PMID- 17624534 TI - [Botulinum toxin injections for the treatment of strabismus. Which indications are still useful today?]. AB - Botulinum toxin treatment was originally developed 25 years ago by Alan B. Scott to produce reversible weakening of extraocular eye muscles in humans (chemodenervation). The following uses are still helpful today in comparison with eye muscle surgery, prism applications etc.: Preoperative evaluation of possible postoperative diplopia in patients in whom this cannot be done by means of prisms or traction test, etc. Acute paretic loss of ocular muscle function when surgical treatment of the ocular muscles is not yet possible but the patient is obviously disturbed by diplopia or a forced head posture. This applies especially to VI cranial nerve paresis. Depending on the surgical approach in VI nerve palsies, Botulinum toxin may be injected in the medial rectus muscle before muscle transposition surgery to loosen contracture. Strabismus in acute Graves' disease. In strabismus in other conditions, Botulinum toxin is mostly inferior surgical treatment of the ocular muscles; this is the case, for example in congenital esotropia or horizontal strabismus in adults. While the reversibility of the Botulinum toxin A effect by fading out after 3-4 months is seen as an advantage, it does also mean that in these cases of constant strabismus it is necessary to keep repeating the injections. PMID- 17624535 TI - [Cryotherapy in discoid lupus erythematosus (DLE)]. AB - Discoid lupus erythematosus (DLE) is a chronic, scarring, photosensitive autoimmune dermatosis that usually occurs in sun-exposed areas. While the face, chest, and extremities are often affected, involvement of the eyelid is rare. In cases of DLE lesions that are resistant to local or systemic recommended therapies, contact cryotherapy should be considered as an alternative treatment option. PMID- 17624536 TI - Extremity fracture characteristics in children with impulsive/hyperactive behavior. AB - INTRODUCTION: To investigate which fracture characteristics were associated with impulsive/hyperactive behavior in children with extremity fractures. MATERIALS AND METHODS: A clinical sample of 95 consecutive children with extremity fractures admitted to the Orthopaedics and Traumatology Outpatient Clinic of a university hospital were included in the study. The Conners Parent Rating Scale (CPRS) was used to assess children's symptoms. Fracture characteristics were grouped according to trauma type, fracture localization, hospitalization requirement, treatment type and history of previous fracture(s). Descriptive analyses were performed; t-tests and univariate ANOVAs were utilized to compare groups with respect to impulsivity/hyperactivity subscale scores on the CPRS. RESULTS: Mean CPRS impulsivity/hyperactivity subscale score for the whole group was 6.94 (SD = 2.69). Children with fractures which occurred during solitary activities presented with more impulsive/hyperactive behavior than those with fractures which occurred during group activities. Children with more severe fractures that required open reduction also presented with more impulsive/hyperactive behavior. Children with lower extremity fractures had showed more impulsive/hyperactive behavior than children with upper extremity fractures. CONCLUSION: Detecting behavior problems in children admitted with fractures and referring them for treatment, is critical in preventing future serious injuries. PMID- 17624537 TI - Effect of high-energy extracorporeal shock waves on the immature epiphysis in a rabbit model. AB - INTRODUCTION: We investigated the effect of high-energy extracorporeal shock wave (ESW) on immature tibial epiphysis in a rabbit model. MATERIALS AND METHODS: Twenty New Zealand white immature rabbit were used in this study. Animals were divided into two groups and they received 14 kW, 0.6 mJ/mm(2), 1,500 or 3,000 shots for three times with an interval of 7 days. After 6 weeks all rabbits were killed. The all tibia epiphysis were assessed by histology. The epiphyseal plaque thickness of right tibiae of the 3,000-shot ESW group was significantly higher than those of the 1,500-shot ESW group and the left tibia epiphyses of the 1,500- and 3,000-shot ESW groups as controls (P < 0.05). RESULTS: The epiphyseal plaque thickness of right tibiae of the 1,500-shot ESW group was significantly higher than that of the left tibia epiphyses of the 1,500- and 3,000-shot ESW groups as controls (P < 0.05). DISCUSSION: We demonstrated that high-energy ESW stimulated the growth of immature rabbit epiphysis. The long-term effect of shock wave on the immature rabbit epiphysis deserves further study. PMID- 17624538 TI - Multiple glomus tumors in gastrocnemius muscle: a case report. AB - Glomus tumors are rare benign tumors that account 1-5% of soft tissue tumors of the hand. Most of the lesions occurred in the subungal region of the distal phalanx. We describe an unusual case of recurrent glomus tumor located in lower leg. The final diagnosis was established by pathologic examination of the surgical resection specimen. PMID- 17624539 TI - Is routine bilateral neck dissection absolutely necessary in the management of N0 neck in patients with supraglottic carcinoma? AB - The supraglottic larynx has a rich lymphatic network that places patients with supraglottic laryngeal carcinomas at high risk for early dissemination of the disease into the cervical lymphatics. Therefore, elective neck treatment of clinically N0 neck in patients with supraglottic carcinomas is widely accepted as a standard approach. However, the issue whether elective neck treatment should routinely be directed on both sides of the neck is still controversial. The present study is aimed at determining whether T2-T4 stage supraglottic carcinomas require bilateral neck dissection in the management of N0 necks. We designed a prospective study on 72 patients with N0 supraglottic laryngeal carcinoma. Patients were divided into three groups according to the site and extension of the primary tumors. Group I consisted of 21 patients with lateralized (clear lateral) lesion reaching but not crossing the midline. Group II comprised 25 patients with cancer largely involving one side and crossing to the midline. Group III included 26 patients with carcinoma equally involving both sides of the larynx or growth into the midline larynx. All patients underwent bilateral lateral neck dissection in conjunction with various types of laryngectomies selected to the status of the primary. Of the 72 patients, 16 were found to have occult regional metastases in pathologic examination (9 pN1, 4 pN2b, 3 pN2c). The prevalence of occult metastases proportionally increased with T stage from 8.3 to 22.7 and 31.2%, respectively, for T2, T3 and T4. Bilateral neck metastases were found in 2 of 26 patients (7.7%) with central lesions. There was only one patient (4%) with both ipsilateral and contralateral lymph node metastasis in group II. None of the 21 patients with lateral lesion (group I) had contralateral neck metastasis. Routine bilateral elective neck dissection may not be a part of the surgical procedure in all supraglottic laryngeal carcinoma patients. Bilateral neck dissection should be preferred for cases with central tumors and lateral tumors with positive nodes in the ipsilateral side of the neck. PMID- 17624540 TI - Roles of Saccharomyces cerevisiae RAD17 and CHK1 checkpoint genes in the repair of double-strand breaks in cycling cells. AB - Checkpoints are components of signalling pathways involved in genome stability. We analysed the putative dual functions of Rad17 and Chk1 as checkpoints and in DNA repair using mutant strains of Saccharomyces cerevisiae. Logarithmic populations of the diploid checkpoint-deficient mutants, chk1Delta/chk1Delta and rad17Delta/rad17Delta, and an isogenic wild-type strain were exposed to the radiomimetic agent bleomycin (BLM). DNA double-strand breaks (DSBs) determined by pulsed-field electrophoresis, surviving fractions, and proliferation kinetics were measured immediately after treatments or after incubation in nutrient medium in the presence or absence of cycloheximide (CHX). The DSBs induced by BLM were reduced in the wild-type strain as a function of incubation time after treatment, with chromosomal repair inhibited by CHX. rad17Delta/rad17Delta cells exposed to low BLM concentrations showed no DSB repair, low survival, and CHX had no effect. Conversely, rad17Delta/rad17Delta cells exposed to high BLM concentrations showed DSB repair inhibited by CHX. chk1Delta/chk1Delta cells showed DSB repair, and CHX had no effect; these cells displayed the lowest survival following high BLM concentrations. Present results indicate that Rad17 is essential for inducible DSB repair after low BLM-concentrations (low levels of oxidative damage). The observations in the chk1Delta/chk1Delta mutant strain suggest that constitutive nonhomologous end-joining is involved in the repair of BLM-induced DSBs. The differential expression of DNA repair and survival in checkpoint mutants as compared to wild-type cells suggests the presence of a regulatory switch-network that controls and channels DSB repair to alternative pathways, depending on the magnitude of the DNA damage and genetic background. PMID- 17624541 TI - Fetal and early post-natal development of the human spleen: from primordial arterial B cell lobules to a non-segmented organ. AB - Immunohistological analysis of 31 human spleens from the 11th week of gestation to the early postnatal period suggested that fetal organ development may be preliminarily divided into four stages. At stage 0 the organ anlage contained erythrocyte precursors, few macrophages and almost no lymphocytes. Fetal spleens of stage I exhibited arterial vascular lobules and lymphocytes just began colonizing the organ. At stage II, B and T lymphocytes formed periarteriolar clusters. B cell clusters predominated, because B cells aggregated around the more peripheral branches of splenic arterioles, while T cells occupied the more centrally located parts of the vessels. The vascular lobules of stage I and II consisted of central arterioles surrounded by B cells, capillaries and peripheral venules. The lobular architecture slowly dissolved at late stage II when sinuses grew out from the peripheral venules into the centre of the lobule. Interestingly, the B cell accumulations around peripheral arterioles did not represent the precursors of follicles, but apparently persisted as periarteriolar B cell clusters in the adult splenic red pulp, while follicles containing FDCs developed at late stage II from B cells in direct contact to T cell clusters around larger arterial vessels. At stage III before birth the lobular architecture was no longer recognized. The chemokine CXCL13 was already present in vascular smooth muscle and adjacent stromal cells at stage I before B cells immigrated. CCL21, on the contrary, was only demonstrated in fibroblast-like cells supporting T cell clusters from stage II onwards. PMID- 17624542 TI - Aerobic-anaerobic transition intensity measured via EMG signals in athletes with different physical activity patterns. AB - The purpose of the present study was to investigate the use of electromyographic signals (EMG), to determine the EMG threshold (EMGT) in four lower extremity muscles and to compare these thresholds with the second ventilatory threshold (VT2) in subjects participating in different sports and at different performance levels. Forty-nine subjects (23.8 +/- 5.7 years, 182.7 +/- 5.3 cm, 79.1 +/- 8.6 kg) including eleven cyclists, ten team-handball players, nine kayakers, eight power lifters and eleven controls were investigated utilizing a cycle ergometer. Respiratory gas exchange measures were collected and EMG activity was continuously recorded from four muscles (vastus lateralis, vastus medialis, biceps femoris and gastrocnemius lateralis). The VO(2)max averaged 56.1 +/- 11.1 ml kg(-1) min(-1), the average aerobic power was 348.5 +/- 61.0 W and the corresponding VT2 occurred at 271.4 +/- 64.0 W. The EMGT ranged from 80 to 98% of power output for the different muscles. The VT2 and EMG thresholds from four different muscles were not different. When thresholds were analyzed among different groups of subjects, no significant difference was observed between VT2 and EMGT despite threshold differences between the groups. All four EMGT were significantly related to maximal aerobic power (r = 0.73-0.83) and were highly correlated to each other (r = 0.57-0.88). In conclusion, EMGT can be used to determine the VT2 for individuals independent of sport specificity or performance level. PMID- 17624543 TI - Cellular patterns of the atrophic response in murine soleus and gastrocnemius muscles submitted to simulated weightlessness. AB - The purpose of the present study was to investigate the mechanisms of cell death (apoptosis vs. necrosis) during muscle atrophy induced by 1 week of hindlimb suspension. Biochemical and morphological parameters were examined in murine soleus and gastrocnemius muscles. A total of 70 male Charles River CD1 mice were randomly assigned to seven groups (n = 10/group): Cont (loading control conditions) and 6HS, 12HS, 24HS, 48HS, 72HS and 1wkHS with respect to the period of hindlimb suspension (HS). Compared to the Cont, skeletal muscle atrophy was confirmed by a significant decrease of 44 and of 17% in fiber cross-sectional areas in the gastrocnemius and soleus, respectively. A significant increase in caspase-3 activity was noticed in 6HS (196%, P < 0.05) and in 12HS (201%, P < 0.05), as well as the amount of cytosolic mono- and oligonucleosomes at 12HS (142%, P < 0.05) and 24HS (203%, P < 0.05) in the gastrocnemius and soleus, respectively. The profile of necrotic markers showed a peak of myeloperoxidase activity at 24HS (170%, P < 0.05) and at 72HS (114%, P < 0.05) in the gastrocnemius and soleus, respectively. The analysis of N-acetylglucosaminidase activity evidenced more increment in the soleus at 72HS (60%, P < 0.05). The analysis of the basal values of these parameters suggested that apoptosis prevailed in the slow-twitch muscle analyzed, whereas lysosomic activity seemed to be more pronounced in the gastrocnemius. The morphological data supported the biochemical results pointing towards a shift from apoptosis to necrosis, which seems to corroborate the aponecrosis theory. PMID- 17624544 TI - Influence of hyperthermia on carotid blood flow using 99mTc-HMPAO. AB - Hyperthermia can be the result of many causes such as environmental conditions, brain tumors and infectious diseases. Since hyperthermia is very common, its role in causing stroke through a decrease in cerebral blood flow needed further emphasis. The aim of this study was to record cerebral blood flow in vitro by using isolated rabbit carotid artery strips and in-vivo using radioactive isotope scanning during temperature elevation. The recording of isometric tension in rabbit carotid artery strips in organ baths, and the scintigraphic cerebral imaging of technetium-99m-hexamethyl-propyleneamineoxime (99mTc-HMPAO) using Gamma camera, were acquired at control and higher body temperature by 4 degrees C. Blood pressure was measured through femoral artery and cerebral blood flow was measured through carotid artery. Elevating temperature by 4 degrees C induced reproducible contraction. During hyperthermia, the carotid artery contraction leads to a decrease in cerebral blood flow although the blood pressure did not decrease. The uptake of 99mTc-HMPAO in the brain was significantly reduced. This decrease in cerebral perfusion is regionally dependent, which is more in the frontal area, the cerebral hemispheres than the cerebellum. The decrease was 36+/ 3, 37+/-2, 22+/-2%, respectively. Hyperthermia causes carotid artery contraction leading to decrease in cerebral blood flow, which was confirmed by 99mTc-HMPAO images. The decrease is regionally dependent. Since the blood pressure did not decrease by heating, the reduction in cerebral perfusion is mainly due to carotid contraction. The applied neck cooling may be considered as a promising therapeutic strategy for the hyperthermic patient to avoid brain damage. This can be achieved by external application of an ice-water-perfused neck collar. PMID- 17624545 TI - Effect of acute exercise on glucose tolerance following post-exercise feeding. AB - It is well documented that a single bout of endurance exercise (EE) can improve insulin sensitivity, whereas relatively little is known about the acute effects of resistance exercise (RE) in humans. The objective of this study is to investigate the insulin and glucose responses to an oral glucose tolerance test (OGTT) following a high intensity