bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical benefit of interventions driven by therapeutic drug monitoring
Authors: Rendón AL , Núñez M , Jiménez‐Nácher I , González de Requena D , González‐Lahoz J , Soriano V
Published: September 2005

Background

Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long‐term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities.

Objective

To evaluate the usefulness of TDM in the care of HIV‐infected patients in an out‐patient clinical setting.

Methods

All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out‐patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC‐UV).

Results

A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again.

Conclusions

Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug‐related toxicities or improve virological response rates.
Long‐term utility of measuring adherence by self‐report compared with pharmacy record in a routine clinic setting
Authors: Fairley CK , Permana A , Read TRH
Published: September 2005

Objectives

To compare long‐term adherence to antiretroviral therapy in an HIV service, as measured by self‐report and by pharmacy records. To determine the level of adherence by each measure required to suppress viral load in a majority of patients.

Methods

The percentage of prescribed doses taken was calculated from (a) the number of missed doses in the previous 28 days reported by patients in a questionnaire at each clinic visit, and (b) pharmacy dispensing records. These were compared with each other and with HIV viral load data.

Results

Mean adherence was 96.2% by pharmacy record over 44 months and 98.6% by self‐report over 25 months. The two methods correlated with each other (P<0.001) and the proportion of patients with viral load <400 HIV‐1 RNA copies/mL increased with adherence as measured by self‐report (P=0.001) and pharmacy record (P=0.004). Fewer than 60% of patients always had viral loads <400 copies/mL if adherence fell below 95% (pharmacy record) or 97% (self‐report). Adherence was higher for once‐daily than for twice‐daily therapy (by pharmacy record: 97.2% vs. 96.0%; P<0.001). Adherence by both measures increased over time.

Conclusions

Self‐reported antiretroviral adherence correlates with pharmacy dispensing records and predicts suppression of viral load at levels ≥97%. It is practical to adopt this into routine HIV clinical care.
Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid‐differentiated human neuroblastoma cells
Authors: Holback Sofia , Adlerz Linda , Iverfeldt Kerstin
Published: September 2005

The amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor‐like proteins, APLP1 and APLP2. We have previously shown that all members of the APP protein family are up‐regulated upon retinoic acid (RA)‐induced neuronal differentiation of SH‐SY5Y neuroblastoma cells. Here, we demonstrate that RA also affects the processing of APLP2 and APP, as shown by increased shedding of both sAPLP2 and sAPPα, as well as elevated levels of the APP intracellular domains (AICDs). Brain‐derived neurotrophic factor (BDNF) has been reported to induce APP promoter activity and RA induces expression of the tyrosine kinase receptor B (TrkB) in neuroblastoma cells. We show that the increase in shedding of both APLP2 and APP in response to RA is not mediated through the TrkB receptor. However, BDNF concomitant with RA increased the expression of APP even further. In addition, the secretion of sAPLP2 and sAPPα as well as the levels of AICDs were increased in response to BDNF. In contrast, the levels of membrane‐bound APP C‐terminal fragment C99 significantly decreased. Our results suggest that RA and BDNF shifts APP processing towards the α‐secretase pathway. In addition, we show that RA and BDNF regulate N‐linked glycosylation of APLP1.
Role of Rho GTPase in astrocyte morphology and migratory response during in vitro wound healing
Authors: Höltje Markus , Hoffmann Anja , Hofmann Fred , Mucke Christian , Große Gisela , Van Rooijen Nico , Kettenmann Helmut , Just Ingo , Ahnert‐Hilger Gudrun
Published: September 2005

Small Rho GTPases are key regulators of the cytoskeleton in a great variety of cells. Rho function mediates morphological changes as well as locomotor activity. Using astrocyte cultures established from neonatal mice we investigated the role of Rho in process formation during astrocyte stellation. Using a scratch‐wound model, we examined the impact of Rho on a variety of morphological and functional variables such as stellation and migratory activity during wound healing. C3 proteins are widely used to study cellular Rho functions. In addition, C3 derived from Clostridium botulinum (C3bot) is considered selectively to promote neuronal regeneration. Because the latter requires a balanced activity of neurones and glial cells, the effects of C3 protein on glial cells such as astrocytes have to be considered carefully. Low nanomolar concentrations of C3 proteins significantly promoted process outgrowth and increased process branching. Besides enzymatic inactivation of Rho by ADP‐ribosylation, changes in protein levels of the various Rho GTPases may also contribute to the observed effects. Furthermore, incubation of scratch‐wounded astrocyte cultures with C3bot accelerated wound healing. By inhibiting the Rho downstream effector ROCK with the selective inhibitor Y27632 we were able to demonstrate that the accelerated wound closure resulted from both enhanced polarized process formation and increased migratory activity of astrocytes into the lesion site. These results suggest that Rho negatively regulates astrocytic process growth and migratory responses after injury and that its inactivation by C3bot in nanomolar concentrations promotes astrocyte migration.
Post‐training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo‐oxygenase‐2‐specific inhibitor celecoxib in rats
Authors: Sharifzadeh Mohammad , Tavasoli Mahtab , Naghdi Nasser , Ghanbari Azam , Amini Mohsen , Roghani Ali
Published: September 2005

