Comparative studies of the sensitivities of sparse and full geometries of Total-Body PET scanners built from crystals and plastic scintillators.

BACKGROUND: Alongside the benefits of Total-Body imaging modalities, such as higher sensitivity, single-bed position, low dose imaging, etc., their final construction cost prevents worldwide utilization. The main aim of this study is to present a simulation-based comparison of the sensitivities of existing and currently developed tomographs to introduce a cost-efficient solution for constructing a Total-Body PET scanner based on plastic scintillators. METHODS: For the case of this study, eight tomographs based on the uEXPLORER configuration with different scintillator materials (BGO, LYSO), axial field-of-view (97.4 cm and 194.8 cm), and detector configurations (full and sparse) were simulated. In addition, 8 J-PET scanners with different configurations, such as various axial field-of-view (200 cm and 250 cm), different cross sections of plastic scintillator, and multiple numbers of plastic scintillator layers (2, 3, and 4), based on J-PET technology have been simulated by GATE software. Furthermore, Siemens' Biograph Vision has been simulated to compare the results with standard PET scans. Two types of simulations have been performed. The first one with a centrally located source with a diameter of 1 mm and a length of 250 cm, and the second one with the same source inside a water-filled cylindrical phantom with a diameter of 20 cm and a length of 183 cm. RESULTS: With regards to sensitivity, among all the proposed scanners, the ones constructed with BGO crystals give the best performance ([Formula: see text] 350 cps/kBq at the center). The utilization of sparse geometry or LYSO crystals significantly lowers the achievable sensitivity of such systems. The J-PET design gives a similar sensitivity to the sparse LYSO crystal-based detectors while having full detector coverage over the body. Moreover, it provides uniform sensitivity over the body with additional gain on its sides and provides the possibility for high-quality brain imaging. CONCLUSION: Taking into account not only the sensitivity but also the price of Total-Body PET tomographs, which till now was one of the main obstacles in their widespread clinical availability, the J-PET tomography system based on plastic scintillators could be a cost-efficient alternative for Total-Body PET scanners.

Efficiency determination of J-PET: first plastic scintillators-based PET scanner.

BACKGROUND: The Jagiellonian Positron Emission Tomograph is the 3-layer prototype of the first scanner based on plastic scintillators, consisting of 192 half-metre-long strips with readouts at both ends. Compared to crystal-based detectors, plastic scintillators are several times cheaper and could be considered as a more economical alternative to crystal scintillators in future PETs. JPET is also a first multi-photon PET prototype. For the development of multi-photon detection, with photon characterized by the continuous energy spectrum, it is important to estimate the efficiency of J-PET as a function of energy deposition. The aim of this work is to determine the registration efficiency of the J-PET tomograph as a function of energy deposition by incident photons and the intrinsic efficiency of the J-PET scanner in detecting photons of different incident energies. In this study, 3-hit events are investigated, where 2-hits are caused by 511 keV photons emitted in [Formula: see text] annihilations, while the third hit is caused by one of the scattered photons. The scattered photon is used to accurately measure the scattering angle and thus the energy deposition. Two hits by a primary and a scattered photon are sufficient to calculate the scattering angle of a photon, while the third hit ensures the precise labeling of the 511 keV photons. RESULTS: By comparing experimental and simulated energy distribution spectra, the registration efficiency of the J-PET scanner was determined in the energy deposition range of 70-270 keV, where it varies between 20 and 100[Formula: see text]. In addition, the intrinsic efficiency of the J-PET was also determined as a function of the energy of the incident photons. CONCLUSION: A method for determining registration efficiency as a function of energy deposition and intrinsic efficiency as a function of incident photon energy of the J-PET scanner was demonstrated. This study is crucial for evaluating the performance of the scanner based on plastic scintillators and its applications as a standard and multi-photon PET systems. The method may be also used in the calibration of Compton-cameras developed for the ion-beam therapy monitoring and simultaneous multi-radionuclide imaging in nuclear medicine.

Voice pathology classification based on High-Speed Videoendoscopy.

This work presents a method for automatical and objective classification of patients with healthy and pathological vocal fold vibration impairments using High-Speed Videoendoscopy of the larynx. We used an image segmentation and extraction of a novel set of numerical parameters describing the spatio-temporal dynamics of vocal folds to classification according to the normal and pathological cases and achieved 73,3% cross-validation classification accuracy. This approach is promising to develop an automatic diagnosis tool of voice disorders.