bout of either EE or RE followed by post exercise carbohydrate-protein hydrolysate ingestion. Eighteen participants were divided into two groups: a group in which nine participants completed 1 h of EE (cycle ergometry at 75% W (max)) and a RE group in which nine participants completed a RE circuit (3 sets of 10 repetitions). Participants ingested 1.5 l of a carbohydrate (200 g)-protein hydrolysate (50 g) beverage within 1 h of exercise completion. An OGTT was performed 6 h post-exercise. On the control day the endurance and resistance groups performed the above protocol without the prior exercise (CEE or CRE). The control and exercise days were counterbalanced. RE reduced plasma glucose AUC (822 +/- 68 vs. 694 +/- 23 mmol l(-1).120 min; CRE vs. RE, respectively; P < 0.05) but EE did not lead to a change (784 +/- 40 vs. 835 +/- 59 mmol l(-1).120 min; CEE vs. EE, respectively). Plasma insulin AUC remained unchanged compared to the control in both the RE and EE groups. The results suggest that the benefit of RE on glucose tolerance following CHO intake remains for 6 h even when a carbohydrate-protein hydrolysate beverage was ingested within 1 h after exercise, while the well documented benefit of EE was not observed. PMID- 17624546 TI - Winner-take-all selection in a neural system with delayed feedback. AB - We consider the effects of temporal delay in a neural feedback system with excitation and inhibition. The topology of our model system reflects the anatomy of the avian isthmic circuitry, a feedback structure found in all classes of vertebrates. We show that the system is capable of performing a 'winner-take-all' selection rule for certain combinations of excitatory and inhibitory feedback. In particular, we show that when the time delays are sufficiently large a system with local inhibition and global excitation can function as a 'winner-take-all' network and exhibit oscillatory dynamics. We demonstrate how the origin of the oscillations can be attributed to the finite delays through a linear stability analysis. PMID- 17624547 TI - A Ds-insertion mutant of OSH6 (Oryza sativa Homeobox 6) exhibits outgrowth of vestigial leaf-like structures, bracts, in rice. AB - OSH6 (Oryza sativa Homeobox6) is an ortholog of lg3 (Liguleless3) in maize. We generated a novel allele, termed OSH6-Ds, by inserting a defective Ds element into the third exon of OSH6, which resulted in a truncated OSH6 mRNA. The truncated mRNA was expressed ectopically in leaf tissues and encoded the N terminal region of OSH6, which includes the KNOX1 and partial KNOX2 subdomains. This recessive mutant showed outgrowth of bracts or produced leaves at the basal node of the panicle. These phenotypes distinguished it from the OSH6 transgene whose ectopic expression led to a "blade to sheath transformation" phenotype at the midrib region of leaves, similar to that seen in dominant Lg3 mutants. Expression of a similar truncated OSH6 cDNA from the 35S promoter (35S::DeltaOSH6) confirmed that the ectopic expression of this product was responsible for the aberrant bract development. These data suggest that OSH6-Ds interferes with a developmental mechanism involved in bract differentiation, especially at the basal nodes of panicles. PMID- 17624548 TI - Metal accumulation and arbuscular mycorrhizal status in metallicolous and nonmetallicolous populations of Pteris vittata L. and Sedum alfredii Hance. AB - Although Pteris vittata L. and Sedum alfredii Hance have been identified as an As hyperaccumulator and a Zn/Cd hyperaccumulator, respectively, for a few years, variations in metal accumulation among populations and their arbuscular mycorrhizal (AM) status have not been fully explored. Six populations of P. vittata and four populations of S. alfredii from southeast China were investigated. Up to 1,373 As, 680 Pb, 376 Zn, 4.8 Cd, 169 Cu mg kg(-1) in fronds of P. vittata and 358 As, 2,290 Pb, 23,403 Zn, 708 Cd, 342 Cu mg kg(-1 )in shoots of S. alfredii were detected. Constitutive properties of As and Zn hyperaccumulation in metallicolous populations of P. vittata and S. alfredii, respectively, were confirmed. However, Cd hyperaccumulation in S. alfredii varied among populations. The two hyperaccumulators varied in efficiency in taking up other heavy metals. Different metal tolerance strategies adopted by the two hyperaccumulators varied among plant species and metal species. Low to moderate levels of AM colonization in P. vittata (4.2-12.8%) and S. alfredii (8.5-45.8%) were observed at uncontaminated and metal-contaminated sites. The relationship between metal concentrations and AM colonization in the two hyperacumulators was also examined. The abundance of AM fungal spores ranged from 16 to 190 spores per 25 g soil. Glomus microaggregatum, Glomus mosseae, Glomus brohultii and Glomus geosporum were the most common species associated with both P. vittata and S. alfredii. To our knowledge, this is the first report of AM fungal status in rhizosphere of P. vittata and S. alfredii. PMID- 17624549 TI - Phosphoenolpyruvate carboxylase protein kinase from developing castor oil seeds: partial purification, characterization, and reversible control by photosynthate supply. AB - Phosphoenolpyruvate carboxylase (PEPC, EC 4.1.1.31) protein kinase (PPCK) was purified approximately 1,500-fold from developing castor oil seeds (COS). Gel filtration and immunoblotting with anti-(rice PPCK2)-immune serum indicated that this Ca2+-insensitive PPCK exists as a 31-kDa monomer. COS PPCK-mediated rephosphorylation of the 107-kDa subunit (p107) of COS PEPC1 (Km = 2.2 microM) activated PEPC1 by approximately 80% when assayed under suboptimal conditions (pH 7.3, 0.2 mM PEP, and 0.125 mM malate). COS PPCK displayed remarkable selectivity for phosphorylating COS PEPC1 (relative to tobacco, sorghum, or maize PEPCs), exhibited a broad pH-activity optima of approximately pH 8.5, and at pH 7.3 was activated 40-65% by 1 mM PEP, or 10 mM Gln or Asn, but inhibited 65% by 10 mM L malate. The possible control of COS PPCK by disulfide-dithiol interconversion was suggested by its rapid inactivation and subsequent reactivation when incubated with oxidized glutathione and then dithiothreitol. In vitro PPCK activity correlated with in vivo p107 phosphorylation status, with both peaking in mid cotyledon to full-cotyledon developing COS. Notably, PPCK activity and p107 phosphorylation of developing COS were eliminated following pod excision or prolonged darkness of intact plants. Both effects were fully reversed 12 h following reillumination of darkened plants. These results implicate a direct relationship between the up-regulation of COS PPCK and p107 phosphorylation during the recommencement of photosynthate delivery from illuminated leaves to the non-photosynthetic COS. Overall, the results support the hypothesis that PEPC and PPCK participate in the control of photosynthate partitioning into C skeletons needed as precursors for key biosynthetic pathways of developing COS. PMID- 17624550 TI - Nodal regulates neural tube formation in the Ciona intestinalis embryo. AB - Overexpression of a lefty orthologue, Ci-lefty, caused a failure of neural tube closure in the protochordate ascidian Ciona intestinalis. The body bent dorsally, and anterior-posterior elongation was inhibited. A similar phenotype was observed in embryos treated with SB431542, an inhibitor of Nodal receptors, suggesting that Ci-Lefty antagonized Nodal signaling as reported in other deuterostome species. Overexpression of Ci-nodal also resulted in a similar phenotype, suggesting that a correct quantity and/or a spatial restriction of Nodal signaling are important for the neural tube to form. In addition to known Ci Nodal target genes, orthologues of Zic (Ci-ZicL) and cdx (Ci-cdx) were activated by Ci-Nodal. Expression of a dominant negative Ci-cdx caused defects in neural tube formation similar to those obtained on treatment with SB431542 or overexpression of Ci-lefty. A regulatory cascade composed of Ci-Nodal, Ci-ZicL, and Ci-Cdx may play an important role in neural tube formation in the Ciona embryo. PMID- 17624551 TI - Evolution of the Groucho/Tle gene family: gene organization and duplication events. AB - The Groucho/Tle family of corepressor proteins has important roles in development and in adult tissue in both Protostomes and Deuterostomes. In Drosophila, a single member of this family has been identified. Unlike in Protostomes, most Deutrostomes contain more than two full-length Tle genes. In this study, I analyse the genomic organization and phylogenetic relationship between the long and short forms of the Groucho/Tle family members in Chordata. The genomic location and sequence similarities suggest that Aes/Grg5 and Tle6/Grg6 arose from duplication of the Tle2 gene; each evolved independently and acquired new functions as negative regulators of the other Tle proteins. Based on these data, a model for Groucho/Tle gene evolution is proposed. PMID- 17624552 TI - Postmortem diagnosis of Fabry disease with acromegaly and a unique vasculopathy. AB - A 44-year-old Japanese man with elevated growth hormone levels and gradual deterioration of mental and renal function was admitted to the hospital. With his deteriorated general condition and renal failure, the patient developed pulmonary thromboembolism and died of respiratory failure. Autopsy examination was conducted, which revealed abnormal accumulation or intracytoplasmic storage of lipid-rich material in the small blood vessels, kidney, heart, and nervous system. After postmortem pathologic studies, including light-microscopic histochemistry, electron microscopy, and biochemical analysis of the stored lipid contents, a final diagnosis of Fabry disease was made. Histopathologic examination revealed a unique vasculopathy characterized by the presence of abnormal intracytoplasmic lipid inclusions and vascular remodeling. With regard to the clinical presentation of acromegaly, hyperplasia but not adenomatous transformation of the acidophils of the anterior pituitary gland with immunohistochemical detection of growth hormone within the cells was noted. In this case, the complication of acromegaly with hyperplasia of the acidophilic cells of the anterior pituitary gland and the unique vasculopathy causing significant organ failure, mainly of the kidney, heart, and central nervous systems, possibly as a result of microcirculatory failure, are considered to be not incidental findings but to be intimately involved in the pathogenesis of Farby disease. PMID- 17624553 TI - Primary epithelioid sarcoma of the oesophagus. AB - Epithelioid sarcoma is a rare soft tissue tumour presenting two main variants: the 'classical' distal type and the more recently described proximal type. The latter is distinguished from the former by occurrence in elderly patients, more axial and deep location, prominent atypical and pleomorphic appearance and eventually aggressive clinical behaviour with poor outcome. To date, only few perivisceral epithelioid sarcomas have been described, and they are mainly related to the colon and bladder in pelvic and perineal sites. We report a hitherto undescribed epithelioid sarcoma of the distal oesophagus and discuss the relevance of molecular cytogenetics. PMID- 17624555 TI - Foraging behavior by Daphnia in stoichiometric gradients of food quality. AB - Mismatches in the elemental composition of herbivores and their resources can impact herbivore growth and reproduction. In aquatic systems, the ratio of elements, such as C, P, and N, is used to characterize the food quality of algal prey. For example, large increases in the C:P ratio of edible algae can decrease rates of growth and reproduction in Daphnia. Current theory emphasizes that Daphnia utilize only assimilation and respiration processes to maintain an optimal elemental composition, yet studies of terrestrial herbivores implicate behavioral processes in coping with local variation in food quality. We tested the ability of juvenile and adult Daphnia to locate regions of high-quality food within a spatial gradient of algal prey differing in C:P ratio, while holding food density constant over space. Both juveniles and adults demonstrated similar behavior by quickly locating (i.e., <10 min) the region of high food quality. Foraging paths were centred on regions of high food quality and these differed significantly from paths of individuals exposed to a homogeneous environment of both food density and food quality. Ingestion rate experiments on algal prey of differing stoichiometric ratio show that individuals can adjust their intake rate over fast behavioral time-scales, and we use these data to examine how individuals choose foraging locations when presented with a spatial gradient that trades off food quality and food quantity. Daphnia reared under low food quality conditions chose to forage in regions of high food quality even though they could attain the same C ingestion rate elsewhere along a spatial gradient. We argue that these aspects of foraging behavior by Daphnia have important implications for how these herbivores manage their elemental composition and our understanding of the dynamics of these herbivore-plant systems in lakes and ponds where spatial variation in food quality is present. PMID- 17624554 TI - The association between RAD18 Arg302Gln polymorphism and the risk of human non small-cell lung cancer. AB - PURPOSE: The repair enzyme RAD18 plays a key role in the post-replication repair process in various organisms from yeast to human, and the molecular function of the RAD18 protein has been elucidated. Single nucleotide polymorphism (SNP) of arginine (Arg, CGA) or glutamine (Gln, CAA) at codon 302 is known on RAD18; however, the association between the SNP and the risk of any human cancers including non-small-cell lung cancer (NSCLC) has not been reported. We therefore investigated the relationship between the polymorphism and the development and progression of human NSCLC. METHODS: The study population included 159 patients with NSCLC and 200 healthy controls. The SNP was genotyped by polymerase chain reaction with the confronting two-pair primer (PCR-CTPP) assay. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological parameters was also studied. RESULTS: The Gln/Gln genotype was significantly more frequent in NSCLC patients (20.7%) than in healthy controls (11.5%)(P = 0.003). The increased risk was detected in NSCLC patients with the Gln/Gln genotype [Odds ratio (OR) = 2.63, 95% confidence interval (CI)=1.38-4.98]. As to the relationship of the SNP with clinicopathological parameters of NSCLC, significantly higher risks were detected in lung squamous cell carcinoma (LSC) (OR = 4.40, 95% CI = 1.60-12.1). CONCLUSIONS: Our results suggested that Gln/Gln genotype of the RAD18 SNP has the increased risk of NSCLC, especially of LSC. This is the first report to provide evidence for an association between the RAD18 Arg302Gln polymorphism and human NSCLC risk. PMID- 17624556 TI - Identifying cardinal dates in phytoplankton time series to enable the analysis of long-term trends. AB - Phenology and seasonal succession in aquatic ecosystems are strongly dependent on physical factors. In order to promote investigations into this coupling, methods of characterising annual time series of phytoplankton were derived and applied to a 31-year data set from Saidenbach Reservoir (Saxony, Germany). Field data are often scarce and irregularly sampled, particularly in the transition period from winter to spring, so reliable methods of determining cardinal dates in the time series are necessary. The proposed methods were used to determine the beginning, maximum and end of the spring mass development of phytoplankton by estimating the inflexion points (A), fitting a Weibull-type function (B) and fitting linear segments to the logarithmic values (C). For the data set from Saidenbach Reservoir, all three methods proved to be relevant to the analysis of long-term trends. Differences between the maxima determined by the different methods seemed small, but there were deviations when the maximum was related to physical factors such as ice-out. The Weibull-type fit gave the most reliable and comprehensible results and is recommended for trend analyses. For all methods, long-term analysis of the duration of the spring mass development and the duration of the spring full circulation revealed a period of consistently low values (1975-1990) followed by a period of higher values (1990-2005). These periods were also identified for the date of ice-out, although in this case there was a period of high values followed by a period of low values. A sensitivity analysis that compared results from subsampled time series with increasing time intervals