Recently, we demonstrated that intrahippocampal infusion of the cyclo‐oxygenase (COX)‐2‐specific inhibitor celecoxib impaired spatial memory retention in the Morris water maze. In the present work, we investigated the effects of nicotine, infused in the rat dorsal hippocampus several minutes after infusion of celecoxib, on memory retention in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained four trials. Test trials were conducted 48 h after surgery. As expected, bilateral intrahippocampal infusion of celecoxib (19 µg/side; 0.1 m) increased escape latency and travel distance in rats, indicating significant impairment of spatial memory retention. We also examined the effects of bilateral infusion of nicotine (0.5, 1.0 and 2.0 µg/side) on memory retention. Infusion of 1 µg nicotine significantly decreased escape latency and travel distance but not swimming speed, compared with controls, suggesting memory retention enhancement by nicotine at this concentration. In separate experiments, bilateral infusion of nicotine, infused 5 min after 0.1 m (19 µg/side) celecoxib infusion, was associated with escape latency, travel distance and swimming speed profiles very similar to those in control animals. Brain tissue sections from several of these animals were subjected to immunohistochemical staining analysis with anti‐COX‐2 antibodies. Quantification analysis by optical density measurements showed that the celecoxib infusion reduced the immunoreactivity of COX‐2‐containing neurons in the CA1 area of the hippocampus compared with controls, although this reduction was not significant. However, infusion of a combination of celecoxib and nicotine significantly increased this immunoreactivity compared with levels in control and celecoxib‐infused groups. These results suggest that nicotine prevented or reversed the adverse effects of celecoxib on spatial memory retention and protected or restored the immunostaining pattern of COX‐2 neurons in the rat dorsal hippocampus.
Effects of perioperative hypothermia and warming in surgical practice
Authors: Kumar Senthil , Wong Peng Foo , Melling Andrew Christian , Leaper David John
Published: September 2005

Perioperative hypothermia is common and adversely affects clinical outcomes due to its effect on a range of homeostatic functions. Many of these adverse consequences are preventable by the use of warming techniques. A literature search was conducted to identify relevant published articles on perioperative hypothermia and warming. The databases searched include MEDLINE (1966 to February 2005), EMBASE (1974 to February 2005), CINAHL, the Cochrane library and the health technology assessment database. Reference lists of key articles were also searched. The primary beneficial effects of warming are mediated through increased blood flow and oxygen tension at tissue level. Reduction in wound infection, blood loss and perioperative pain with warming is promising. However, more evidence from good‐quality prospective randomised controlled trials is needed to evaluate the role of warming in improving overall morbidity, mortality and hospital stay as well as to clarify its role as an adjunct to resuscitation and during the pre‐hospital transport phase of critically ill patients. Awareness of the risks of perioperative hypothermia is the key to prevention. Achieving normothermia throughout the patient's journey is a worthwhile goal in surgical patients.
Generalised cutaneous necrosis: a complication of low‐molecular‐weight heparin
Authors: Patel Girish K , Knight Arthur G
Published: September 2005

Subcutaneous low‐molecular‐weight heparin (LMWH) injections have a predictable dose‐dependent anticoagulant effect and have therefore become popular for the prevention and management of thromboembolic diseases. It was initially hoped that use of the smaller molecule and better dose titration would reduce the incidence of side‐effects associated with conventional heparin therapy. However, case reports such as this have demonstrated that LMWHs still have the capacity to cause heparin‐induced thrombocytopaenia and heparin‐induced thrombocytopaenia with thrombosis, as well as heparin necrosis. To our knowledge, this is the first‐ever‐reported case of heparin necrosis associated with tinazaparin. Heparin necrosis is characterised by widespread life‐threatening cutaneous necrosis and systemic thrombosis, in which fatal progression of disease can only be halted by stopping heparin therapy. As heparin necrosis is an uncommon disorder, in this report we focus on the clinical clues that may help woundcare professionals consider and confirm the diagnosis.
Use of the sensory nerve stimulator to accelerate healing of a venous leg ulcer with sensory nerve dysfunction: a case study
Authors: Ogrin Rajna , Darzins Peteris , Khalil Zeinab
Published: September 2005

A new therapy using sensory nerve stimulation [International Patent Application Number PCT/AU2004/001079: ‘nerve function and tissue healing’ (Khalil, Z)] has been developed in our vascular physiology laboratory. This treatment has been found to improve the deficient sensory nerve function and associated deficient wound healing of older persons to levels seen in young people. An 82‐year‐old man with a small but persistent venous leg ulcer for 18 months, despite apparently appropriate wound dressings and compression therapy, was seen in a specialist wound management service. The patient's sensory and microvascular function was assessed in great detail using the vascular physiology laboratory techniques, and he was provided the sensory nerve stimulation therapy in addition to conventional therapy. His wound healed after 4 weeks. We report the case here. Prior to nerve stimulation therapy, cutaneous sensation, microvascular blood flow and oxygen tension were found to be reduced near the ulcer when compared with the opposite, non ulcerated leg. After therapy, oxygen tension and microvascular blood flow had improved. This case provides further evidence that sensory nerve stimulation therapy at the stipulated parameters improves wound healing. The observation that sensory nerve function improved provides support for the notion that improvement in healing is mediated by improved nerve function.
Economic comparison of methods of wound closure: wound closure strips vs. sutures and wound adhesives
Authors: Zempsky William T , Zehrer Cindy L , Lyle Christopher T , Hedbloom Edwin C
Published: September 2005