Drug development from natural products: exploiting synergistic effects.

Drug development in phytomedicine has been focused in the past on the discovery and analysis of new structures from natural products. The search aimed at the determination of the single "active principle" in plants, based on the assumption that a plant has one or a few ingredients which determine its therapeutic effects. But traditional systems of medicines like Ayurveda, traditional Chinese medicine or the European phytotherapy generally assume that a synergy of all ingredients of the plants will bring about the maximum of therapeutic efficacy. This approach has for long been impossible to investigate since adequate methods to standardize complex plant mixtures as well as to rationalize complex mode of actions were lacking. The introduction of high throughput technologies provides the opportunity to determine profiles of plants and to systematically explore the mode of action of combinatory drug regimes. The present review highlights the concept of synergy and gives examples of synergistic effects of plant constituents. It elaborates on how the high throughput technologies can be used in drug development from natural products with the aim of creating evidence-based plant medications in prevention and treatment of different diseases in the form of new single treatments or new combinatory drug regimes while exploiting synergy-effects.

New perspectives for synergy research with the "omic"-technologies.

Synergistic effects, understood as true overadditive effects, are often observed in experimental and clinical studies using phytopharmaceuticals. The introduction of the "omic"-technologies is now opening new perspectives in rationalizing these effects and making use of them in the development of a new generation of phytopharmaceuticals. This review describes possible mechanism of synergistic actions of herbal drugs by mono- and multitargeting and by the activation of signal cascades. It examines the possibilities of the standardization of single and multi component plant extracts and the prediction and assessment of the toxicity and safety of plant extracts with the support of the "omic"-technologies. It further discusses the use of phytopharmaceuticals in the context of an "individualized medicine". It makes proposals how to use the "omic"-technologies to rationalize and develop combination therapies of phytopharmaceuticals and synthetic drugs to minimize adverse reactions (ARs) or improve the therapeutic efficacy. Examples of clinical studies are given which explore already the potential of such co-medications. Modern medical therapy has acknowledged for quite some time the usefulness of combination therapies in the treatment of multifactorial diseases like cancer, cardiovascular or rheumatic diseases. The term "synergy" is rarely used in this context, the combinatory mechanisms of actions seldom completely understood and the potentially occurring adverse reactions feared. A systematic exploitation of synergy effects of phytomedical interventions alone or in combination with synthetic drugs should lead in a long term perspective to the discovery and development of more rational evidence-based interventions in the prevention and therapy of multifactorial diseases and should thereby enrich modern pharmacotherapy.

Application of the "-Omic-" technologies in phytomedicine.

The proof of efficacy of phytopreparations and the determination of their mode of action are permanent challenges for an evidence-based phytotherapy. The technology platform of genomics, proteomics and metabolomics ("-omic-" technologies) are high-throughput technologies. They increase substantially the number of proteins/genes that can be detected simultaneously and have the potential to relate complex mixtures to complex effects in the form of gene/protein expression profiles. Provided that phytopreparation-specific signatures in the form of gene/protein expression profiles can be developed, these technologies will be useful for the chemical and pharmacological standardization and the proof of the toxicological potential of a plant extract. Over a long-term perspective they may economize the proof of efficacy, the determination of the mode of action of phytomedicines and allow to investigate herbal extracts without prominent active principle(s). The application of this genomics revealed already that gene expression profiles induced by single drugs and the ones induced by the combination of the same drugs can be entirely different. These results make the information of the mode of action of isolated "active principles/lead substances" of phytopreparations questionable. The application of the "-omic-" technologies may lead to a change of paradigms towards the application of complex mixtures in medicine and open the new field of phytogenomics, -proteomics and -metabolomics.

The moderating impact of social support following childhood sexual abuse.