indicated that a minimum of one sample every three weeks is needed to obtain reliable results. PMID- 17624557 TI - [ Botulinum toxin in chronic myofascial pain]. PMID- 17624558 TI - Presenting the alternative: cancer and complementary and alternative medicine in the Canadian print media. AB - GOALS OF WORK: Cancer patients repeatedly identify the mass media as a primary information source to support their decisions to use complementary and alternative medicine (CAM). Accordingly, the objectives of this research are to describe: (1) what has been reported in the Canadian print media regarding CAM treatment for cancer between January 1, 1990 and December 31, 2005; (2) how that information was represented; and (3) trends in reporting frequency and reporting characteristics. MATERIALS AND METHODS: Content analysis of all articles published in four Canadian newspapers and five magazines that discussed CAM treatment for cancer. MAIN RESULTS: 915 articles were identified: 760 newspaper articles and 155 magazine articles. The CAM therapies most commonly described in media reports were: natural health products, CAM therapies in general, special diets, spirituality, and meditation. CAM therapies were most often described in a positive fashion, and CAM use was most often described as a potential cure for cancer. The majority of articles did not present information on the risks, benefits, and costs of CAM use and few provided a recommendation to speak with a health care provider before use. CONCLUSIONS: The results correspond with the commercial interests of media outlets, as coverage appears to be focused around entertainment rather than information provision. The media play a role in introducing a range of treatment options to cancer patients that may not be discussed by conventional health care providers; however, the information provided in media articles appears insufficient to assist patients with informed decision-making. PMID- 17624559 TI - Effect of defocused infrared diode laser on salivary flow rate and some salivary parameters of rats. AB - This study aims to investigate whether infrared diode low-level laser therapy (LLLT) increased salivary flow rate and altered pH value, protein concentration, and peroxidase and amylase activities in saliva of rats. Wistar rats were used and divided into three groups. Experimental groups (A and B) had their parotid, submandibular and sublingual glands submitted to diode laser, 808-nm wavelength, on two consecutive days. The dose results were 4 and 8 J/cm(2), respectively. A red guide light was used to visualize the irradiated area. Group C was irradiated only with red pilot beam and served as control. The saliva samples were collected after each irradiation step (first and second collection days) and 1 week after the first irradiation (seventh day). Statistical analysis was performed, and differences were observed according to different days of salivary collection. The results showed that salivary flow rate for groups A and B was higher on the seventh day if it is compared to data obtained for the first day (p < 0.05). LLLT applications on salivary glands are a therapy procedure that requires further studies. PMID- 17624560 TI - Evaluation of an internally controlled real-time polymerase chain reaction assay targeting the groEL gene for the detection of Bartonella spp. DNA in patients with suspected cat-scratch disease. AB - Bartonella (B.) henselae is the causative agent of cat-scratch disease (CSD), which usually presents as a self-limiting lymphadenopathy. This study reports the development and evaluation of an internally controlled real-time polymerase chain reaction targeting the groEL gene for detection of Bartonella spp. DNA was extracted using the MagNA Pure system. The lower detection limit was 10-100 fg DNA and the in vitro sensitivity of the assay was not affected by duplexing with an internal control PCR. The real-time PCR assay detected DNA from all five B. henselae strains tested, and from B. birtlesii, B. vinsonii subsp. vinsonii, B. vinsonii subsp. arupensis and B. doshiae. The assay generated negative results with a selection of other bacteria, including several Mycobacterium spp., Streptococcus pyogenes and Staphylococcus aureus. Results of real-time PCR in clinical samples were compared with those of a conventional 16S rDNA-based PCR assay. During the period described in the Material and methods section, real-time PCR and conventional 16S PCR were performed on 73 clinical samples. Of these samples, 29 (40%) were found to give positive results and 44 (60%) gave negative results, both by real-time PCR and by conventional PCR, with a 100% agreement between the two tests. The PCR developed in this study is a rapid, sensitive, and simple method for the detection of Bartonella spp. in CSD and is suitable for implementation in the diagnostic laboratory. PMID- 17624561 TI - Imaging findings of pulmonary infection caused by Scedosporium prolificans in a deep immunocompromised patient. AB - Scedosporium prolificans is an emerging fungus that causes rapid progressive and disseminated infections in immunodepressed patients. We present a case of a 34 year-old woman with chronic myelogenous leukemia who received a bone marrow transplantation and suffered a sudden respiratory failure in +67 day. Chest radiographies showed growing bilateral patchy condensations. Computed Tomography depicted bilateral nodular condensation of alveolar space. S. prolificans was detected from sputum, but the patient died 72 h later. Imaging findings of lung scedosporiosis are nonspecific, but CT may provide a prompter diagnosis and allow to add newer antifungal treatments. This report presents the first imaging report of lung scedosporiosis. PMID- 17624562 TI - The Institute for Music Physiology and Musicians' Medicine. AB - The Institute of Music Physiology and Musicians' Medicine of the University of Music and Drama in Hannover, Germany, is a unique Institution in Europe whose scope includes teaching the basics of music physiology and musicians' medicine and research into the physiological and neurobiological principles of professional music performance and music perception. Furthermore, the institute conducts research into the causes of occupational injuries in musicians and provides means for prevention, diagnosis and treatment of such injuries. PMID- 17624563 TI - Simulation of an anterior spine instrumentation in adolescent idiopathic scoliosis using a flexible multi-body model. AB - Anterior spinal instrumentation is an alternative option to posterior instrumentation for surgical treatment of adolescent idiopathic scoliosis (AIS). However, optimal instrumentation configuration and strategies are not yet clearly defined. A biomechanical kinematic model using flexible mechanism was developed to study instrumentation strategies. Preoperative 3D reconstruction of scoliotic patient's spine was used to define the patient-specific geometry of the model. Mechanical properties were adjusted to consider the discectomy and surgical manoeuvres were reproduced. Anterior spine surgeries of ten patients were simulated and results were compared to immediate post-operative data and showed differences of <5 degrees for the Cobb angles. The validated model was used to find optimal instrumentation configurations for one patient prior to surgery. Six strategies were tested out of which the optimal one was identified while two were not recommended for surgery since screw forces exceeded published pullout forces. This study demonstrates the possibility to simulate anterior spine instrumentations. PMID- 17624564 TI - Microbubbling by co-axial electrohydrodynamic atomization. AB - The preparation of microbubble suspensions is an important feature of medical engineering research. Recently, co-axial electrohydrodynamic atomization was used in our laboratory for the first time to prepare microbubble suspensions. In this paper, using a model glycerol-air system, we investigate in detail the characteristics of this microbubbling process. Modes of microbubbling are elucidated with respect to applied voltage and liquid and air flow rates. Thus, a parametric plot is constructed to identify a liquid and gas flow rate regime, which allows continuous microbubbling. This map provides a basis for the selection of a suitable combination of liquid and gas flow rates particularly in relation to yield and bubble size. The mechanism of microbubbling in microfluidic systems is compared with that of microbubbling by co-axial electrohydrodynamic atomization to identify the advantages and the limiting factors of the latter. Stability of microbubbles prepared by this method in terms of variation of diameter as a function of time is compared with previous literature on the dissolution of microbubbles with an air core and suggests the need for further work to stabilize the bubbles. PMID- 17624565 TI - On-Board Imager-based MammoSite treatment verification. AB - Contemporary radiation oncology departments are often lacking a conventional simulator due to common use of virtual simulation and recent implementation of image guided radiation therapy. A protocol based on MammoSite method was developed using CT based planning, a Source Position Simulator (SPS) with a Simulator Wire and a linear accelerator based On-Board Imager (OBI) for daily verification. After MammoSite balloon implantation, the patient undergoes a CT study. The images are evaluated for tissue conformance, balloon symmetry, and balloon surface to skin distance according to the departmental procedure. Prior to the CT study the SPS is attached to the transfer tube that in turn is attached to the balloon catheter. The length from the indexer to the first dwell position is measured using the simulator wire with X-ray markers. After the CT study is performed, the data set is sent to the Varian Eclipse treatment planning system (TPS) and to the Nucletron PLATO brachytherapy planning system. The reference digitally reconstructed radiographs (DRRs) of anterior and lateral setup fields are created using Eclipse TPS and are immediately available on the OBI console via the Varian Vision integrated system. The source dwell position coinciding with the balloon center is identified in the CT dataset, followed by the offset calculation, catheter reconstruction, dose points placement and dwell time calculation. OBI fluoroscopy images are acquired and marked as initial. Prior to each treatment fraction balloon diameter and symmetry are evaluated using OBI fluoroscopy and tools available on the OBI console. Acquired images are compared with reference DRRs and/or initial OBI images. The whole process from initial evaluation to daily verification is filmless and does not undermine the precision of the procedure. This verification time does not exceed 10 min. The balloon diameter correlates well (within 1 mm) between initial CT and OBI verification images. The balloon symmetry is defined with 1 mm accuracy using existing OBI console tools. It is feasible to use OBI based simulation for the MammoSite balloon placement evaluation, balloon integrity daily verification, and treatment dwell position coincidence with balloon center. This verification is a rapid process and is an alternative to the conventional simulator based technique. The simulator wire with X-ray markers for the SPS is the recommended tool for the CT based MammoSite procedure. PMID- 17624566 TI - Mixed-phase modeling in snore sound analysis. AB - Obstructive sleep apnea (OSA) is a highly prevalent disease in which upper airways are collapsed during sleep, leading to serious consequences. The gold standard of diagnosis, called Polysomnography (PSG), requires a full-night hospital stay connected to over 15 channels of measurements requiring physical contact with sensors. PSG is expensive and unsuited for community screening. Snoring is the earliest symptom of OSA, but its potential in OSA diagnosis is not fully recognized yet. In this paper, we propose a novel model for SRS as the response of a mixed-phase system (total airways response, TAR) to a source excitation at the input. The TAR/source model is similar to the vocal tract/source model in speech synthesis, and is capable of capturing acoustical changes brought about by the collapsing upper airways in OSA. We propose an algorithm based on higher-order-spectra (HOS) to jointly estimate the source and TAR, preserving the true phase characteristics of the latter. Working on a clinical database of signals, we show that TAR is indeed a mixed-phased signal and second-order statistics cannot fully characterize it. Night-time speech sounds can corrupt snore recordings and pose a challenge to snore based OSA diagnosis. We show that the TAR could be used to detect speech segments embedded in snores, and derive features to diagnose OSA via non-contact, low-cost instrumentation holding potential for a community screening device. PMID- 17624567 TI - Imaging findings of Castleman disease of the abdomen and pelvis. AB - BACKGROUND: The purpose of this study was to analyze the characteristic features of Castleman disease in the abdomen and pelvis as suggested by imaging findings in order to deepen the recognition and understanding of this rare disease. METHODS: A group of ten patients with pathologically proven Castleman disease in the abdomen (n = 9) and pelvis (n = 1) were included in this study. Patients were 18 approximately 56-year-old (mean = 40); seven of them were men and three were women. Imaging findings (CT&MRI, n = 4; only CT, n = 4; only MRI, n = 2) were retrospectively reviewed and correlated with clinical and pathologic findings. RESULTS: The lesions were divided into those with localized Castleman (n = 9) and disseminated Castleman (n = 1). The pathologic subtype of all nine cases of localized disease was hyaline vascular with six patients showing a solitary mass and three having a single dominant mass surrounded by small satellite nodules. On nonenhanced CT images, the lesions were manifested as homogeneous masses of soft tissue attenuation, which was isoattenuated relative to normal muscle. On MRI, the lesions were isointense or slightly hypointense compared with that of normal muscle on T1-weighted images and hyperintense on T2-weighted images. After intravenous injection of contrast media, most of the masses (7/9) showed marked enhancement and slow washout with the degree of enhancement approaching that of the large arteries. And in the interior of four cases of larger masses (>5 cm) was observed fissured and radial patterns in both low-density area on CT and low signal area on MRI. These patterns were pathologically proved to be fibrous. The pathological subtype of a sole disseminated case was plasma-cell type, where imaging findings showed a lining of well defined, sharply enhanced soft-tissue nodules in retroperitoneal zone. CONCLUSION: Imaging findings of Castleman disease in the abdomen and pelvis are closely related to pathological type diagnosed. The characteristic features of localized and hyaline vascular type of Castleman disease include a solitary mass or a dominant mass surrounded with small satellite nodules, and high enhancement and slow washout with the degree of enhancement approaches that of large arteries. The presence of central areas of fibrosis of the larger tumors is one of the characteristic features of this disease. PMID- 17624568 TI - Diffusion-weighted magnetic resonance imaging of the body in venous thrombosis: a report of four cases. PMID- 17624569 TI - Groove pancreatitis: MRI and pathologic findings. AB - OBJECTIVE: Our purpose is to describe the MRI findings with pathologic correlation, in five patients with groove pancreatitis, a specific form of chronic pancreatitis affecting the groove between the pancreatic head, the common bile duct and duodenum. MATERIALS AND METHODS: Five patients with pathologically proven (four cases) and clinical and MRI findings (follow-up) consistent with the diagnosis of groove pancreatitis (one case) were reviewed. Three patients underwent cephalic pancreatoduodenectomy (Whipple procedure) due to severe duodenal stenosis; MRI findings were correlated with the histological findings. RESULTS: In all patients a mass was seen affecting the groove between the pancreatic head and the duodenum. Precontrast images demonstrated hypointense tissue relative to pancreatic parenchyma on T1-weighted images and iso to slightly hyperintense tissue on STIR and T2-weighted images. Postcontrast dynamic Gd-DTPA images, showed peripheral mass enhancement on immediate postgadolinium images and progressive and centripetal mass enhancement on delayed images with good delineation of multiple cysts. Histologically, fibro-inflammatory tissue was