Our objective was to review and assess the treatment of low‐tension wounds and evaluate the cost‐effectiveness of wound closure methods. We used a health economic model to estimate cost/closure of adhesive wound closure strips, tissue adhesives and sutures. The model incorporated cost‐driving variables: application time, costs and the likelihood and costs of dehiscence and infection. The model was populated with variable estimates derived from the literature. Cost estimates and cosmetic results were compared. Parameter values were estimated using national healthcare and labour statistics. Sensitivity analyses were used to verify the results. Our analysis suggests that adhesive wound closure strips had the lowest average cost per laceration ($7·54), the lowest cost per infected laceration ($53·40) and the lowest cost per laceration with dehiscence ($25·40). The costs for sutures were $24·11, $69·91 and $41·91, respectively; the costs for tissue adhesives were $28·77, $74·68 and $46·68, respectively. The cosmetic outcome for all three treatments was equivalent. We conclude adhesive wound closure strips were both a cost‐saving and a cost‐effective alternative to sutures and tissue adhesives in the closure of low‐tension lacerations.
Evaluation of x‐ray scatter properties in a dedicated cone‐beam breast CT scanner
Authors: Kwan Alexander L. C. , Boone John M. , Shah Nikula
Published: September 2005

The magnitude of scatter contamination on a first‐generation prototype breast computed tomography (CT) scanner was evaluated using the scatter‐to‐primary ratio (SPR) metric. The SPR was measured and characterized over a wide range of parameters relevant to breast CT imaging, including x‐ray beam energy, breast diameter, breast composition, isocenter‐to‐detector distance, collimated slot thickness, and grid ratio. The results demonstrated that in the absence of scatter reduction techniques, the SPR levels for the average breast (e.g., 14 cm diameter composition cylindrical phantom) are quite high ( at the center of the phantom for 80 kVp in true cone‐beam CT geometry), and increases as the diameter of the phantom is increased (to at the center of a 18 cm diameter phantom). The x‐ray beam energy and the phantom compositions had only minimal impact on the measured SPR. When an ideal bowtie filter was used, the SPRs at the central axis of the 14 and 18 cm cylindrical phantoms were reduced while the SPRs at the edge of the phantoms were increased. Lastly, collimation in the vertical direction had a significant impact on the SPRs at the central axis of the phantoms. These high SPR levels might lead to cupping artifacts and increased noise in the reconstructed CT images, and this suggests that efficient scatter rejection and/or correction techniques may be required to improve the quality and accuracy of cone beam CT images.
The application of the sinusoidal model to lung cancer patient respiratory motion
Authors: George R. , Vedam S. S. , Chung T. D. , Ramakrishnan V. , Keall P. J.
Published: September 2005

Accurate modeling of the respiratory cycle is important to account for the effect of organ motion on dose calculation for lung cancer patients. The aim of this study is to evaluate the accuracy of a respiratory model for lung cancer patients. Lujan et al. [Med. Phys. 26(5), 715–720 (1999)] proposed a model, which became widely used, to describe organ motion due to respiration. This model assumes that the parameters do not vary between and within breathing cycles. In this study, first, the correlation of respiratory motion traces with the model as a function of the parameter was undertaken for each breathing cycle from 331 four‐minute respiratory traces acquired from 24 lung cancer patients using three breathing types: free breathing, audio instruction, and audio‐visual biofeedback. Because and had similar correlation coefficients, and and have a trigonometric relationship, for simplicity, the value was consequently used for further analysis in which the variations in mean position , amplitude of motion and period with and without biofeedback or instructions were investigated. For all breathing types, the parameter values, mean position , amplitude of motion , and period exhibited significant cycle‐to‐cycle variations. Audio‐visual biofeedback showed the least variations for all three parameters (, , and ). It was found that mean position could be approximated with a normal distribution, and the amplitude of motion and period could be approximated with log normal distributions. The overall probability density function (pdf) of for each of the three breathing types was fitted with three models: normal, bimodal, and the pdf of a simple harmonic oscillator. It was found that the normal and the bimodal models represented the overall respiratory motion pdfs with correlation values from 0.95 to 0.99, whereas the range of the simple harmonic oscillator pdf correlation values was 0.71 to 0.81. This study demonstrates that the pdfs of mean position , amplitude of motion , and period can be used for sampling to obtain more realistic respiratory traces. The overall standard deviations of respiratory motion were 0.48, 0.57, and for free breathing, audio instruction, and audio‐visual biofeedback, respectively.
Characteristics of induced activity from medical linear accelerators
Authors: Wang Yi Zhen , Evans Michael D. C. , Podgorsak Ervin B.
Published: September 2005