The role of social support in moderating the impact of childhood sexual abuse on adult psychological adjustment was examined. Subjects included 475 women, age 18-45, some of whom were currently receiving treatment, others who were not. Women in the treatment group were receiving therapy for either alcoholism, for being battered, or for mental health problems. The comparison group was drawn from two sources: a random household sample and a sample of women attending drinking driver classes. Among both groups, women who had been sexually abused exhibited more psychological symptoms and lower self-esteem compared to those who were not abused. Latency of disclosure of childhood sexual abuse had no impact on long-term consequences of the abuse for either the treatment or the comparison group. However, among women in the comparison group, those who experienced supportive reactions following disclosure of sexual abuse had fewer psychological symptoms and somewhat higher self-esteem relative to those who did not receive support. Social support had no apparent effect on the long-term adjustment of women in the treatment group. Possible explanations for this pattern and directions for future research are discussed.

Regulation of trehalose metabolism in Saccharomyces cerevisiae mutants during temperature shifts.

Temperature shifts from 23 degrees C to 36 degrees C resulted in trehalose accumulation in Saccharomyces independently of genetic lesions in the cAMP-protein kinase cascade. In parallel, trehalose 6-phosphate synthase activity increased about 3-fold in all strains; the increase could be inhibited by cycloheximide, suggesting that protein synthesis was required. Heat shock treatment after the temperature shift led to a drastic increase in trehalose activity, and deactivation of the biosynthetic enzyme with a consequent drop in trehalose. Up to now no definite correlation between acquisition of thermotolerance and trehalose accumulation has been made.

Application of amperometric detection to the analysis of the diffusion and O-methylation of a catecholamine and a catechol steroid across the blood vessel wall.

A novel amperometric detection procedure was developed to determine the ability of the catechol, 2-hydroxyestradiol (2OHE2), to diffuse through and be O-methylated during its passage from the lumen to the adventitial surface of the rabbit ear artery. The diffusion and O-methylation of d-norepinephrine (d-NE) also was determined. When arteries were perfused with either 2OHE2 or d-NE (10 microM), the bulk of the material effluxing from the adventitial surface was O-methylated. The vessel wall offered a considerable barrier to the diffusion of both NE and 2OHE2, because the concentrations of NE and 2OHE2 found in the solution perfusing the adventitial surface were as much as 1,000-fold lower than their concentration in the intralumenal perfusion stream. It is concluded that the blood vessel wall offers a significant physical and metabolic barrier to the penetration of unchanged 2OHE2 and NE.

Studies with the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogs.

The nigrostriatal dopaminergic neurotoxicity of MPTP was prevented in mice in a dose-dependent manner by the monoamine oxidase-B (MAO-B) inhibitor deprenyl. This finding, combined with other observations, points out the important role of MAO-B in the bioactivation of MPTP. In the present study, some comparisons between MPTP and several of its structural analogs will be presented.

The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines.

In the present study the influence of oestradiol, catechol oestrogens, and O-methylated oestrogens was determined on the contractile responses of the isolated rabbit aorta to (-)-adrenaline. Oestradiol (40 mumol/l), 2-hydroxyoestradiol (2OHE2) (20 mumol/l), and 2-methoxyoestradiol (2MeOE2) (20 mumol/l) all sensitized the rabbit aorta to contractile responses to (-)-adrenaline. Similarly, the 2-hydroxy and 2-methoxy derivatives of oestrone and oestriol also sensitized the aorta to (-)-adrenaline-induced contractions. The largest degree of sensitization was seen in the presence of the 2-methoxysteroids. Oestradiol and 2OHE2 did not increase responses of the aorta to (-)-noradrenaline, while slight potentiation of contraction was seen in the presence of 2MeOE3. The potentiating effect of 2OHE2 on contractile responses to (-)-adrenaline was abolished by prior treatment of the tissue with a COMT inhibitor (U-0521, 55 mumol/l). Conversely, pretreatment of the tissue with 2OHE2 prevented the augmented aortic contraction to (-)-adrenaline usually seen after inhibition of COMT. The non-additive nature of the sensitization seen after combined treatment with 2OHE2 and U-0521 was qualitatively similar to that seen following combined exposure to maximally effective concentrations of U-0521 and an inhibitor of extraneuronal uptake (hydrocortisone 100 mumol/l). Oestradiol and 2MeOE2 reduced the formation of both the 3H-O-methylated, 3H-deaminated and the 3H-O-methylated deaminated metabolites of 3H-(-)-adrenaline (0.15 mumol/l) during exposure of the aorta to the tritiated catecholamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of tyrosine hydroxylase in rabbit mesenteric artery and vas deferens by catechol oestrogens.