demonstrated in the groove and the duodenal wall with obliterative concentric scarring of the distal common bile duct. CONCLUSIONS: MRI findings are demonstrative of the pathologic features characteristic of this entity: the fibrous tissue in the pancreaticoduodenal groove, the duodenal wall inflammation and the groove and/or duodenal wall cyst formation. PMID- 17624570 TI - Recurrent ovarian granulosa cell tumors: clinical and imaging features. AB - BACKGROUND: Granulosa cell tumor of the ovary differs from epithelial ovarian tumors in histologic appearance, clinical course and imaging findings. The purpose of this study was to evaluate clinical and imaging features of recurrent ovarian granulosa cell tumors. METHODS: We performed retrospective evaluation of the medical, surgicopathologic records and CT or MR images of 11 patients with pathologically proven recurrent ovarian granulosa cell tumor. RESULTS: The first recurrence of granulosa cell tumor was diagnosed at between 4 months and 18 years after the initial surgical resection of tumor (mean; 9.7 years). Six patients relapsed after 10 years after initial diagnosis. The recurrent tumors were located in the pelvic cavity alone in three patients, extrapelvic peritoneal cavity alone in two, both pelvic and extrapelvic peritoneal cavity in three, and paraaortic retroperitoneal space in three. The imaging appearances of recurrent masses were variable ranging from solid masses to completely cystic masses. CONCLUSION: Recurrent granulosa cell tumor is characterized by late tumor recurrence manifested as a relatively small number of discrete peritoneal or retroperitoneal masses with variable imaging appearances from solid to cystic masses. PMID- 17624571 TI - Patient presentation and management of labial ulceration following uterine artery embolization. AB - Uterine artery embolization is a safe and effective procedure for the treatment of symptomatic uterine fibroids. Nontarget embolization of adjacent internal iliac artery branches is a reported complication of uterine artery embolization. The following report describes the presentation and management of ulcerations of the labium minora due to nontarget embolization of the internal pudendal artery. PMID- 17624572 TI - Preoperative uterine artery embolization (PUAE) before uterine fibroid myomectomy. AB - PURPOSE: To evaluate the potential of uterine artery embolization to minimize blood loss and facilitate easier removal of fibroids during subsequent myomectomy. METHODS: This retrospective study included 22 patients (median age 37 years), of whom at least 15 wished to preserve their fertility. They presented with at least one fibroid (mean diameter 85.6 mm) and had undergone preoperative uterine artery embolization (PUAE) with resorbable gelatin sponge. RESULTS: No complication or technical failure of embolization was identified. Myomectomies were performed during laparoscopy (12 cases) and laparotomy (9 cases). One hysterectomy was performed. The following were noted: easier dissection of fibroids (mean 5.6 per patient, range 1-30); mean intervention time 113 min (range 25-210 min); almost bloodless surgery, with a mean peroperative blood loss of 90 ml (range 0-806 ml); mean hemoglobin pretherapeutically 12.3 g/dl (range 5.9-15.2 g/dl) and post-therapeutically 10.3 g/dl (range 5.6-13.3 g/dl), with no blood transfusion needed. Patients were discharged on day 4 on average and the mean sick leave was 1 month. CONCLUSION: Preoperative embolization is associated with minimal intraoperative blood loss. It does not increase the complication rate or impair operative dissection, and improves the chances of performing conservative surgery. PMID- 17624573 TI - Sensitivity of direct plating for detection of high levels of E. coli O157:H7 in bovine fecal samples. AB - To assess the sensitivity of direct plating of bovine fecal samples for detection of Escherichia coli O157:H7, calves (n = 28) were orally inoculated with 10(9) colony-forming units (cfu) per calf of a mixture of three strains of nalidixic acid-resistant E. coli O157:H7, and fecal samples were collected for analysis. One-gram samples from inoculated calves were mixed with 9 mL of Gram-negative broth with vancomycin, cefixime, and cefsoludin. From this suspension, serial dilutions were made (10(-1) to 10(-4)) and spread plated in triplicate on Sorbitol MacConkey agar with nalidixic acid for enumeration of E. coli O157:H7 in fecal samples. Direct plating samples were streaked for isolation on Sorbitol MacConkey agar with cefixime, and tellurite (SMACct). After incubation overnight at 37 degrees C, morphologically typical colonies from direct streak plates were plated onto blood agar and incubated overnight at 37 degrees C; then an indole test was performed on each colony. Indole-positive colonies were confirmed by O157 agglutination and were then plated on SMAC agar with 20 microg/mL nalidixic acid (SMACnal) to confirm nalidixic acid resistance. Overall sensitivity of detection was 32.5% (110/338 samples). Sensitivity to detect fecal samples shedding at above 5 x 10(4) cfu/g was 83% (71/86 samples). Based on these data, direct plating of fecal samples might be an effective way to identify cattle that are likely to be shedding E. coli O157 at high levels. PMID- 17624574 TI - Expression vectors for the rapid purification of recombinant proteins in Bacillus subtilis. AB - We describe the construction of six novel plasmid-based IPTG-inducible expression vectors for Bacillus subtilis and related species. While one vector allows intracellular production of recombinant proteins, the second provides a strong secretion signal. The third vector allows addition of the c-Myc epitope tag, and the remaining three vectors provide the purification tags His and Strep. The versatility of all six vectors was demonstrated by the insertion of several reporter genes and by their regulated overexpression. Recombinant proteins with a His- or Strep-tag could be purified to near homogeneity in a single step. PMID- 17624575 TI - Differential gene expression in a marine sponge in relation to its symbiotic state. AB - The molecular mechanisms involved in the establishment and maintenance of sponge photosymbiosis, and in particular the association with cyanobacteria, are unknown. In the present study we analyzed gene expression in a common Mediterranean sponge (Petrosia ficiformis) in relation to its symbiotic (with cyanobacteria) or aposymbiotic status. A screening approach was applied to identify genes expressed differentially in symbiotic specimens growing in the light and aposymbiotic specimens growing in a dark cave at a short distance from the illuminated specimens. Out of the various differentially expressed sequences, we isolated two novel genes (here named PfSym1 and PfSym2) that were up-regulated when cyanobacterial symbionts were harbored inside the sponge cells. The sequence of one of these genes (PfSym2) was found to contain a conserved domain: the scavenger receptor cysteine rich (SRCR) domain. This is the first report on the expression of sponge genes in relation to symbiosis and, according to the presence of an SRCR domain, we suggest possible functions for one of the genes found in the sponge-cyanobacteria symbiosis. PMID- 17624577 TI - Cultivation of sponge larvae: settlement, survival, and growth of juveniles. AB - The aim of this study was to culture sponge juveniles from larvae. Starting from larvae we expected to enhance the survival and growth, and to decrease the variation in these parameters during the sponge cultures. First, settlement success, morphological changes during metamorphosis, and survival of Dysidea avara, Ircinia oros, Hippospongia communis, under the same culture conditions, were compared. In a second step, we tested the effects of flow and food on survival and growth of juveniles from Dysidea avara and Crambe crambe. Finally, in a third experiment, we monitored survival and growth of juveniles of D. avara and C. crambe transplanted to the sea to compare laboratory and field results. The results altogether indicated that sponge culture from larvae is a promising method for sponge supply and that laboratory culture under controlled conditions is preferred over sea cultures in order to prevent biomass losses during these early life stages. PMID- 17624576 TI - A novel glycosylphosphatidylinositol-anchored alkaline phosphatase dwells in the hepatic duct of the pearl oyster, Pinctada fucata. AB - Alkaline phosphatases are ubiquitous enzymes involved in many important biological processes. Mammalian tissue-nonspecific alkaline phosphatase (TNAP) has long been thought to play an important role in bone mineralization. In this study, we identified a full-length cDNA encoding a potential alkaline phosphatse from pearl oyster Pinctada fucata by RT-PCR and RACE and designated the encoded protein as PFAP. The sequence of PFAP shares an overall similarity of 67% with that of human TNAP. Prediction and analysis of its secondary and tertiary structure revealed that the PFAP contains two mammalian-specific regions, the crown domain, involved in collagen binding, and the calcium binding domain, which hint its potential ability to participate in biomineralization. RT-PCR and in situ hybridization showed that the PFAP mRNA distributes specifically in the hepatic duct of the digestive diverticula. These findings implied its possible role in calcium absorption and transportation. In vivo, PFAP could be specifically released by phosphatidylinositol-specific phospholipase C (PIPLC), suggesting it is glycophosphatidylinositol-anchored to the plasma membrane. Therefore, a human growth hormone-PFAP fusion was constructed to locate the cleavage/attachment site. Immunofluorescent labeling and immunoblotting showed that Asn-477 is the cleavage/attachment site and the 25-residue peptide COOH terminal to Asn-477 is removed during glycophosphatidylinositol anchoring. This research will hopefully pave the way to illustrate the role PFAP plays in calcium transportation related to pearl biomineralization. PMID- 17624578 TI - Altered esophageal motility and gastroesophageal barrier in patients with jejunal interposition after distal esophageal resection for early stage adenocarcinoma. AB - INTRODUCTION: Limited resection of the esophagogastric junction has been proven to be safe and oncologically radical in patients with early esophageal cancer. Reconstruction with interposition of isoperistaltic jejunal loop (Merendino procedure) is supposed to prevent gastroesophageal reflux and therefore the recurrence of intestinal metaplasia at the anastomosis. The aim of this study was to assess the frequency of acid and nonacid refluxes after Merendino procedure using multichannel intraluminal impedance-pH (MII-pH) monitoring. PATIENTS AND METHODS: Between 2002 and 2005, 12 patients with esophageal adenocarcinoma underwent limited resection and jejunal interposition. Ten patients agreed to undergo a Gastrointestinal Symptom Rating Scale assessment, upper gastrointestinal (GI) endoscopy, esophageal manometry, and combined 24-h MII-pH monitoring more than 10 months postoperatively. RESULTS: Postoperatively, 4 (40%) patients reported belching without heartburn or acid regurgitation, 3 of them having a positive symptom index during 24-h MII-pH monitoring. Upper GI endoscopy revealed no inflammation, metaplasia, or stenosis at the esophagojejunal anastomosis. Esophageal manometry showed ineffective esophageal motility in four of ten patients. Combined 24-h MII-pH monitoring revealed normal distal esophageal acid exposure (% time pH < 4: 0.1% [0-1.5]), normal number of acid reflux episodes (3 [0-11]) but a high number of nonacid reflux episodes (82 [33 184]). Overall, eight patients revealed an abnormal number of nonacid reflux episodes. CONCLUSION: The limited resection with jejunal interposition for early esophageal cancer is efficient in controlling acid but not nonacid reflux. While the clinical relevance of nonacid reflux in the recurrence of Barrett's esophagus is currently unknown, endoscopic surveillance should be considered in these patients. PMID- 17624579 TI - Decreased biosynthesis of lung surfactant constituent phosphatidylcholine due to inhibition of choline transporter by gefitinib in lung alveolar cells. AB - PURPOSE: We investigated whether gefitinib, an anticancer agent, inhibits phosphatidylcholine (PC) biosynthesis and choline uptake by alveolar epithelial type II cells. MATERIALS AND METHODS: Uptake of choline and PC biosynthesis were examined in vitro, using human alveolar epithelia-derived cell line A549 and rat alveolar type (AT) II cells as models. RESULTS: Gefitinib reduced the incorporation of [3H]choline into PC in A549 and rat ATII cells. The uptake of [3H]choline by A549 and rat ATII cells was concentration-dependent, and the Km values were 15.0 and 10-100 microM, respectively. The uptake of [3H]choline by A549 and rat ATII cells was weakly Na+-dependent, and inhibited by hemicholinium 3. RT-PCR revealed expression of choline transporter-like protein (CTL)1 and organic cation transporter (OCT)3 mRNAs in both cells. The choline uptake by A549 and rat ATII cells was strongly inhibited by gefitinib with the IC50 value of 6.77 microM and 10.5 microM, respectively. CONCLUSIONS: Our results demonstrate that gefitinib reduces PC biosynthesis via inhibition of cellular choline uptake by A549 and rat ATII cells, which is mainly mediated by CTL1, resulting in abnormality of lung surfactant that can be one of mechanisms of the interstitial lung disease associated with gefitinib. PMID- 17624580 TI - Recent advances in the use of intrinsic fluorescence for bacterial identification and characterization. AB - Live bacteria contain a variety of intracellular biomolecules that have specific excitation and emission wavelength spectra characterizing their intrinsic fluorescence. This paper reviews recent developed methods using bacterial intrinsic fluorescence for identification and characterization purposes. Potential applications of such methods at the industrial level are also addressed. PMID- 17624581 TI - Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? AB - Investigating the causes of increased aerobic glycolysis in tumors (Warburg Effect) has gone in and out of fashion many times since it was first described almost a century ago. The field is currently in ascendance due to two factors. Over a million FDG-PET studies have unequivocally identified increased glucose uptake as a hallmark of metastatic cancer in humans. These observations, combined with new molecular insights with HIF-1alpha and c-myc, have rekindled an interest in this important phenotype. A preponderance of work has been focused on the molecular mechanisms underlying this effect, with the expectation that a mechanistic understanding may lead to novel therapeutic approaches. There is also an implicit assumption that a mechanistic understanding, although fundamentally reductionist, will nonetheless lead to a more profound teleological understanding of the need for altered metabolism in invasive cancers. In this communication, we describe an alternative approach that begins with teleology; i.e. adaptive landscapes and selection pressures that promote emergence of aerobic glycolysis during the somatic evolution of invasive cancer. Mathematical models and empirical observations are used to define the adaptive advantage of aerobic glycolysis that would explain its remarkable prevalence in human cancers. These studies have led to the hypothesis that increased consumption of glucose in metastatic lesions is not used for substantial energy production via Embden Meyerhoff glycolysis, but rather for production of acid, which gives the cancer cells a competitive advantage for invasion. Alternative hypotheses, wherein the glucose is used for generation of reducing equivalents (NADPH) or anabolic precursors (ribose) are also discussed. PMID- 17624582 TI - Acidic vesicles of the endo-exocytic pathways as targets for some anti-monoamine oxidase drugs. AB - Acidic vesicles are cytoplasmatic organelles delimited by a single lipoprotein membrane. They contain a large number of enzymes, mostly acidic hydrolases, catalysing various reactions at optimal acidic pH, capable of participating in intracellular digestion. In this paper, some anti-monoamine oxidase drugs (clorgyline, pargyline, amantadine and deprenyl), utilized as pharmacological treatment in some neurological disorders (e.g., Alzheimer's, Parkinson's etc. diseases), were tested for their ability to influence the pH of the acidic intracellular organelles with the aim of exploring their possible pharmacological action. Of the above mentioned drugs, clorgyline showed the most effective action in modifying the acidic vesicles' internal pH, followed by deprenyl, pargyline and amantadine. The effect was not ascribed to an increased proton conductance, but was most likely due to a weak base-like mechanism, in that they exhibit equilibria among species associated with H(+) ions and species lacking this association. PMID- 17624583 TI - Induction of human monocyte interleukin (IL)-8 by fibrinogen through the toll like receptor pathway. AB - Fibrinogen, in addition to its role in coagulation, is also an acute phase protein of inflammation. Treatment of adherent human monocytes with fibrinogen increases IL-8, IL-6, and TNF-alpha, but has no effect on MCP-1, IFN-beta, or IP 10. Treatment of monocytes with fibrinogen and C5a doubles IL-8 and IL-6 production, compared to fibrinogen alone. The increase in cytokine production was accompanied by a transient increase in IL-8 mRNA and increased NF-kappaB activity. Monocytes from an IRAK-4- and two NEMO-deficient patients had 80% reduced IL-8 responses to fibrinogen. Moreover, responses to fibrinogen were blocked with anti-CD14 antibody (MY4), a subunit of the LPS receptor. The data indicate that fibrinogen alone and fibrinogen plus C5a are potent inducers of cytokine production in monocytes, and that signaling by fibrinogen is mediated through the TLR-4 pathway. PMID- 17624584 TI - The effect of hydrogen peroxide in human internal thoracic arteries: role of potassium channels, nitric oxide and cyclooxygenase products. AB - INTRODUCTION: We investigated both the effect and the role(s) of potassium channels, nitric oxide (NO) and cyclooxygenase (COX) products in the effect of hydrogen peroxide (H(2)O(2)) in human internal thoracic artery (ITA) rings. MATERIALS AND METHODS: Samples of redundant ITA obtained from patients undergoing a coronary artery bypass graft surgery were cut into 3 mm wide rings and suspended in 20 ml organ baths. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system. RESULTS: H(2)O(2) (10(-7)-10(-4) M) produced concentration-dependent relaxation responses in human ITA precontracted by phenylephrine. The relaxant responses to H(2)O(2) did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of human ITA rings with superoxide dismutase (50 U/ml) did not affect the relaxant responses to H(2)O(2), while 1,000 U/ml catalase caused a significant decrease. Incubation of endothelium intact or endothelium-denuded human ITA rings with voltage-dependent potassium channel blocker 4-aminopyridine (5 mM) significantly inhibited the relaxant responses to H(2)O(2). COX inhibitor indomethacin (10(-5) M) also caused a significant inhibition. Incubation with ATP-dependent potassium channel blocker glibenclamide (10(-6) M) or Ca(2+)-activated potassium channel blocker iberiotoxin (10(-7) M) or NO synthase (NOS) blocker N(omega)-nitro-L: -arginine methyl ester (10(-4) M) did not alter relaxant responses of ITA rings to H(2)O(2). CONCLUSION: The findings of the present study suggested that H(2)O(2) induced relaxation responses in human ITA were neither dependant on the endothelium nor blocked by NOS inhibition but they rather seem to depend on the activation of voltage-dependent potassium channels and COX. PMID- 17624585 TI - 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways. AB - 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing para trifluoromethyl (DIM-C-pPhCF(3)), t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C pPhC(6)H(5)) groups are methylene-substituted diindolylmetyhanes (C-DIMs) that activate peroxisome proliferator-activated receptor gamma (PPARgamma) in estrogen receptor alpha-negative MDA-MB-231 and MDA-MB-453 breast cancer cells. C-DIMs inhibit breast cancer cell proliferation; however, inhibition of G(0)/G(1) to S phase progression and cyclin D1 downregulation was observed in MDA-MB-231 but not MDA-MB-453 cells. Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a transforming growth factor beta-like peptide, was also induced by these compounds, and the response was dependent on cell-context dependent activation of kinase pathways. However, inhibition of cell growth, induction of NAG-1 and activation of kinases by C-DIMs were not inhibited by PPARgamma antagonists. Despite the induction of NAG-1 and downregulation of the antiapoptotic protein survivin by C-DIMs in both MDA-MB-231 and MDA-MB-453 cells, apoptotic cell death was not observed. Nevertheless, the cytotoxicity of C-DIMs in vitro was complemented by inhibition of tumor growth in athymic nude mice bearing MDA-MB 231 cells as xenografts and treated with DIM-C-pPhC(6)H(5) (40 mg/kg/day). The growth inhibition of tumors derived from highly aggressive MDA-MB-231 cells suggests a potential role for the C-DIM compounds in the clinical treatment of ER negative breast cancer. PMID- 17624586 TI - Prevalence and prognostic and predictive relevance of PRAME in breast cancer. AB - Preferentially expressed antigen of melanoma (PRAME) has been described as a potential candidate for immunotherapeutic targeting. However, the prognostic and predictive relevance of PRAME in breast cancer has never been investigated. PRAME gene expression was evaluated in 103 breast tumour biopsies, using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Normal breast tissue was also analysed for comparative purposes. All qRT-PCRs were performed in triplicate. Kaplan-Meier survival curves, Chi-squared and Cox Regression analyses were used to identify associations between PRAME expression and patients' clinicopathological and survival data. PRAME mRNA was detected in approximately 53% of tumour specimens and 37% of normal breast specimens. Kaplan-Meier analysis showed expression of PRAME to correlate significantly with unfavourable disease outcome for patients, in terms of both their disease-free survival (p = 0.0004) and overall survival (OS) (p = 0.0052) times from diagnosis. Multivariate analysis indicated PRAME expression to be an independent prognostic factor for shortened disease-free survival (p = 0.026) and OS (p = 0.02). Furthermore, for patients who received adjuvant chemotherapy, significantly (p = 0.0291) shorter relapse-free survival was achieved for those whose tumour expressed PRAME, compared to those that did not express this transcript. Our results suggest that PRAME mRNA expression may be a useful prognostic and predictive marker for breast cancer. PMID- 17624587 TI - The role of cyclooxygenase-2 in breast cancer: review. AB - There is a growing body of evidence that COX-2 expression s a fundamental step in breast cancer pathogenesis acting through prostaglandin-dependent and independent mechanisms. Epidemiological studies suggest that NSAIDs confer a moderate degree of benefit against breast cancer. However further work is required to establish how this enzyme system can be best manipulated for therapeutic benefit. PMID- 17624588 TI - Progressive resistance training in breast cancer: a systematic review of clinical trials. AB - BACKGROUND: Progressive resistance training (PRT) may be effective for targeting the sequelae of breast cancer and its treatment given the unique anabolic nature of this exercise modality. Therefore, our objectives were: (1) to systematically review studies that have prescribed PRT after breast cancer surgery, (2) to summarize the efficacy of PRT in this cohort, and (3) to delineate areas for future investigations. METHOD: A systematic review using computerized databases was performed. RESULTS: The systematic review located 10 trials: Four uncontrolled trials, one controlled trial and five randomized controlled trials (RCTs). PRT was prescribed with aerobic training in 8/10 trials reviewed, and in isolation in 2/10 trials reviewed. Upper body PRT was prescribed in 7/10 trials, including 4/5 RCTs. No exacerbation of objectively measured or subjectively reported lymphedema symptoms was reported in any of these trials. Adverse events were rare, generally musculoskeletal in nature, and were managed effectively by conservative means. Overall, the studies we reviewed suggest that women surgically treated for breast cancer can derive health-related and clinical benefits by performing PRT after breast cancer surgery. Further research may be required to stimulate greater advocacy for PRT among oncologists, and in community care settings. CONCLUSIONS: Robustly designed RCTs prescribing targeted PRT regimens throughout various phases of breast cancer treatment are warranted. RCTs with thorough, standardized reporting of interventions and adverse events are required to establish the efficacy of this intervention for the post treatment management of breast cancer patients and survivors as a means to improve health status and quality of life. PMID- 17624589 TI - Glutathione S-transferase M1 and P1 polymorphisms and risk of breast cancer and fibrocystic breast conditions in Chinese women. AB - Enzymes encoded by the glutathione S-tranferase mu 1 (GSTM1) and pi 1 (GSTP1) genes, which are expressed in breast tissue, catalyze the detoxification of endogenous and exogenous electrophiles. Reduced enzyme activity, due to carriage of the GSTM1 deletion or the GSTP1 Ile105Val Val allele, may therefore affect susceptibility to breast cancer and related conditions. In a case-control study of Chinese women, we examined whether these polymorphisms were associated with risk of breast cancer and fibrocystic breast conditions. Women diagnosed with breast cancer (n=615) or fibrocystic breast conditions (n=467) were compared to women without clinical breast disease (n=878). We also examined whether these associations differed by menopausal status or by presence of proliferation in the extra-tumoral epithelium among women with breast cancer and in lesions among women with fibrocystic conditions. No overall association of either GST polymorphism with risk of breast cancer or fibrocystic breast conditions was observed. There was some evidence of slightly elevated cancer risk associated with carriage of the GSTM1 null genotype and at least one GSTP1 105-Val allele (OR=1.33, 95% CI, 0.99-1.80), compared to carriage of the GSTM1 non-null and GSTP1 Ile/Ile genotypes. This relationship was stronger in women who had breast cancer with extra-tumoral tissue proliferation (OR=1.77, 95% CI, 1.03-3.04). Our results suggest that GSTM1 and GSTP1 genotypes do not individually influence susceptibility to breast cancer or fibrocystic breast conditions. The observed increased risk of breast cancer associated with joint carriage of the GSTM1 null genotype and GSTP1 105-Val allele needs confirmation in other studies. PMID- 17624590 TI - No evidence of human papillomavirus DNA sequences in invasive breast carcinoma. AB - Breast cancer is one of the most frequently diagnosed cancers in women in France, but its aetiology remains unknown. Viruses including Epstein-Barr virus (EBV), a human equivalent of murine mammary tumour virus (MMTV) and human papillomavirus (HPV) have been detected in benign breast tissues and breast tumours and are considered to be involved in the aetiology of breast cancer. The aim of this study was to determine the prevalence of high-risk oncogenic HPVs in breast carcinoma from French patients. Fifty unselected DNA samples extracted from invasive breast carcinoma tissues were analysed. Polymerase chain reaction (PCR) was performed to amplify both consensus GP5+/GP6+HPV sequences and specific sequences for HPV types 16, 18, 33, 45 and 6-11. No HPV-DNA sequences were detected in our series of 50 samples. These data argue against the role of oncogenic HPV in the pathogenesis of breast cancer. PMID- 17624591 TI - Genetic variation of TP53, polycyclic aromatic hydrocarbon-related exposures, and breast cancer risk among women on Long Island, New York. AB - BACKGROUND: p53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function. OBJECTIVES: We evaluated whether three well characterized TP53 variants -- Ex4 + 119 C > G (rs#1042522, Arg72Pro), IVS6 + 62 A > G (rs#1625895), and an IVS3 16 bp insertion/ deletion (INDEL; rs#17878362) -- were associated with breast cancer risk in a population-based case-control study. METHODS: Genotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls. RESULTS: For the Ex4 + 19 C > G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH-DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6 + 62 A > G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (OR = 0.49, 95% CI 0.27-0.90; OR = 0.42, 95% CI 0.22-0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk. CONCLUSIONS: These results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53. PMID- 17624592 TI - Prevention of TGF-beta-induced apoptosis by interlukin-4 through Akt activation and p70S6K survival signaling pathways. AB - In this study, we demonstrate that interleukin-4 (IL-4) protects human hepatocellular carcinoma (HCC) cell line Hep3B from apoptosis induced by transforming growth factor-beta (TGF-beta). Further investigation of IL-4 transduced signaling pathways revealed that both insulin response substrate 1 and 2 (IRS-1/-2) and extracellular signal-regulated kinase (ERK) pathways were activated after IL-4 stimulation. The IRS-1/-2 activation was accompanied by the activation of phosphotidylinositol-3-kinase (PI3K), leading to Akt and p70 ribosomal protein S6 kinase (p70S6K). Interestingly, a protein kinase C (PKC) inhibitor, Go6976, inhibited the phosphorylation of Akt, suggesting that the Akt activation was PKC-dependent. Using specific inhibitors for PI3K or ERK, we demonstrated that the PI3K pathway, but not the ERK pathway, was required for protection. The constitutively active form of PI3K almost completely rescued TGF beta-induced apoptosis, further supporting the importance of the PI3K pathway in the protective effect of IL-4. Furthermore, a dominant negative Akt and/or Go6976 only partially blocked the anti-apoptotic effect of IL-4. Similarly, rapamycin, which interrupted the activation of p70S6K, also only partially blocked the protective effect of IL-4. However, in the presence of both rapamycin and dominant negative Akt with or without Go6976, IL-4 almost completely lost the anti-apoptotic effect, suggesting that both Akt and p70S6K pathways were required for the protective effect of IL-4 against TGF-beta-induced apoptosis. PMID- 17624593 TI - Staurosporine-induced cell death in salmonid cells: the role of apoptotic volume decrease, ion fluxes and MAP kinase signaling. AB - Apoptotic cell death in mammalian models is frequently associated with cell shrinkage. Inhibition of apoptotic volume decrease (AVD) is cytoprotective, suggesting that cell shrinkage is an important early event in apoptosis. In salmonid hepatoma and gill cells staurosporine induced apoptosis, as assessed by activation of effector caspases, nuclear condensation, and a decrease of mitochondrial membrane potential (MMP), and these changes were accompanied by cell shrinkage. The Cl- transport inhibitor DIDS and the K+ channel inhibitor quinidine prevented AVD, but only DIDS inhibited apoptosis. Other Cl- flux inhibitors, as well as a pan-caspase inhibitor, did not prevent cell shrinkage, but still prevented caspase activation. Furthermore, regulatory volume decrease (RVD) under hypotonic conditions was not facilitated, but diminished in apoptotic cells. Since all transport inhibitors used blocked RVD, but only DIDS and quinidine inhibited AVD, the ion transporters involved in both processes are apparently not identical. In addition, our data indicate that inhibition of Cl- fluxes rather than blocking cell shrinkage or K+ fluxes is important for preventing apoptosis. In line with this, inhibition of MAP kinases reduced RVD and not AVD, but still diminished caspase activation. Finally, we observed that MAP kinases were activated upon staurosporine treatment and that at least activation of ERK was prevented when AVD was inhibited. PMID- 17624594 TI - Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis. AB - Plasma membrane potassium (K+) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K+ channel dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K+ channel-dependent tumor cell cycle and apoptosis. The patch clamping study using the whole-cell mode revealed two components of voltage-gated outward K+ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca2+-activated K+ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K+ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G1 phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K+ channel blocker, did not influence K+ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90alpha, hsp90beta, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G1 phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp. PMID- 17624595 TI - Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase 8 at the level of the DISC independently of death receptors in dendritic cells. AB - Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55-/- mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC. PMID- 17624597 TI - Ecosystem classification for EU habitat distribution assessment in sandy coastal environments: an application in central Italy. AB - Many recent developments in coastal science have gone against the demands of European Union legislation. Coastal dune systems which cover small areas of the earth can host a high level of biodiversity. However, human pressure on coastal zones around the world has increased dramatically in the last 50 years. In addition to direct habitat loss, the rapid extinction of many species that are unique to these systems can be attributed to landscape deterioration through the lack of appropriate management. In this paper, we propose to use of an ecosystem classification technique that integrates potential natural vegetation distribution as a reference framework for coastal dune EU Habitats (92/43) distribution analysis and assessment. As an example, the present study analyses the EU Habitats distribution within a hierarchical ecosystem classification of the coastal dune systems of central Italy. In total, 24 land elements belonging to 8 land units, 5 land facets, 2 land systems and 2 land regions were identified for the coastal dunes of central Italy, based on diagnostic land attributes. In central Italy, coastal dune environments including all the beach area, mobile dunes and all the fixed-dune land elements contain or could potentially hold at least one EU habitat of interest. Almost all dune slack transitions present the potentiality for the spontaneous development of EU woodlands of interest. The precise information concerning these ecosystems distribution and ecological relationships that this method produces, makes it very effective in Natura 2000 European network assessment. This hierarchical ecosystem classification method facilitates the identification of areas to be surveyed and eventually bound, under the implementation of EU Habitat directive (92/43) including areas with highly disturbed coastal dune ecosystems. PMID- 17624596 TI - Genetic insights into human isolated gonadotropin deficiency. AB - The identification of naturally occurring genetic mutations has provided unique insight into the current knowledge of the human hypothalamic-pituitary-gonadal axis. In the past decade, several monogenic causes have been reported in patients with isolated gonadotropin deficiency. Kallmann Syndrome is a clinically and genetically heterogeneous disorder, characterized by isolated hypogonadotropic hypogonadism and anosmia or hyposmia. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. More recently, several heterozygous, homozygous or compound heterozygous mutations in the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2) were described in Kallmann syndrome. In addition, complex genetic transmission (digenic inheritance) was recently demonstrated in this condition. Regarding isolated hypogonadotropic hypogonadism without olfactory abnormalities, loss-of-function mutations in the Gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) or the G protein coupled receptor 54 (GPR54) genes, both encoding transmembrane receptors, have been described, as well as FGFR1 mutations. Finally, mutations of the beta sub-units of LH and FSH have been described in patients with selective gonadotropin deficiency. We review the role of these distinct genetic factors in human isolated hypogonadotropic hypogonadism. PMID- 17624598 TI - Restoration of fly ash dump through biological interventions. AB - Field experiment on 10 ha area of fly ash dump was conducted to restore and revegetate it using biological interventions, which involves use of organic amendment, selection of suitable plant species along with specialized nitrogen fixing strains of biofertilizer. The results of the study indicated that amendment with farm yard manure at 50 t/ha improved the physical properties of fly ash such as maximum water holding capacity from 40.0 to 62.42% while porosity improved from 56.78 to 58.45%. The nitrogen content was increased by 4.5 times due to addition of nitrogen fixing strains of Bradyrhizobium and Azotobacter species, while phosphate content was increased by 10.0 times due to addition of VAM, which helps in phosphate immobilization. Due to biofertilizer inoculation different microbial groups such as Rhizobium, Azotobacter and VAM spores, which were practically absent in fly ash improved to 7.1 x 10(7), 9.2 x 10(7) CFU/g and 35 VAM spores/10 g of fly ash, respectively. Inoculation of biofertilizer and application of FYM helped in reducing the toxicity of heavy metals such as cadmium, copper, nickel and lead which were reduced by 25, 46, 48 and 47%, respectively, due to the increased organic matter content in the fly ash which complexes the heavy metals thereby decreasing the toxicity of metals. Amendment of fly ash with FYM and biofertilizer helped in profuse root development showing 15 times higher growth in Dendrocalamus strictus plant as compared to the control. Thus amendment and biofertilizer application provided better supportive material for anchorage and growth of the plant. PMID- 17624599 TI - Student experiences of problem-based learning in pharmacy: conceptions of learning, approaches to learning and the integration of face-to-face and on-line activities. AB - This study investigates fourth-year pharmacy students' experiences of problem based learning (PBL). It adopts a phenomenographic approach to the evaluation of problem-based learning, to shed light on the ways in which different groups of students conceive of, and approach, PBL. The study focuses on the way students approach solving problem scenarios in class, and using professional pharmacy databases on-line. Qualitative variations in student approaches to solving problem scenarios in both learning situations are identified. These turn out to be associated with qualitatively different conceptions of PBL and also with levels of achievement. Conceptions and approaches that emphasis learning for understanding correlate with attaining higher course marks. The outcomes of the study reinforce arguments that we need to know more about how students interpret the requirements of study in a PBL context if we are to unravel the complex web of influences upon study activities, academic achievement and longer-term professional competence. Such knowledge is crucial to any theoretical model of PBL and has direct practical implications for the design of learning tasks and the induction of students into a PBL environment. PMID- 17624600 TI - Roles and responsibilities of a medical geneticist. AB - Medical geneticists must generate a differential diagnosis, practice evidence based medicine, and apply ethical, legal, and social issue (ELSI) principles in the clinical setting. Several clinical scenarios are presented which illustrate dilemmas in the cancer genetics setting. These include the differential diagnosis of breast and gastric cancer, and the predicament posed by the need to practice evidence-based medicine in light of limitations in the medical genetics literature, which may mean recommending prophylactic surgery. Also discussed are three BRCA1/2 genetic testing scenarios which illustrate the difficulty of knowing where to "draw the line", i.e., when to offer testing and what level of testing to pursue. Decision-making about BRCA1/2 gene testing including Ashkenazi Jewish founder mutation testing, comprehensive reflex testing, and expedited testing, is explored. The duty to recontact as standard of care evolves requires that medical geneticists determine how to prospectively set expectations with patients as well as to decide which situations require recontact and to determine how to systematically do so. The case of patient recontact regarding new mutation detection techniques with improved sensitivity, e.g., BART testing which is based on the ability to detect large BRCA1/2 rearrangements, is discussed. General principles are highlighted so that these specific cases can be extrapolated to other genes and hereditary conditions by medical geneticists, genetic counselors, and others practicing in the field of cancer genetics. PMID- 17624601 TI - Hereditary breast cancer: pathobiology, clinical translation, and potential for targeted cancer therapeutics. AB - BRCA1 and BRCA2 breast cancers have distinct biological features as evidenced by histopathologic, immunohistochemical, gene expression profiling, and array comparative genomic hybridization data. BRCA1 breast cancers may have a worse prognosis but may, however be amenable to treatment such as chemotherapy for small high-grade, lymph node negative breast cancers. Paradoxically, tamoxifen may provide effective adjuvant and chemopreventive therapy despite the predominantly negative estrogen receptor status of BRCA1 breast cancers. The distinctive biology of BRCA1 and BRCA2 breast cancers bodes well for the development of targeted cancer therapies. Cells with BRCA1 or BRCA2 loss of function are deficient in DNA double strand break repair and are sensitized to poly(ADP-ribose) polymerase (PARP) inhibitors, causing the persistence of DNA lesions which are usually repaired by homologous recombination and ultimately leading to apoptosis. The potentially high efficacy and low toxicity of poly(ADP ribose) polymerase inhibitors presents an opportunity for targeted cancer therapeutics for BRCA1 and BRCA2 germline mutation carriers. Genotype-tailored chemoprevention may be feasible which could theoretically eliminate single cells that have sustained a second hit, before cancer progression takes place. If targeted cancer therapies emerge, it will become crucially important to identify BRCA carriers at the time of diagnosis for optimal therapy and to identify unaffected carriers for chemoprevention. If so, then to the extent that barriers in the recognition and referral of patients to genetic counseling cannot be surmounted, pathological and genomic methods to identify a BRCA1 or BRCA2 breast cancer profile will gain increasing clinical importance. PMID- 17624602 TI - BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. AB - PURPOSE: From epidemiological studies it appears that breast cancer (BC) and cutaneous melanoma (CMM) in the same individual occur at a higher frequency than expected by chance. Genetic factors common to both cancers can be suspected. Our goal was to estimate the involvement of "high risk" genes in patients presenting these two neoplasia, selected irrespectively from family history and age at diagnosis. EXPERIMENTAL DESIGN: Eighty two patients with BC and CMM were screened for BRCA1, BRCA2, TP53, CDKN2A and CDK4 (exon 2) germline mutations. RESULTS: Deleterious mutations were identified in 6 patients: two carriers of a BRCA1 germline mutation, two carriers of TP53 germline mutations (one of which also harbored a BRCA2 deleterious mutation, the other one a BRCA2 unclassified variant), and two carriers of a CDKN2A germline mutation. In addition, 6 variants of unknown signification were identified in BRCA1 or BRCA2 genes. Regarding family history, 3/13 (23%) patients with a positive family history of BC or CMM were carriers of a germline mutation, whereas only 3/69 (4%) patients without family history were carriers of a germline mutation. CONCLUSION: Our findings show that few patients with BC and CMM who lacked family histories of these cancers are carriers of deleterious germline mutations in four of the five genes we examined. We describe for the first time, two simultaneous BRCA2 and TP53 mutations, suggesting that analysis in more than one gene could be performed if a patient's personal or familial history does not match a single syndrome. PMID- 17624603 TI - Knock down of gfp and no tail expression in zebrafish embryo by in vivo transcribed short hairpin RNA with T7 plasmid system. AB - A short-hairpin RNA (shRNA) expression system, based on T7 RNA polymerase (T7RP) directed transcription machinery, has been developed and used to generate a knock down effect in zebrafish embryos by targeting green fluorescent protein (gfp) and no tail (ntl) mRNA. The vector pCMVT7R harboring T7RP driven by CMV promoter was introduced into zebrafish embryos and the germline transmitted transgenic individuals were screened out for subsequent RNAi application. The shRNA transcription vectors pT7shRNA were constructed and validated by in vivo transcription assay. When pT7shGFP vector was injected into the transgenic embryos stably expressing T7RP, gfp relative expression level showed a decrease of 68% by analysis of fluorescence real time RT-PCR. As a control, injection of chemical synthesized siRNA resulted in expression level of 40% lower than the control when the injection dose was as high as 2 microg/microl. More importantly, injection of pT7shNTL vector in zebrafish embryos expressing T7RP led to partial absence of endogenous ntl transcripts in 30% of the injected embryos when detected by whole mount in situ hybridization. Herein, the T7 transcription system could be used to drive the expression of shRNA in zebrafish embryos and result in gene knock down effect, suggesting a potential role for its application in RNAi studies in zebrafish embryos. PMID- 17624604 TI - Transitions between irregular and rhythmic firing patterns in excitatory inhibitory neuronal networks. AB - Changes in firing patterns are an important hallmark of the functional status of neuronal networks. We apply dynamical systems methods to understand transitions between irregular and rhythmic firing in an excitatory-inhibitory neuronal network model. Using the geometric theory of singular perturbations, we systematically reduce the full model to a simpler set of equations, one that can be studied analytically. The analytic tools are used to understand how an excitatory-inhibitory network with a fixed architecture can generate both activity patterns for possibly different values of the intrinsic and synaptic parameters. These results are applied to a recently developed model for the subthalamopallidal network of the basal ganglia. The results suggest that an increase in correlated activity, corresponding to a pathological state, may be due to an increased level of inhibition from the striatum to the inhibitory GPe cells along with an increased ability of the excitatory STN neurons to generate rebound bursts. PMID- 17624606 TI - Effectiveness of a self-administered, home-based exercise rehabilitation program for women following a modified radical mastectomy and axillary node dissection: a preliminary study. AB - OBJECTIVE: This pilot study examined the effects of a self-administered, home based exercise (HBE) rehabilitation programme designed to help women regain shoulder mobility immediately following surgery for a modified radical mastectomy and axillary node dissection. METHODS: Twenty-seven women who were scheduled for surgery were randomly assigned to either a post-surgical experimental HBE rehabilitation group (n = 16) or a usual care group (UC; n = 11). Women assigned to the HBE group followed an 11 day (days 3-14 post-surgery), home-based rehabilitation programme consisting of shoulder flexibility and stretching exercises that were described on videotape. The videotape programme was modelled after the exercises and guidelines described in a brochure produced by the Canadian Cancer Society. RESULTS: As a result of the exercise programme intervention, there was a time x group interaction indicating that the HBE group demonstrated a significantly greater increase in shoulder flexion range of motion (ROM) (p = 0.003) and abduction ROM (p = 0.036) when compared to the UC. There were no statistical differences in shoulder strength between groups over time. External rotation (p = 0.036) and grip strength (p = 0.001) significantly increased in both groups during the intervention period but there were no interaction effects. With respect to the forearm circumferences, there was a significant decrease over time (p < 0.001) but no interaction between groups. CONCLUSION: This HBE rehabilitation programme is an effective way to improve shoulder mobility and ROM during the immediate 2-week recovery period following surgery. PMID- 17624605 TI - Mismatch negativity in children with autism and typical development. AB - Children with autism are often characterized as having abnormalities in auditory processing. This study examined automatic and active processing of simple auditory stimuli in children using a component of event related potentials, the mismatch negativity (MMN). Amplitude of MMN in children with autism was significantly