A study of the induced activity in a medical linear accelerator (linac) room was carried out on several linac installations. Higher beam energy, higher dose rate, and larger field size generally result in higher activation levels at a given point of interest, while the use of multileaf collimators (MLC) can also increase the activation level at the isocenter. Both theoretical and experimental studies reveal that the activation level in the morning before any clinical work increases from Monday to Saturday and then decreases during the weekend. This weekly activation picture keeps stable from one week to another during standard clinical operation of the linac. An effective half‐life for a given point in the treatment room can be determined from the measured or calculated activity decay curves. The effective half‐life for points inside the treatment field is longer than that for points outside of the field in the patient plane, while a larger field and longer irradiation time can also make the effective half‐life longer. The activation level reaches its practical saturation value after a continuous irradiation, corresponding to at a “dose rate” of . A “dose” of was given 20 times in intervals to determine the trends in the activation level in a typical clinical mode. As well, a long‐term ( over a long weekend) decay curve was measured to evaluate the long‐term decay of room activation after a typical day of clinical linac use. A mathematical model for the activation level at the isocenter has been established and shown to be useful in explaining and predicting the induced activity levels for typical clinical and experimental conditions. The activation level for a electron beam was also measured and the result shows it is essentially negligible.
Time‐frequency analysis of the second cardiac sound in phonocardiogram signals
Authors: Debbal S. M. , Bereksi‐Reguig F.
Published: September 2005

The paper is concerned with the analysis of the phonocardiogram signals (PCG) in the time‐frequency domain. Three techniques are studied and evaluated in PCG signal analysis. These are the short time Fourier transform (STFT), the Wigner distribution function (WD) and the continuous wavelet transforms (CWTs). The analysis is first carried out on the second cardiac sound (S2) in order to show the aptitude of each method in distinguishing the internal components of this sound. The results we obtain show that the STFT cannot detect the two internal components of S2 (A2 and P2, respectively, the aortic and pulmonary components). The WD can provide time‐frequency characteristics of S2, but with insufficient diagnostic information: the two components are not accurately detected and appear to be only one component. It is found that the CWT (it can also provide the time‐frequency characteristic of S2) is capable of detecting its two components, A2 and P2, allowing therefore the measurement of the delay between them. This delay, called the split, is very important in the diagnosis of many pathological cases, as it is emphasized in the results we obtain by applying the CWT on different pathological cases (mitral stenosis, pulmonary stenosis and atrial septal defect).
Effects of point configuration on the accuracy in 3D reconstruction from biplane images
Authors: Dmochowski Jacek , Hoffmann Kenneth R. , Singh Vikas , Xu Jinhui , Nazareth Daryl P.
Published: September 2005

Two or more angiograms are being used frequently in medical imaging to reconstruct locations in three‐dimensional (3D) space, e.g., for reconstruction of 3D vascular trees, implanted electrodes, or patient positioning. A number of techniques have been proposed for this task. In this simulation study, we investigate the effect of the shape of the configuration of the points in 3D (the “cloud” of points) on reconstruction errors for one of these techniques developed in our laboratory. Five types of configurations (a ball, an elongated ellipsoid (cigar), flattened ball (pancake), flattened cigar, and a flattened ball with a single distant point) are used in the evaluations. For each shape, 100 random configurations were generated, with point coordinates chosen from Gaussian distributions having a covariance matrix corresponding to the desired shape. The 3D data were projected into the image planes using a known imaging geometry. Gaussian distributed errors were introduced in theandcoordinates of these projected points. Gaussian distributed errors were also introduced into the gantry information used to calculate the initial imaging geometry. The imaging geometries and 3D positions were iteratively refined using the enhanced‐Metz‐Fencil technique. The image data were also used to evaluate the feasiblesolution volume. The 3D errors between the calculated and true positions were determined. The effects of the shape of the configuration, the number of points, the initial geometry error, and the input image error were evaluated. The results for the number of points, initial geometry error, and image error are in agreement with previously reported results, i.e., increasing the number of points and reducing initial geometry and/or image error, improves the accuracy of the reconstructed data. The shape of the 3D configuration of points also affects the error of reconstructed 3D configuration; specifically, errors decrease as the “volume” of the 3D configuration increases, as would be intuitively expected, and shapes with larger spread, such as spherical shapes, yield more accurate reconstructions. These results are in agreement with an analysis of the solution volume of feasible geometries and could be used to guide selection of points for reconstruction of 3D configurations from two views.
Energy modulated electron therapy using a few leaf electron collimator in combination with IMRT and 3D‐CRT: Monte Carlo‐based planning and dosimetric evaluation
Authors: Al‐Yahya Khalid , Schwartz Matthew , Shenouda George , Verhaegen Frank , Freeman Carolyn , Seuntjens Jan
Published: September 2005