In the present study we have investigated the effects of oestrogens, catechol oestrogens, and catecholamines on tyrosine hydroxylase (TH) activity derived from rabbit mesenteric artery and vas deferens. Both catechol oestrogens, 2-hydroxyoestradiol (2OHE2) and 2-hydroxyoesterone (2OHE1), inhibited TH activity in mesenteric artery and vas deferens in a concentration-dependent manner with potencies that were higher than those for noradrenaline but lower than that for dopamine. When added to the reaction medium along with increasing concentrations of a pterin cofactor (200 to 1,500 mumol/l DMPH4), the catechol oestrogens (200 mumol/l) increased the apparent Km for DMPH4 without altering the maximum velocity (Vmax) of the reaction. Similar results were obtained with the addition of noradrenaline (200 mumol/l) and dopamine (120 mu/mol). Apparent Ki values obtained for the catecholamines and catechol oestrogens were within the same order of magnitude and varied from 30 mumol/l for dopamine and 2OHE2 to 183 mumol/l for 2OHE1. Oestradiol (E2) and 2-methoxyoestradiol (2MeOE2), i.e., oestrogens that do not possess a catechol moiety, exhibited only weak inhibitory effects on TH activity. At the highest concentration tested (1 mmol/l), they did not reduce enzyme activity below 58% of control values. Kinetic analysis revealed that these two oestrogens did not consistently affect either the Vmax of hydroxylation or the Km for DMPH4. It is concluded that catechol oestrogens inhibit TH activity with a potency comparable to noradrenaline and dopamine. This inhibition is by competition with the pterin cofactor. Oestrogens that to not possess a catechol moiety are not effective inhibitors of TH.(ABSTRACT TRUNCATED AT 250 WORDS)

Early recurrences of otitis media: reinfection or relapse?

In a prospective study, 36 (35%) of 103 patients had early recurrence of acute otitis media. We wished to identify risk factors for early recurrences (those recurring within 1 month of initial diagnosis) and to determine if the second episode was caused by the same pathogen (relapse) or a new organism (reinfection). When the same bacterial species was recovered in both episodes, Streptococcus pneumoniae were serotyped and Haemophilus influenzae were classified by biotypes and by electrophoretic pattern of the outer membrane proteins. Twenty-nine patients underwent tympanocentesis at the time of the recurrent episode. In 13, no pathogen was recovered either initially or at the time of recurrence. Twelve (75%) of the remaining 16 patients had reinfection; only four (25%) had relapse. Thus, early recurrences of acute otitis media were more often caused by a new organism. This finding suggests that underlying susceptibility to middle ear infection is important in the development of recurrent otitis media. Pediatricians should not assume that early recurrences are necessarily the result of failure of initial treatment. Tympanocentesis may be helpful in this setting to aid in choosing appropriate antibiotic therapy.

A randomized controlled trial of amoxicillin plus clavulanate compared with cefaclor for treatment of acute otitis media.

We performed a randomized controlled trial of amoxicillin plus clavulanate versus cefaclor for treatment of acute otitis media. Total daily doses given in three divided doses were 40 mg/kg amoxicillin plus 10 mg/kg clavulanate, and 40 mg/kg cefaclor. Pathogens were eradicated from the middle ear exudate after 3 to 6 days of therapy in 35 (97%) of 36 patients given amoxicillin-clavulanate compared with 24 (75%) of 32 given cefaclor (P = 0.028). When analysis was restricted to patients with positive urine or serum drug assays during therapy, pathogens were eliminated in 33 (97%) of 34 patients given amoxicillin-clavulanate compared with 21 (75%) of 28 given cefaclor (P = 0.026). Bacterial isolates associated with bacteriologic failure of cefaclor therapy were Streptococcus pneumoniae (two patients), beta-lactamase-negative Haemophilus influenzae (four), and beta-lactamase-positive Branhamella catarrhalis (two). The single failure with amoxicillin-clavulanate therapy was associated with non-beta-lactamase-producing H. influenzae isolated from the middle ear exudate. We conclude that cefaclor is less efficacious than amoxicillin-clavulanate for the treatment of acute otitis media.