smaller than in children with typical development in unattended conditions. However, children with autism exhibited a typical amplitude MMN when attending to the stimuli. Receptive language and MMN were not related in children with autism. Findings support the idea of abnormal automatic auditory processing by children with autism. Auditory discrimination of infrequent changes in streams of sounds appears to be accomplished through a different mechanism than in typical children, specifically through the investment of attention. PMID- 17624607 TI - Vitamin D intake may be a predictor of response to aromatase inhibitors in postmenopausal women with hormone receptor positive breast cancer. PMID- 17624608 TI - Assessment of clinical response after two cycles of primary chemotherapy in breast cancer. AB - BACKGROUND: Complete clinical (cCR) and pathological (pCR) response to neoadjuvant chemotherapy in breast cancer is associated with improved survival. Various imaging and immunological techniques have been tested as predictors of response early in the course of chemotherapy, but their predictive value has not been compared with that of a simple early clinical assessment. PATIENTS AND METHODS: Two hundred breast cancer patients (T2-4, N0-1) were treated with neoadjuvant chemotherapy. Clinical response after two cycles of treatment was compared with final clinical and pathological response. The likelihood of achieving cCR or pCR was compared by response after two cycles. RESULTS: Overall final clinical response rate was 79% (30.5% cCR and 11.9% pCR). After two cycles of chemotherapy, clinical response rate was 54.5%. For responders after two cycles, final cCR = 51.3% and pCR = 21.5%. For non-responders after two cycles, cCR = 5.5% and pCR = 1.2%. Response after two cycles predicts for pCR (P = 0.003; sensitivity 95.2%, specificity 52.9%). CONCLUSIONS: Clinical response after two cycles of chemotherapy predicts for pCR and is a valid early endpoint that could be incorporated into the design of future neoadjuvant trials. PMID- 17624610 TI - Lexical association and false memory for words in two cultures. AB - This study examined the relationship between language experience and false memory produced by the DRM paradigm. The word lists used in Stadler, et al. (Memory & Cognition, 27, 494-500, 1999) were first translated into Chinese. False recall and false recognition for critical non-presented targets were then tested on a group of Chinese users. The average co-occurrence rate of the list word and the critical word was calculated based on two large Chinese corpuses. List-level analyses revealed that the correlation between the American and Taiwanese participants was significant only in false recognition. More importantly, the co occurrence rate was significantly correlated with false recall and recognition of Taiwanese participants, and not of American participants. In addition, the backward association strength based on Nelson et al. (The University of South Florida word association, rhyme and word fragment norms, 1999) was significantly correlated with false recall of American participants and not of Taiwanese participants. Results are discussed in terms of the relationship between language experiences and lexical association in creating false memory for word lists. PMID- 17624609 TI - Binding kinetics of influenza viruses to sialic acid-containing carbohydrates. AB - To elucidate the molecular mechanisms of transmission of influenza viruses between different host species, such as human and birds, binding properties of sialic acid-containing carbohydrates that are recognized by human and/or avian influenza viruses were characterized by the surface plasmon resonance (SPR) method. Differences in the binding of influenza viruses to three gangliosides were monitored in real-time and correlated with receptor specificity between avian and human viruses. SPR analysis with ganglioside-containing lipid bilayers demonstrated the recognition profile of influenza viruses to not only sialic acid linkages, but also core carbohydrate structures on the basis of equilibrated rate constants. Kinetic analysis showed different binding preferences to gangliosides between avian and human strains. An avian strain bound to Neu5Acalpha2-3nLc4Cer with much slower dissociation rate than its sialyl-linkage analog, Neu5Acalpha2 6nLc4Cer, on the lipid bilayer. In contrast, a human strain bound equally to both gangliosides. An avian strain, but not a human strain, also interacted with GM3 carrying a shorter carbohydrate chain. Our findings demonstrated the remarkable distinction in the binding kinetics of sialic acid-containing carbohydrates between avian and human influenza viruses on the lipid bilayer. PMID- 17624611 TI - Identification of differentially expressed genes from contaminant and thermal exposed goldfish Carassius auratus in Gaobeidian Lake in Beijing, China. AB - Gaobeidian Lake, located in Beijing, China, derives its water mainly from the effluent of the Gaobeidian Wastewater Treatment Plant, which is moderately polluted. Additionally, as this water is used as a coolant in the nearby thermal power plant, the water of this lake has an elevated temperature. To screen differential gene expression in Gaobeidian Lake, suppressive subtractive hybridization (SSH) methodology was performed on RNA in goldfish Carassius auratus hepatic tissues from the lake, using Huairou Reservoir as reference site. A total of 768 candidate clones were selected to perform differential screening. Of these, 264 clones were differentially expressed between the two sites, 124 of which were then subjected to DNA sequencing. Consequently, 36 different genes with known functions were obtained, and some of these differential genes were further confirmed by semiquantitative RT-PCR experiments. Many genes related to detoxification, stress and immune response, and metabolism, such as glutathione S transferase (GST), cytochrome P450, family 2, subfamily b, polypeptide 10 (CYP2B10), CYP2X10, alpha-1-antitrypsin, and apolipoprotein A-I (Apo-AI), had higher expression levels in goldfish hepatic tissue from Gaobeidian Lake than those from the reference site. A set of nine genes with known functions were downregulated in Gaobeidian Lake compared to the reference site. The results provided evidence that organisms inhabiting Gaobeidian Lake were suffering a complex stress process and showing metabolism changes and disturbance of homeostasis. PMID- 17624612 TI - Simplified models to analyse time- and dose-dependent responses of populations to toxicants. AB - The basis of ecotoxicology lies currently in the dose-response of organisms to toxicants, as typically described by probit and logistic models. While recognising its merits, standard endpoints ignore the process of toxicity with time, and consequently our ability to predict direct toxic effects in environmental risk assessments is seriously curtailed. Although the response of toxicants with time has been studied before, its application in ecotoxicology remains underutilised. One reason is that no convincing mechanism has been proposed to explain the hyperbolic curves of such responses, whereas a variety of models have been used to describe them. The explanation of both time- and dose dependent responses is found ultimately in the natural variability of receptor sites among individuals of populations exposed to a toxicant inhibitor with time. The process can be explained by the kinetics of inhibition, and is appropriately described by a simple mathematical expression like the Michaelis-Menten equation, though other asymptotic models (e.g. logistic model) can also be used. The advantage of the hyperbolic model is that median effect values (e.g. LC(50) for dose- and ET(50) for time-dependent responses) enable calculation of toxicity effects at any concentration level and/or time of exposure, thus making it especially attractive for risk assessment. PMID- 17624613 TI - Inhibitory effect of polyunsaturated fatty acids on MMP-9 release from microglial cells--implications for complementary multiple sclerosis treatment. AB - We investigated whether polyunsaturated fatty acids (PUFA), which might be a useful complementary therapy among patients with multiple sclerosis (MS), are able to modulate matrix metalloproteinase (MMP) production in microglial cultures. MMPs are myelinotoxic factors. Primary cultures of rat microglia were treated with different doses of omega-3 (omega-3) PUFA or purified fish oil, containing a mixture of omega-3 and omega-6 PUFA, and simultaneously activated by exposure to lipopolysaccharide (LPS). Culture supernatants were subjected to zymography and Western blot analysis for the assessment of MMP-2 and MMP-9 levels. Increased amounts of MMP-9, but not of the constitutively expressed MMP 2, were observed in supernatants from LPS-treated microglia in comparison with non-treated control cells. The treatment with both omega-3 PUFA and fish oil dose dependently inhibited the LPS-induced production of MMP-9. Our results suggest that a low fat diet supplemented with omega-3 PUFA may become recommended for the well being of MS patients under therapy. PMID- 17624615 TI - The Hoosier Assurance Plan Instrument for Adults (HAPI-A): the psychometric properties of a level of functioning assessment instrument designed for use in a state managed care mental health program. AB - The psychometric properties of the HAPI-A were examined at intake and 90-day follow-up in consumers with mental illness (MI) or chronic addiction (CA) being served at one of 11 treatment facilities (n = 1168). A 4-factor subscale structure was confirmed and factor invariance tests indicated a single model for the CA and MI samples. Internal consistency and inter-rater reliability were good (ICCs = 0.72-0.88). Factor scores correlated with GAF ratings and predicted membership in severity/cost groupings proposed for setting reimbursement rates. Sensitivity to change was confirmed for all four factors for the CA sample and for three of four factors for the MI sample. PMID- 17624616 TI - Health coverage of low-income citizen and noncitizen wage earners: sources and disparities. AB - The health coverage of low-income workers represents an area of continuing disparities in the United States system of health insurance. Using the 2001 California Health Interview Survey, we estimate the effect of low-income wage earners' citizenship and gender on the odds of obtaining primary employment-based health insurance (EBHI), dependent EBHI, public program coverage, and coverage from any source. We find that noncitizen men and women who comprise 40% of California's low-income workforce, share the disadvantage of much lower rates of insurance coverage, compared to naturalized and U.S.-born citizens. However, poor coverage rates of noncitizen men, regardless of permanent residency status, result from the cumulative disadvantage in obtaining dependent EBHI and public insurance. If public policies designed to provide a health care safety net fail to address the health care coverage needs of low-wage noncitizens, health disparities will continue to increase in this group that contributes essentially to the U.S. economy. PMID- 17624617 TI - The impact of Project Northland on selected MMPI-A problem behavior scales. AB - Project Northland was a randomized community trial to prevent or delay alcohol use among adolescents. Students in the intervention communities were exposed to a multi-component prevention program in early adolescence and high school. This paper examines the impact of Project Northland on the trajectories of four scales of the adolescent form of the Minnesota Multiphasic Personality Inventory (MMPI A). Students in the intervention communities demonstrated lower rates of growth of family problems and alcohol/drug use proneness than students in the delayed program control communities. The results were more robust for baseline non drinkers. EDITORS' STRATEGIC IMPLICATIONS: This experimental study extends the scope of the impact of Project Northland, already recognized as a model substance abuse prevention program by the Substance Abuse and Mental Health Services Administration. The results suggest that focused prevention programs have the potential to impact young adolescents' lives more broadly. Replication and further examination of the mechanisms by which risk factors and outcomes are modified is necessary, but school administrators and public health officials could learn from this promising program and evaluation. PMID- 17624618 TI - Does structural complexity necessarily imply processing difficulty? AB - Our goal is to establish a link between the time needed to plan a sentence containing an embedded clause and the structure of this sentence. Contrary to a traditional monolithic conception of subordination, three types of embeddings were considered, depending on their degree of syntactic integration: subcategorized, modifier and pseudo-embedded clauses. We hypothesized that in the case of subcategorization, fewer pauses should occur between the matrix and the subordinate clause since the latter is required by the lexical properties of verbs. By contrast, pseudo-embedded clauses are the less integrated. Hence, they should exhibit planning characteristics similar to the ones of simple sentences, the matrix clause and the subordinate clauses being planned in two steps. Twenty texts produced by French speaking adults were recorded. Pauses were characterized according to their duration and position. Globally, both predictions were confirmed. We conclude that supposedly complex sentences are not necessarily difficult to process. PMID- 17624619 TI - A cell culturing system that integrates the cell loading function on a single platform and evaluation of the pulsatile pumping effect on cells. AB - In this paper, we present a novel microfluidic system with pulsatile cell storing, cell-delivering and cell culturing functions on a single PDMS platform. For this purpose, we have integrated two reservoirs, a pulsatile pumping system containing two soft check valves, which were fabricated by in situ photopolymerization, six switch valves, and three cell culture chambers all developed through a simple and rapid fabrication process. The sample volume delivered per stroke was 120 nl and the transported volume was linearly related to the pumping frequency. We have investigated the effect of the pulsatile pneumatic micropumping on the cells during transport. For this purpose, we pumped two types of cell suspensions, one containing human breast adenocarcinoma cells (MCF-7) and the other mesenchymal stem cells (hMSCs) derived from bone marrow. The effect of pulsatile pumping on both cell types was examined by short and long term culture experiments. Our results showed that the characteristics of both cells were maintained; they were not damaged by the pumping system. Evaluations were carried out by morphological inspection, viability assay and immunophenotyping analysis. The delivered MCF-7 cells and hMSCs spread and proliferated onto the gelatin coated cell culture chamber. This total micro cell culture system can be applied to cell-based high throughput screening and for co culture of different cells with different volume. PMID- 17624622 TI - Habitat fragmentation: panchreston or paradigm? PMID- 17624620 TI - Adult neurogenesis and cell cycle regulation in the crustacean olfactory pathway: from glial precursors to differentiated neurons. AB - Adult neurogenesis is a characteristic feature of the olfactory pathways of decapod crustaceans. In crayfish and clawed lobsters, adult-born neurons are the progeny of precursor cells with glial characteristics located in a neurogenic niche on the ventral surface of the brain. The daughters of these precursor cells migrate during S and G(2 )stages of the cell cycle along glial fibers to lateral (cluster 10) and medial (cluster 9) proliferation zones. Here, they divide (M phase) producing offspring that differentiate into olfactory interneurons. The complete lineage of cells producing neurons in these animals, therefore, is arranged along the migratory stream according to cell cycle stage. We have exploited this model to examine the influence of environmental and endogenous factors on adult neurogenesis. We find that increased levels of serotonin upregulate neuronal production, as does maintaining animals in an enriched (versus deprived) environment or augmenting their diet with omega-3 fatty acids; increased levels of nitric oxide, on the other hand, decrease the rate of neurogenesis. The features of the neurogenic niche and migratory streams, and the fact that these continue to function in vitro, provide opportunities unavailable in other organisms