckhoff catheter in CAPD patients. The Lunderquist guide wire has the advantages of being relatively non-invasive and easily used and it provides a reduced morbidity rate. Moreover, using this guidewire allows the Tenckhoff catheter to produce torque and whiplash, buckling, sweeping and rotating maneuvers that can help to correct malposition of the catheter and redirect the catheter to its ideal position. We therefore suggest that patients who receive surgical revision for a malfunctioning Tenckhoff catheter have at least one attempt at correction using this safe and easy procedure before surgery.

The value of gallium-67 and thallium-201 whole-body and single-photon emission tomography images in dialysis-related beta 2-microglobulin amyloid.

The aim of this study was to investigate the value of gallium-67 and thallium-201 whole-body and single-photon emission tomography (SPET) images in long-term dialysis patients in whom dialysis-related beta 2-microglobulin amyloid (beta 2-MA) was clinically suspected. Twenty-three patients who had received dialysis for at least 10 years were included in the study. A technetium-99m methylene diphosphonate (MDP) whole-body scan was performed in all of the patients. If there was any MDP accumulation in the articular and/or peri-articular region, 67Ga and 201Tl whole-body and SPET images were then acquired. If any 67Ga and/or 201Tl uptake was observed, a CT-guided biopsy was done. In those patients who had articular and/or peri-articular uptake of 99mTc MDP, 67Ga and/or 201Tl and who were pathologically proven to have beta 2-MA, 99mTc MDP, 67Ga and 201Tl whole-body scans and SPET were carried out again, both 3 months and 1 year after initiation of treatment. This served to evaluate the therapeutic effect and allowed comparison with the clinical findings. Of the 23 patients, eight had abnormal 99mTc MDP uptake. Among these eight, six had intense 99mTc MDP, 67Ga and 201Tl uptake in the articular and peri-articular regions before medication. Three months after the start of treatment, there were very marked decreases in uptake on both the 67Ga and 201Tl scans but less obvious changes in uptake of 99mTc-MDP. In comparison with the other clinical manifestations such as limitation in range of motion, the more the painful disability improved, the less was the uptake on both 67Ga and 201Tl scans. There were virtually no differences in uptake pattern between the three scans of each radiopharmaceutical obtained for each patient in both 3 months and 1 year after initial of treatment. It is concluded that 99mTc-MDP whole-body bone scan can both detect active and pre-existing inactive deposits of beta 2-MA. 67Ga and 201Tl scans are helpful to differentiate active from inactive deposits of beta 2-MA and to evaluate the therapeutic effect on these patients. SPET images are usually needed to distinguish articular and periarticular lesions from bone lesions.

GSTT1 and GSTM1 null genotypes and the risk of gastric cancer: a case-control study in a Chinese population.

Glutathione S-transferase (GST) enzymes are involved in detoxification of many potentially carcinogenic compounds. The homozygous deletions or null genotypes of GSTT1 (theta class) and GSTM1 (mu class) genes may be associated with an increased risk of cancer. Few studies have evaluated the relationship between GSTT1, GSTM1 and the risk of gastric cancer, as well as the potential interactions between these genetic markers and other risk factors of gastric cancer in the Chinese population. We conducted a case-control study with 143 cases with gastric cancer, 166 chronic gastritis (CG) cases and 433 cancer-free population controls from Yangzhong County, China. The epidemiological data were collected by a standard questionnaire for all of the subjects, and blood samples were obtained from 91 gastric cancer cases, 146 CG cases, and 429 controls. GSTT1 and GSTM1 genotypes were assayed by the PCR method, and Helicobacter pylori infection was measured by the ELISA method. Using logistic regression model in SAS, we assessed the independent effects of GSTT1 and GSTM1 null genotypes on the risk of gastric cancer and their potential interactions with other factors. The prevalence of GSTM1 null genotype was 48% in gastric cancer cases, 60% in CG patients, and 51% in controls. The prevalence of GSTT1 null genotype was 54% in gastric cancer cases, 48% in CG patients, and 46% in controls. After controlling for age, gender, education, pack-years of smoking, alcohol drinking, body mass index, H. pylori infection, and fruit and salt intake, the adjusted odds ratio (OR) for GSTT1 and gastric cancer was 2.50 (95% confidence interval (CI), 1.01-6.22). When gastric cancer cases were compared with CG patients, the adjusted OR for GSTT1 was 2.33 (95% CI, 0.75-7.25). However, GSTT1 null genotype was not associated with the risk of CG when using population controls. No obvious association was found between GSTM1 and the risk of both gastric cancer and CG. Our results suggest that GSTT1 null genotype may be associated with an increased risk of gastric cancer in a Chinese population.