Energy modulated electron therapy (EMET) based on Monte Carlo dose calculation is a promising technique that enhances the treatment planning and delivery of superficially located tumors. This study investigated the application of EMET using a novel few‐leaf electron collimator (FLEC) in head and neck and breast sites in comparison with three‐dimensional conventional radiation therapy (3D‐CRT) and intensity modulated radiation therapy (IMRT) techniques. Treatment planning was performed for two parotid cases and one breast case. Four plans were compared for each case: 3D‐CRT, IMRT, 3D‐CRT in conjunction with EMET (EMET‐CRT), and IMRT in conjunction with EMET (EMET‐IMRT), all of which were performed and calculated with Monte Carlo techniques. For all patients, dose volume histograms (DVHs) were obtained for all organs of interest and the DVHs were used as a means of comparing the plans. Homogeneity and conformity of dose distributions were calculated, as well as a sparing index that compares the effect of the low isodose lines. In addition, the whole‐body dose equivalent (WBDE) was estimated for each plan. Adding EMET delivered with the FLEC to 3D‐CRT improves sparing of normal tissues. For the two head and neck cases, the mean dose to the contralateral parotid and brain stem was reduced relative to IMRT by 43% and 84%, and by 57% and 71%, respectively. Improved normal tissue sparing was quantified as an increase in sparing index of 47% and 30% for the head and neck and the breast cases, respectively. Adding EMET to either 3D‐CRT or IMRT results in preservation of target conformity and dose homogeneity. When adding EMET to the treatment plan, the WBDE was reduced by between 6% and 19% for 3D‐CRT and by between 21% and 33% for IMRT, while WBDE for EMET‐CRT was reduced by up to 72% when compared with IMRT. FLEC offers a practical means of delivering modulated electron therapy. Although adding EMET delivered using the FLEC results in perturbation of target conformity when compared to IMRT, it significantly improves normal tissue sparing while offering enhanced target conformity to the 3D‐CRT planning. The addition of EMET systematically leads to a reduction in WBDE especially when compared with IMRT.
Oblique needle segmentation and tracking for 3D TRUS guided prostate brachytherapy
Authors: Wei Zhouping , Gardi Lori , Downey Donal B. , Fenster Aaron
Published: September 2005

An algorithm was developed in order to segment and track brachytherapy needles inserted along oblique trajectories. Three‐dimensional (3D) transrectal ultrasound (TRUS) images of the rigid rod simulating the needle inserted into the tissue‐mimicking agar and chicken breast phantoms were obtained to test the accuracy of the algorithm under ideal conditions. Because the robot possesses high positioning and angulation accuracies, we used the robot as a “gold standard,” and compared the results of algorithm segmentation to the values measured by the robot. Our testing results showed that the accuracy of the needle segmentation algorithm depends on the needle insertion distance into the 3D TRUS image and the angulations with respect to the TRUS transducer, e.g., at a 10° insertion anglulation in agar phantoms, the error of the algorithm in determining the needle tip position was less than when the insertion distance was greater than . Near real‐time needle tracking was achieved by scanning a small volume containing the needle. Our tests also showed that, the segmentation time was less than , and the scanning time was less than , when the insertion distance into the 3D TRUS image was less than . In our needle tracking tests in chicken breast phantoms, the errors in determining the needle orientation were less than 2° in robot yaw and 0.7° in robot pitch orientations, for up to 20° needle insertion angles with the TRUS transducer in the horizontal plane when the needle insertion distance was greater than .
Absorbed dose to water reference dosimetry using solid phantoms in the context of absorbed‐dose protocols
Authors: Seuntjens Jan , Olivares Marina , Evans Michael , Podgorsak Ervin
Published: September 2005

For reasons of phantom material reproducibility, the absorbed dose protocols of the American Association of Physicists in Medicine (AAPM) (TG‐51) and the International Atomic Energy Agency (IAEA) (TRS‐398) have made the use of liquid water as a phantom material for reference dosimetry mandatory. In this work we provide a formal framework for the measurement of absorbed dose to water using ionization chambers calibrated in terms of absorbed dose to water but irradiated in solid phantoms. Such a framework is useful when there is a desire to put dose measurements using solid phantoms on an absolute basis. Putting solid phantom measurements on an absolute basis has distinct advantages in verification measurements and quality assurance. We introduce a phantom dose conversion factor that converts a measurement made in a solid phantom and analyzed using an absorbed dose calibration protocol into absorbed dose to water under reference conditions. We provide techniques to measure and calculate the dose transfer from solid phantom to water. For an Exradin A12 ionization chamber, we measured and calculated the phantom dose conversion factor for six Solid Water™ phantoms and for a single Lucite phantom for photon energies between and photons. For Solid Water™ of certified grade, the difference between measured and calculated factors varied between 0.0% and 0.7% with the average dose conversion factor being low by 0.4% compared with the calculation whereas for Lucite, the agreement was within 0.2% for the one phantom examined. The composition of commercial plastic phantoms and their homogeneity may not always be reproducible and consistent with assumed composition. By comparing measured and calculated phantom conversion factors, our work provides methods to verify the consistency of a given plastic for the purpose of clinical reference dosimetry.
Spatiotemporal processing of gated cardiac SPECT images using deformable mesh modeling
Authors: Brankov Jovan G. , Yang Yongyi , Wernick Miles N.
Published: September 2005