Objective diagnosis of otitis media in early infancy by tympanometry and ipsilateral acoustic reflex thresholds.

Otitis media in early infancy carries a high risk of recurrent otitis media and prolonged middle ear effusion. To fulfill the need for objective diagnostic methods in this age group, we investigated susceptance tympanograms and ipsilateral acoustic reflex thresholds in infants younger than 5 months of age. Tympanometry and acoustic reflex thresholds were performed with an otoadmittance meter using a 660 Hz probe tone. Tympanograms were interpreted using quantitative measures. These findings were compared with independent otoscopic diagnoses in 67 ears with middle ear effusion and 69 ears that were effusion free. Diagnoses were confirmed by tympanocentesis when clinically indicated. There was excellent agreement among otoscopy, peak tympanogram susceptance, and ipsilateral acoustic reflex thresholds (kappa 0.82 to 0.86, agreement 91% to 93%). We conclude that susceptance tympanograms and ipsilateral acoustic reflex thresholds are accurate diagnostic tests for otitis media in infants younger than 5 months of age.

Effect of continuous intraventricular estrogen or catechol estrogen treatment on catecholamine turnover in various brain regions.

The effect of 7-day i.v.t. administration of catechol estrogens (CE) or estrogens (5 micrograms/day) on the catecholamine turnover rate of various brain areas was examined in ovariectomized rats. Norepinephrine turnover was increased significantly in the hypothalamus and cerebral cortex by estradiol treatment but not by any CEs tested when compared to control values. However, the turnover rate of dopamine in the cerebral cortex was increased compared to control values only by the 2-hydroxyestrogens (2-hydroxyestradiol and 2-hydroxyestrone) and estradiol was without effect. Only estrogens and CEs with physiologically significant estrogen receptor binding affinities (17 beta-estradiol, moxestrol, 2-hydroxyestradiol and 4-hydroxyestradiol) decreased the turnover rate of dopamine in the corpus striatum compared to control values. Estrogens (17 alpha-estradiol and 2-hydroxyestrone) which are weak ligands for the estrogen receptor did not affect striatal dopamine turnover. In addition, body weight gain measured during estrogen treatment was reduced by CEs and estrogens which have significant estrogen receptor affinities. These results suggest that the CEs may play a role in central modulation of catecholaminergic function by estrogens either through direct actions of the catechol moiety or activation of estrogen receptors.

Identification of children requiring radiologic evaluation for urinary infection.

Sixty-nine children younger than 13 years of age with urinary tract infection were evaluated to identify risk factors for treatable urologic problems; i.e. those requiring surgery or prolonged antibiotic prophylaxis. All children had a renal ultrasound, intravenous pyelogram and voiding cystogram performed 4 to 6 weeks after the infection. Eleven children with treatable problems were identified, 10 with vesicoureteral reflux and 1 with a ureterocele. For identification of treatable problems the predictive value of a positive test was: (1) fever, 10 of 24 (41.7%); (2) abnormal D-deaminoarginine vasopressin renal concentrating ability, 8 of 24 (33.3%); (3) serum C-reactive protein greater than or equal to 1.0, 8 of 25 (32.0%); (4) Elevated urine N-acetylglucosaminidase, 5 of 16 (31.2%); (5) erythrocyte sedimentation rate greater than or equal to 25, 6 of 21 (28.6%); and (6) age less than 5 years, 10 of 43 (23.3%). Absence of fever denotes a low risk (less than 3%) of finding a treatable problem. Afebrile girls older than 5 years of age can have radiologic evaluation deferred until infection recurs. The presence of fever indicates a high risk of treatable urologic problems (41.7%) and warrants complete radiologic evaluation with the first urinary infection.

Effect of intraventricular administration of catechol estrogens on catecholamine content in various brain regions.

Male rats treated for 7 days with either 2-hydroxyestradiol, 4-hydroxyestradiol or 2-hydroxyestrone had significantly lower striatal dihydroxy phenylacetic acid (DOPAC) levels when compared to the control group. After 14 days of treatment, groups which were treated with estradiol, 2-hydroxyestradiol or 4-hydroxyestradiol had significantly higher striatal dopamine levels and had gained significantly less weight when compared to the control group. These results indicate that estradiol and the catechol estrogens may act to reduce the activity of striatal dopaminergic neurons.