Screening of protective antigens of Japanese encephalitis virus by DNA immunization: a comparative study with conventional viral vaccines.

In this study, we evaluated the relative role of the structural and nonstructural proteins of the Japanese encephalitis virus (JEV) in inducing protective immunities and compared the results with those induced by the inactivated JEV vaccine. Several inbred and outbred mouse strains immunized with a plasmid (pE) encoding the JEV envelope protein elicited a high level of protection against a lethal JEV challenge similar to that achieved by the inactivated vaccine, whereas all the other genes tested, including those encoding the capsid protein and the nonstructural proteins NS1-2A, NS3, and NS5, were ineffective. Moreover, plasmid pE delivered by intramuscular or gene gun injections produced much stronger and longer-lasting JEV envelope-specific antibody responses than immunization of mice with the inactivated JEV vaccine did. Interestingly, intramuscular immunization of plasmid pE generated high-avidity antienvelope antibodies predominated by the immunoglobulin G2a (IgG2a) isotype similar to a sublethal live virus immunization, while gene gun DNA immunization and inactivated JEV vaccination produced antienvelope antibodies of significantly lower avidity accompanied by a higher IgG1-to-IgG2a ratio. Taken together, these results demonstrate that the JEV envelope protein represents the most critical antigen in providing protective immunity.

Folding funnels and binding mechanisms.

The long-held views on lock-and-key versus induced fit in binding arose from the notion that a protein exists in a single, most stable conformation, dictated by its sequence. However, in solution proteins exist in a range of conformations, which may be described by statistical mechanical laws and their populations follow statistical distributions. Upon binding, the equilibrium will shift in favor of the bound conformation from the ensemble of conformations around the bottom of the folding funnel. Hence here we extend the implications and the usefulness of the folding funnel concept to explain fundamental binding mechanisms.

Distinguishing between sequential and nonsequentially folded proteins: implications for folding and misfolding.

We describe here an algorithm for distinguishing sequential from nonsequentially folding proteins. Several experiments have recently suggested that most of the proteins that are synthesized in the eukaryotic cell may fold sequentially. This proposed folding mechanism in vivo is particularly advantageous to the organism. In the absence of chaperones, the probability that a sequentially folding protein will misfold is reduced significantly. The problem we address here is devising a procedure that would differentiate between the two types of folding patterns. Footprints of sequential folding may be found in structures where consecutive fragments of the chain interact with each other. In such cases, the folding complexity may be viewed as being lower. On the other hand, higher folding complexity suggests that at least a portion of the polypeptide backbone folds back upon itself to form three-dimensional (3D) interactions with noncontiguous portion(s) of the chain. Hence, we look at the mechanism of folding of the molecule via analysis of its complexity, that is, through the 3D interactions formed by contiguous segments on the polypeptide chain. To computationally splice the structure into consecutively interacting fragments, we either cut it into compact hydrophobic folding units or into a set of hypothetical, transient, highly populated, contiguous fragments ("building blocks" of the structure). In sequential folding, successive building blocks interact with each other from the amino to the carboxy terminus of the polypeptide chain. Consequently, the results of the parsing differentiate between sequentially vs. nonsequentially folded chains. The automated assessment of the folding complexity provides insight into both the likelihood of misfolding and the kinetic folding rate of the given protein. In terms of the funnel free energy landscape theory, a protein that truly follows the mechanism of sequential folding, in principle, encounters smoother free energy barriers. A simple sequentially folded protein should, therefore, be less error prone and fold faster than a protein with a complex folding pattern.

Does quantitative serologic testing for Helicobacter pylori predict peptic ulcer disease in cirrhosis?

BACKGROUND: Helicobacter Pylori is strongly associated with peptic ulcer disease. A correlation between high IgG serum antibody concentrations and a clinical diagnosis has been reported. It has been recognized that peptic ulcer disease occurs with increased frequency in cirrhosis. In this study, we attempted to establish a relation between the magnitude of serum IgG antibody to H pylori and the endoscopic diagnoses in H pylori-infected cirrhotic patients. METHODS: All cirrhotic patients who had undergone esophagogastroduodenoscopy with a positive H pylori IgG serology and who did not receive anti-H pylori treatment or take medications noxious to the gastroduodenal mucosa were included in the study. H pylori IgG serology was determined by an enzyme-linked immunosorbent assay with values of greater than 50 units/mL being seropositive. The functional reserve of cirrhosis was classified by modified Pugh-Child criteria. RESULTS: One hundred four seropositive cirrhotic patients were recruited. The serum IgG titers ranged from 51 to 1200 units/mL with a peak frequency at 50 to 99 units/mL (35. 6%). Statistical analysis did not reveal any relation between the quantitative H pylori IgG values and the endoscopic diagnoses, which included gastric ulcers, duodenal ulcers, gastroduodenal erosions, and normal findings. CONCLUSIONS: In cirrhosis, the magnitude of H pylori IgG serology cannot be used to predict the presence or absence of peptic ulcer disease.