In this paper we present a spatiotemporal processing approach, based on deformable mesh modeling, for noise reduction in gated cardiac single‐photon emission computed tomography images. Because of the partial volume effect (PVE), clinical cardiac‐gated perfusion images exhibit a phenomenon known as brightening—the myocardium appears to become brighter as the heart wall thickens. Although brightening is an artifact, it serves as an important diagnostic feature for assessment of wall thickening in clinical practice. Our proposed processing algorithm aims to preserve this important diagnostic feature while reducing the noise level in the images. The proposed algorithm is based on the use of a deformable mesh for modeling the cardiac motion in a gated cardiac sequence, based on which the images are processed by smoothing along space‐time trajectories of object points while taking into account the PVE. Our experiments demonstrate that the proposed algorithm can yield significantly more‐accurate results than several existing methods.
Detection of Immune Complexes Is Not Independent of Detection of Antibodies in Lyme Disease Patients and Does Not Confirm Active Infection with
Borrelia burgdorferi
Authors: Marques Adriana R. , Hornung Ronald L. , Dally Len , Philipp Mario T.
Published: September 2005

The
Borrelia burgdorferi
-specific immune complex (IC) test, which uses polyethylene glycol (PEG) precipitation to isolate ICs from serum, has been used as a research test in the laboratory diagnosis of early Lyme disease (LD) and has been proposed as a marker of active infection. We examined whether
B. burgdorferi
-specific antibodies were present within PEG-precipitated ICs (PEG-ICs) in patients with LD, posttreatment Lyme disease syndrome, and controls, including individuals who received the outer surface protein A (OspA) vaccine. Using a
B. burgdorferi
whole-cell enzyme-linked immunosorbent assay (ELISA), we obtained positive PEG-IC results not only in patients with a history of LD, but also in individuals vaccinated with OspA vaccine. The frequency of positive PEG-IC ELISAs in OspA vaccinees was significantly higher with ELISA-reactive than with ELISA-negative unprocessed serum samples (
P
= 0.001), demonstrating dependency between the tests. Similar results were found using samples from rhesus macaques infected with
B. burgdorferi
, uninfected macaques vaccinated with OspA, and controls. Therefore, testing for the presence of antibodies against
B. burgdorferi
in PEG-IC preparations is not more likely to reflect active infection than testing in unprocessed serum and should not be used in individuals who received the OspA vaccine.
Monoclonal Immunoglobulin G1 Directed againstAspergillus fumigatusCell Wall Glycoprotein Protects against Experimental Murine Aspergillosis
Authors: Chaturvedi Ashok K. , Kavishwar A. , Shiva Keshava G. B. , Shukla P. K.
Published: September 2005

Most of the biological functions related to pathogenicity and virulence reside in the fungal cell wall, which, being the outermost part of the cell, mediates the host-fungus interplay. For these reasons much effort has focused on the discovery of useful inhibitors of cell wall glucan, chitin, and mannoprotein biosynthesis. In the absence of a wide-spectrum, safe, and potent antifungal agent, a new strategy for antifungal therapy is directed towards the development of monoclonal antibodies (MAbs). In the present study the MAb A9 (immunoglobulin G1 [IgG1]) was identified from hybridomas raised in BALB/c mice immunized with cell wall antigen ofAspergillus fumigatus. The immunoreactive epitopes for this IgG1 MAb appeared to be associated with a peptide moiety, and indirect immunofluorescence microscopy revealed its binding to the cell wall surface of hyphae as well as with swollen conidia. MAb A9 inhibited hyphal development as observed by MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (25.76%), reduced the duration of spore germination, and exerted an in vitro cidal effect againstAspergillus fumigatus. The in vivo protective efficacy of MAb A9 was also evaluated in a murine model of invasive aspergillosis, where a reduction in CFU (>4 log10units) was observed in kidney tissue of BALB/c mice challenged withA. fumigatus(2 × 105CFU/ml) and where enhanced mean survival times (19.5 days) compared to the control (7.1 days) and an irrelevant MAb (6.1 days) were also observed.
A Decline in C
6
Antibody Titer Occurs in Successfully Treated Patients with Culture-Confirmed Early Localized or Early Disseminated Lyme Borreliosis
Authors: Philipp Mario T. , Wormser Gary P. , Marques Adriana R. , Bittker Susan , Martin Dale S. , Nowakowski John , Dally Leonard G.
Published: September 2005