Psychiatric co-morbidity among male heroin addicts: differences between hospital and incarcerated subjects in Taiwan.

AIMS: To examine the differences in psychiatric co-morbidity between hospital and incarcerated groups of heroin addicts in Taiwan. DESIGN: Life-time prevalence of DSM-III-R-based coexisting psychiatric disorders, including personality disorders, were surveyed. SETTINGS: A psychiatric hospital and two prisons. PARTICIPANTS: Two hundred and sixty heroin users who were incarcerated in prisons, and 47 heroin users who voluntarily sought help in a psychiatric hospital were interviewed by board-certified psychiatrists. MEASUREMENTS: Using two psychometric instruments, the Psychiatric Diagnostic Assessment (PDA) and the Structured Interview for DSM-III-R Personality Disorders (SIPD-R), psychiatric co-morbidity was assessed. FINDINGS: Different life-time rates of coexisting psychiatric disorders among heroin addicts in different settings were found: 83% of hospital subjects and 66% of incarcerated subjects were diagnosed as having at least one coexisting axis I or II disorder. The most prevalent coexisting DSM-III-R defined axis I disorders were additional substance use disorders (alcohol and methamphetamine), while the axis II disorder was antisocial personality disorder. The hospital group had a significantly higher prevalence rate of mood disorder (p < 0.001), paranoid personality disorder (p < 0.05) and antisocial personality disorder (p < 0.001) than the incarcerated group. CONCLUSIONS: We suggest that heroin addicts with coexisting psychiatric disorders receive relevant psychiatric treatment. Those with personality disorders, especially the antisocial type, should be considered for specialized therapeutic community programmes instead of incarceration.

Ultrasound features of disseminated adenomucinosis (pseudomyxoma).

Pseudomyxoma is a clinical entity in which the peritoneal surfaces and omentum are involved with gelatinous, mucinous implants, and often massive gelatinous ascites. Most cases originate from ruptured ovarian cysts or appendiceal mucoceles, and involve only the intraperitoneal cavity. This report describes a case of disseminated adenomucinosis, the benign form of pseudomyxoma, with both peritoneal and retroperitoneal involvement. The diagnosis was suggested by real-time ultrasound and confirmed at surgery. The ultrasound characteristics of this rare entity and the differential diagnoses are discussed.

Mechanism and evolution of protein dimerization.

We have investigated the mechanism and the evolutionary pathway of protein dimerization through analysis of experimental structures of dimers. We propose that the evolution of dimers may have multiple pathways, including (1) formation of a functional dimer directly without going through an ancestor monomer, (2) formation of a stable monomer as an intermediate followed by mutations of its surface residues, and (3), a domain swapping mechanism, replacing one segment in a monomer by an equivalent segment from an identical chain in the dimer. Some of the dimers which are governed by a domain swapping mechanism may have evolved at an earlier stage of evolution via the second mechanism. Here, we follow the theory that the kinetic pathway reflects the evolutionary pathway. We analyze the structure-kinetics-evolution relationship for a collection of symmetric homodimers classified into three groups: (1) 14 dimers, which were referred to as domain swapping dimers in the literature; (2) nine 2-state dimers, which have no measurable intermediates in equilibrium denaturation; and (3), eight 3-state dimers, which have stable intermediates in equilibrium denaturation. The analysis consists of the following stages: (i) The dimer is divided into two structural units, which have twofold symmetry. Each unit contains a contiguous segment from one polypeptide chain of the dimer, and its complementary contiguous segment from the other chain. (ii) The division is repeated progressively, with different combinations of the two segments in each unit. (iii) The coefficient of compactness is calculated for the units in all divisions. The coefficients obtained for different cuttings of a dimer form a compactness profile. The profile probes the structural organization of the two chains in a dimer and the stability of the monomeric state. We describe the features of the compactness profiles in each of the three dimer groups. The profiles identify the swapping segments in domain swapping dimers, and can usually predict whether a dimer has domain swapping. The kinetics of dimerization indicates that some dimers which have been assigned in the literature as domain swapping cases, dimerize through the 2-state kinetics, rather than through swapping segments of performed monomers. The compactness profiles indicate a wide spectrum in the kinetics of dimerization: dimers having no intermediate stable monomers; dimers having an intermediate with a stable monomer structure; and dimers having an intermediate with a stable structure in part of the monomer. These correspond to the multiple evolutionary pathways for dimer formation. The evolutionary mechanisms proposed here for dimers are applicable to other oligomers as well.