C
6
, a
Borrelia burgdorferi-
derived peptide, is used as the antigen in the C
6
-Lyme disease diagnostic test. We assessed retrospectively whether a fourfold decrease or a decrease to a negative value in anti-C
6
antibody titer is positively correlated with a positive response to treatment in a sample of culture-confirmed patients with either early localized (single erythema migrans [EM];
n
= 93) or early disseminated (multiple EM;
n
= 27) disease. All of these patients had been treated with antibiotics and were free of disease within 6 to 12 months of follow-up. Results show that a serum specimen taken at this time was either C
6
negative or had a ≥4-fold decrease in C
6
antibody titer with respect to a specimen taken at baseline (or during the early convalescent period if the baseline specimen was C
6
negative) for all of the multiple-EM patients (
P
< 0.0001) and in 89% of the single-EM patients (
P
< 0.0001). These results indicate that a decline in anti-C
6
antibody titer coincides with effective antimicrobial therapy in patients with early localized or early disseminated Lyme borreliosis.
Role of Intestinal Epithelial Cells in Immune Effects Mediated by Gram-Positive Probiotic Bacteria: Involvement of Toll-Like Receptors
Authors: Vinderola Gabriel , Matar Chantal , Perdigon Gabriela
Published: September 2005

The mechanisms by which probiotic bacteria exert their effects on the immune system are not completely understood, but the epithelium may be a crucial player in the orchestration of the effects induced. In a previous work, we observed that some orally administered strains of lactic acid bacteria (LAB) increased the number of immunoglobulin A (IgA)-producing cells in the small intestine without a concomitant increase in the CD4
+
T-cell population, indicating that some LAB strains induce clonal expansion only of B cells triggered to produce IgA. The present work aimed to study the cytokines induced by the interaction of probiotic LAB with murine intestinal epithelial cells (IEC) in healthy animals. We focused our investigation mainly on the secretion of interleukin 6 (IL-6) necessary for the clonal expansion of B cells previously observed with probiotic bacteria. The role of Toll-like receptors (TLRs) in such interaction was also addressed. The cytokines released by primary cultures of IEC in animals fed with
Lactobacillus casei
CRL 431 or
Lactobacillus helveticus
R389 were determined. Cytokines were also determined in the supernatants of primary cultures of IEC of unfed animals challenged with different concentrations of viable or nonviable lactobacilli and
Escherichia coli
, previously blocked or not with anti-TLR2 and anti-TLR4. We concluded that the small intestine is the place where a major distinction would occur between probiotic LAB and pathogens. This distinction comprises the type of cytokines released and the magnitude of the response, cutting across the line that separates IL-6 necessary for B-cell differentiation, which was the case with probiotic lactobacilli, from inflammatory levels of IL-6 for pathogens.
Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats
Authors: Tavares Eva , Maldonado Rosario , Ojeda Maria L. , Miñano Francisco J.
Published: September 2005

Gram-negative and gram-positive infections have been considered the most important causes of morbidity and mortality in patients with leukopenia following chemotherapy. However, discrimination between bacterial infections and harmless fever episodes is difficult. Because classical inflammatory signs of infection are often absent and fever is frequently the only sign of infection, the aim of this study was to assess the significance of serum interleukin-6 (IL-6), IL-10, macrophage inflammatory protein-2 (MIP-2), procalcitonin (PCT), and C-reactive protein (CRP) patterns in identifying bacterial infections during start of fever in normal and cyclophosphamide-treated (leukopenic) rats following an injection of lipopolysaccharide (LPS) or muramyl dipeptide (MDP) as a model for gram-negative and gram-positive bacterial infections. We found that, compared to normal rats, immunosuppressed animals exhibited significantly higher fevers and lesser production of all mediators, except IL-6, after toxin challenge. Moreover, compared to rats that received MDP, both groups of animals that received an equivalent dose of LPS showed significantly higher fevers and greater increase in serum cytokine levels. Furthermore, in contrast to those in immunocompetent rats, serum levels of IL-6 and MIP-2 were not significantly changed in leukopenic animals after MDP injection. Other serum markers such as PCT and CRP failed to discriminate between bacterial stimuli in both groups of animals. These results suggest that the use of the analyzed serum markers at an early stage of fever could give useful information for the clinician for excluding gram-negative from gram-positive infections.
Application of a Stool Antigen Test To Evaluate the Incidence ofHelicobacter pyloriInfection in Children and Adolescents from Tehran, Iran
Authors: Falsafi Tahereh , Valizadeh Nargess , Sepehr Shayesteh , Najafi Mehri
Published: September 2005

Helicobacter pyloriinfection is acquired mainly in childhood, especially in developing countries, where a low-cost, rapid diagnostic technique which is reliable for all age groups may be useful for the management ofH. pyloriinfection. For this purpose, we used an HpSA test (Equipar) to detectH. pyloriinfection in children and adolescents from Tehran, Iran. Thirty-five children who were positive or negative forH. pyloriinfection by endoscopy-based tests were used as positive and negative controls for the HpSA test. Stools were collected from 430 randomly selected children and adolescents (4 to 18 years old) from southwest, near the center, and northwest of Tehran. A questionnaire that included presence of recurrent abdominal pain (RAP), family history of infection and/or peptic ulcer disease (PUD), and income of parents was completed. A good agreement was found between the results of endoscopy-based tests and those of the HpSA test; the sensitivity and specificity of the Equipar-HpSA test were 100% and 83.4%, respectively. Among 430 children and adolescents, 47% were positive by the HpSA test, of whom 82% had RAP. No difference in incidence was observed between the two sexes; the various categories of age showed an increasing incidence, ranging from 24% (ages 4 to 6) to 58% (ages 16 to 18). The rate of infection in children and adolescents from the southwest was significantly higher (70%) than the rate in those from the northwest (32%), and a family history ofH. pyloriinfection or PUD was observed in 59% of the HpSA positive subjects. The HpSA test is a useful test to detectH. pyloriinfection in children and adolescents from developing countries.
Detection of Aerosolized
Alternaria alternata
Conidia, Hyphae, and Fragments by Using a Novel Double-Immunostaining Technique
Authors: Green Brett James , Schmechel Detlef , Tovey Euan Roger
Published: September 2005

A double-immunostaining halogen immunoassay was developed to identify aerosolized conidia, hyphae, and fragments of
Alternaria alternata
by using an anti-
Alternaria
polyclonal antiserum, while, simultaneously, allergy to these components was concurrently determined by using human immunoglobulin E antibodies.
Laboratory-Directed Protein Evolution
Authors: Yuan Ling , Kurek Itzhak , English James , Keenan Robert
Published: September 2005

Systematic approaches to directed evolution of proteins have been documented since the 1970s. The ability to recruit new protein functions arises from the considerable substrate ambiguity of many proteins. The substrate ambiguity of a protein can be interpreted as the evolutionary potential that allows a protein to acquire new specificities through mutation or to regain function via mutations that differ from the original protein sequence. All organisms have evolutionarily exploited this substrate ambiguity. When exploited in a laboratory under controlled mutagenesis and selection, it enables a protein to “evolve” in desired directions. One of the most effective strategies in directed protein evolution is to gradually accumulate mutations, either sequentially or by recombination, while applying selective pressure. This is typically achieved by the generation of libraries of mutants followed by efficient screening of these libraries for targeted functions and subsequent repetition of the process using improved mutants from the previous screening. Here we review some of the successful strategies in creating protein diversity and the more recent progress in directed protein evolution in a wide range of scientific disciplines and its impacts in chemical, pharmaceutical, and agricultural sciences.
Fate of Heterotrophic Microbes in Pelagic Habitats: Focus on Populations
Authors: Pernthaler Jakob , Amann Rudolf
Published: September 2005

Major biogeochemical processes in the water columns of lakes and oceans are related to the activities of heterotrophic microbes, e.g., the mineralization of organic carbon from photosynthesis and allochthonous influx or its transport to the higher trophic levels. During the last 15 years, cultivation-independent molecular techniques have substantially contributed to our understanding of the diversity of the microbial communities in different aquatic systems. In parallel, the complexity of aquatic habitats at a microscale has inspired research on the ecophysiological properties of uncultured microorganisms that thrive in a continuum of dissolved to particulate organic matter. One possibility to link these two aspects is to adopt a “Gleasonian” perspective, i.e., to study aquatic microbial assemblages in situ at the population level rather than looking at microbial community structure, diversity, or function as a whole. This review compiles current knowledge about the role and fate of different populations of heterotrophic picoplankton in marine and inland waters. Specifically, we focus on a growing suite of techniques that link the analysis of bacterial identity with growth, morphology, and various physiological activities at the level of single cells. An overview is given of the potential and limitations of methodological approaches, and factors that might control the population sizes of different microbes in pelagic habitats are discussed.
Replication Termination inEscherichia coli: Structure and Antihelicase Activity of the Tus-TerComplex
Authors: Neylon Cameron , Kralicek Andrew V. , Hill Thomas M. , Dixon Nicholas E.
Published: September 2005

The arrest of DNA replication inEscherichia coliis triggered by the encounter of a replisome with a Tus protein-TerDNA complex. A replication fork can pass through a Tus-Tercomplex when traveling in one direction but not the other, and the chromosomalTersites are oriented so replication forks can enter, but not exit, the terminus region. The Tus-Tercomplex acts by blocking the action of the replicative DnaB helicase, but details of the mechanism are uncertain. One proposed mechanism involves a specific interaction between Tus-Terand the helicase that prevents further DNA unwinding, while another is that the Tus-Tercomplex itself is sufficient to block the helicase in a polar manner, without the need for specific protein-protein interactions. This review integrates three decades of experimental information on the action of the Tus-Tercomplex with information available from the Tus-TerAcrystal structure. We conclude that while it is possible to explain polar fork arrest by a mechanism involving only the Tus-Terinteraction, there are also strong indications of a role for specific Tus-DnaB interactions. The evidence suggests, therefore, that the termination system is more subtle and complex than may have been assumed. We describe some further experiments and insights that may assist in unraveling the details of this fascinating process.
First examples of intramolecular addition of primary amidyl radicals to olefins
Authors: Gaudreault Philippe , Drouin Christian , Lessard Jean
Published: September 2005

The first examples of intramolecular addition of primary amidyl radicals to olefins are described. Amidyl radicals were generated from N-(phenylthio)amides in refluxing benzene using a catalytic amount of 2,2′-azobis(isobutyronitrile) (5 mol%) and tributyltin hydride (~2.2 equiv.). The resulting yields of cyclic products ranged from 63% to 85%.Key words: radical cyclization, amidyl radicals, nitrogen heterocycles.