to explore the sequence of cellular and molecular events leading to the production of new neurons in adult brains. PMID- 17624623 TI - The impact of total body photography on biopsy rate in patients from a pigmented lesion clinic. AB - BACKGROUND: Total body cutaneous photography is increasingly being used by dermatologists to monitor patients at risk for the development of melanoma, but limited evidence exists regarding the impact of such photography on melanoma and melanoma-related outcomes. OBJECTIVE: We sought to compare biopsy number in patients with multiple atypical nevi in their first year of care at our pigmented lesion clinic (PLC) between those who received total body skin examination alone and those who received total body skin examination and total body digital photography (TBDP). We sought to identify predictors of biopsy number and number of dysplastic nevi diagnosed in patients with multiple atypical nevi. METHODS: A chart review was performed of patients attending the PLC during the years 1998 to 2003 to identify the number of biopsies performed in the first year of care. Patient demographics, melanoma risk factors, and melanoma outcome events were also abstracted from the charts. RESULTS: The mean number of biopsies performed in patients in their first year of care at the PLC in those who did not receive TBDP was equal to the mean number of biopsies performed in patients who did receive TBDP (0.82 and 0.8, respectively). Linear regression analysis revealed that the interaction term between a lack of both personal history of melanoma and severe dysplastic nevi (-0.930, P = .005) has a significant protective effect on the number of biopsies. Similar regression analysis also showed that the interaction term between a lack of both personal history of melanoma and of severe dysplastic nevi (-1.209, P < .0001), increasing provider experience ( 0.047, P = .029), and increased number of biopsies before the initial PLC ( 0.028, P = .050) have a statistically significant protective effect on the number of dysplastic nevi diagnosed in the first year of PLC. TBDP did not have an effect on the number of biopsies or on the number of dysplastic nevi diagnosed in the first year of care at the PLC. LIMITATIONS: This study is limited by being retrospective in nature, having a small sample size, and having a short follow-up period. CONCLUSION: Overall, this small retrospective study does not provide evidence that would suggest that TBDP changes provider behavior in caring for patients at high risk for melanoma. Rather, our study supports the fact that a patient's positive history of melanoma and a history of severe dysplastic nevi have the most significant impact on provider biopsy behavior, resulting in a lower threshold to biopsy suggestive lesions. PMID- 17624624 TI - Structure of the relationship between parents' and children's food preferences and avoidances: an explorative study. AB - The aims of the present research were to uncover the underlying structure of the relationship between parents' and children's preferences and avoidances in the food domain, and to determine whether this structure revealed any differences as a function of children's age. Two hundred and eighty-two parent-child dyads (children aged 10-20) completed a self-administered questionnaire on eating attitudes and practices. The results led to a descriptive model of the connection between parents' and children's food repertories, made of four overlap and four autonomy areas. This structure was then compared with the structure that emerged from random pairs of an adult and a child/adolescent. Our findings showed that parents' repertory had an anchoring function in the formation of that of their children, not only in terms of imitation, but also in terms of influencing the direction of differentiation and innovation. As far as the second aim of our study is concerned, only two out of eight areas (that of parent preferences limitation, and that of child autonomous avoidances) differed in relation to the children's age. The theoretical and practical impact of these results is discussed. PMID- 17624625 TI - Contextual influences on liking and preference. AB - The paper addresses the topic of how much an individual likes a stimulus and also how much that individual prefers it to other stimuli. Research is reviewed showing that the context in which the stimulus is presented affects both liking and preference judgments. Having subjects think of the context stimuli and the test stimuli as being in different categories reduces the impact of the context stimuli on the ratings of the test stimuli and might be used to avoid such context effects in determining liking of and preferences for stimuli. PMID- 17624626 TI - Monoamine oxidase B activity is increased in human gliomas. AB - Glial tumours are the most common type of brain neoplasm in humans. Tumour classification and grading represent key factors for patient management. However, current grading schemes are still limited by subjective histological criteria. In this context, gliosis has been linked to increases in monoamine oxidase B (MAO-B) activity. Thus, in the present study, MAO-B activity in membranes of glial tumours (n=20), meningiomas (n=12) and non-pathological human brains (n=15) was quantified by [14C]PEA oxidation. MAO-B activity was significantly greater in glioblastoma multiformes than in postmortem control brains (p<0.01) or meningiomas (p<0.001). There were no significant differences in MAO-B activity between glioblastoma multiformes (n=11) and low-grade astrocytomas (n=3) or anaplastic astrocytomas (n=6). In conclusion, the present results demonstrate a significant and selective increase in MAO-B activity in human gliomas when compared with meningiomas or non-tumoural tissue. These results suggest that the quantification of MAO-B activity may be a useful diagnostic tool for differentiating glial tumours from other types of brain tumours or surrounding normal brain tissue. PMID- 17624628 TI - Intracellular Ca2+ dynamics of hippocampal interneurons following nicotinic acetylcholine receptor activation. AB - Ca2+ permeability of central nicotinic acetylcholine receptors (nAChRs), especially the alpha7 subunits, are exceptionally high and this important feature provide a special functional importance for these receptors at the system level. Although studies at the cellular level extensively characterized the molecular properties of Ca2+ influx following nAChR activation, much less is known about the time-related Ca2+ dynamics during nicotine administration in integration units of neurons. Such studies are of particular relevance to understanding in situ nonsynaptic actions of nicotine. Puff ejection of drugs produce a rapid drug delivery and elimination from the cell surface allowing the activation of extrasynaptic receptors within desensitization time-frame. In this report we provide evidence that rapid nicotine application is able to produce irregular Ca2+ transients in the dendrites of stratum radiatum interneurons in the hippocampal CA1 region. Potential components and mechanisms of nAChR-mediated Ca2+ influx are discussed in details to demonstrate the unique feature of activation of nAChRs involved in nonsynaptic function in interneurons as compared to other types of nicotinic activity. PMID- 17624629 TI - Association study of the paraoxonase 1 gene with the risk of developing Alzheimer's disease. AB - Recently, a region encompassing the promoter and intron 1 of the paraoxonase 1 gene (PON1) have been associated with the risk of developing Alzheimer's disease (AD) in a large pan-ethnic (Caucasian and African-American) dataset. We attempted to replicate this observation in a large French study of sporadic cases and controls. We confirmed that the proximal promoter and 5' sequence of the PON1 gene may harbor unknown functional variant(s) associated with the risk of developing AD. PMID- 17624627 TI - Mass spectrometric assay and physiological-pharmacological activity of androgenic neurosteroids. AB - Steroid hormones play a key role in the pathophysiology of several brain disorders. Testosterone modulates neuronal excitability, but the underlying mechanisms are obscure. There is emerging evidence that testosterone-derived "androgenic neurosteroids", 3alpha-androstanediol and 17beta-estradiol, mediate the testosterone effects on neural excitability and seizure susceptibility. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17beta-estradiol. Reduction of testosterone by 5alpha-reductase generates 5alpha dihydrotestosterone, which is then converted to 3alpha-androstanediol, a powerful GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Although the 3alpha-androstanediol is an emerging neurosteroid in the brain, there is no specific and sensitive assay for determination of 3alpha-androstanediol in biological samples. This article describes the development and validation of mass spectrometric assay of 3alpha-androstanediol, and the molecular mechanisms underlying the testosterone modulation of seizure susceptibility. A liquid chromatography-tandem mass spectrometry assay to measure 3alpha-androstanediol is validated with excellent linearity, specificity, sensitivity, and reproducibility. Testosterone modulation of seizure susceptibility is demonstrated to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. The proconvulsant effect of testosterone is associated with increases in plasma 17beta-estradiol concentrations. The 5alpha reduced metabolites of testosterone, 5alpha-dihydrotestosterone and 3alpha androstanediol, had powerful anticonvulsant activity. Overall, the testosterone derived neurosteroids 3alpha-androstanediol and 17beta-estradiol could contribute to the net cellular actions of testosterone in the brain. Because 3alpha androstanediol is a potent positive allosteric modulator of GABA(A) receptors, it could serve as an endogenous neuromodulator of neuronal excitability in men. The 3alpha-androstanediol assay is an important tool in this area because of the growing interest in the potential to use adjuvant aromatase inhibitor therapy to improve treatment of epilepsy. PMID- 17624630 TI - Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age. AB - Regions of diffuse periventricular white matter hyperintensities (PVWMH) are a common finding on T(2)-weighted MRI scans of older subjects, but their aetiology remains unclear. The aim of this study was to characterize differences in water diffusion and magnetization transfer MRI parameters between macroscopically normal-appearing white matter (NAWM) and PVWMH in a cohort of normal older subjects. Forty-two non-demented 83-year olds underwent structural, diffusion tensor and magnetization transfer MRI. Mean diffusivity (), fractional anisotropy (FA), axial (lambda(ax)) and radial (lambda(rad)) diffusivity, and magnetization transfer ratio (MTR) were measured in both NAWM and PVWMH in frontal and parieto-occipital white matter, and centrum semiovale. For all three regions, PVWMH had greater , lambda(ax) and lambda(rad) than NAWM, while FA and MTR were significantly reduced compared with normal tissue (p<<0.01). For PVWMH, MTR was significantly correlated (Spearman's rho in the range -0.93 to 0.70; p<0.01) with , FA, lambda(ax) and lambda(rad) in all three regions. Conversely, for NAWM, the only significant correlation between MTR and a water diffusion parameter was for lambda(rad) in parieto-occipital white matter (rho= 0.40; p<0.05), with all other correlations close to the rho=0 level. These data indicate that in normal white matter, characterized by structurally coherent cell membranes, the degree of water molecule diffusion and myelination are held within relatively tight limits. However, within PVWMH, MTR correlates strongly with water diffusion parameters probably because of the pathologically associated neuronal loss, demyelination and gliosis. PMID- 17624631 TI - Chemiluminescent high-throughput microassay applied to imidazo[2,1-b]thiazole derivatives as potential acetylcholinesterase and butyrylcholinesterase inhibitors. AB - The synthesis of a new series of imidazo[2,1-b]thiazole derivatives is described. They were tested as potential acetylcholinesterase and butyrylcholinesterase inhibitors by means of a chemiluminescent microassay. Although most of the new compounds did not show significant cholinesterase inhibition potency, three of them displayed selective antiacetylcholinesterase activity in the micromolar range. PMID- 17624632 TI - Synthesis and anticonvulsant activity of some novel 3-aryl amino/amino-4-aryl-5 imino-Delta2-1,2,4-thiadiazoline. AB - A series of 3-aryl amino/amino-4-aryl-5-imino-Delta(2)-1,2,4-thiadiazoline have been synthesized using an appropriate synthetic route and characterized by elemental analyses and spectral data. The anticonvulsant activity of all the synthesized compounds was evaluated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (ScPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. All the test compounds were administered at doses of 30, 100, and 300 mg/kg body weight and the anticonvulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. Some of the compounds were evaluated for the Phenobarbitone induced hypnosis potentiation test. Among the compounds tested, all except 2h showed protection from MES seizures, whereas only 3b was found to be active in the ScPTZ test. PMID- 17624633 TI - Bioactivity of novel transition metal complexes of N'-[(4 methoxy)thiobenzoyl]benzoic acid hydrazide. AB - Cu(II), Fe(III), and Mn(II) complexes of a novel ligand N'-[(4 methoxy)thiobenzoyl]benzoic acid hydrazide (H(2)mtbh) have been synthesized and characterized by elemental analyses, IR, UV-vis, NMR, mass, EPR and Mossbauer spectroscopy. The results suggest a square planar structure for [Cu(Hmtbh)Cl] and [Cu(mtbh)] whereas an octahedral structure for [Mn(Hmtbh)(2)] and [Fe(Hmtbh)(mtbh)]. Mn(II) and Fe(III) complexes were found to inhibit proliferation of HT29 cells. [Mn(Hmtbh)(2)] and [Fe(Hmtbh)(mtbh)] inhibited proliferation of HT29 cells with half maximal inhibition (IC(50)) of 8.15+/-0.87 and 68.1+/-4.8 microM, respectively, whereas H(2)mtbh showed growth inhibition with IC(50) of 90.9+/-7.8 microM and were able to inhibit NMT activity in vitro. Mn(II) and Fe(III) complexes inhibited NMT activity in a dose dependent manner with IC(50) values of 20+/-2.2 and 60+/-7.2 microM, respectively, whereas ligand (H(2)mtbh) displayed IC(50) of 3.2+/-0.5 mM. PMID- 17624634 TI - Antibacterial activity of a novel series of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro 1H-2,5-pyrroledione derivatives--an extended structure-activity relationship study. AB - Compounds containing 3-bromo-2,5-dihydro-1H-2,5-pyrroledione and indole substructures were found to have antibacterial activity against resistant strains of Staphylococcus aureus and some other Gram positive bacteria. The investigated compounds exhibit minimal inhibition concentrations (MICs) lower than those of common antibiotics like vancomycin or ciprofloxacin. Activity against multiresistant strains suggests a mechanism of action different from common antibiotics. This might be important in circumventing existing resistance mechanisms. Here we report about the antibacterial activity in an extended structure-activity relationship study. PMID- 17624635 TI - Synthesis, crystal structure and antimicrobial activity of deoxybenzoin derivatives from genistein. AB - A series of deoxybenzoin derivatives from genistein were synthesized and their structures were elucidated by (1)H NMR, mass spectral data and micro analyses. The structures of 2, 7 and 10 were determined by single-crystal X-ray analysis. These obtained compounds were evaluated for their assayed antibacterial (Bacillus subtilis, Escherichia coli, Pseudomonas fluorescence and Staphylococcus aureus) and antifungal (Aspergillus niger, Candida albicans and Trichophyton rubrum) activities by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) method. Most compounds have displayed comparable antibacterial activity against bacterial. On the basis of the biological results, structure-activity relationships are discussed. PMID- 17624636 TI - [Role of pharmacogenetics in chemotherapy of colorectal cancers]. AB - SCOPE: Clinical implications associated with polymorphisms in drug-metabolizing genes involved in the chemotherapy of colorectal cancers (5-flurorouracil, oxaliplatin and irinotecan) are reviewed. CURRENT SITUATION AND SALIENT POINTS: Treatments of colorectal cancers have been greatly improved last years but patients respond differently to identical medication. Genetic polymorphisms are one of the major causes of these individual responses to drugs associated with sometimes severe adverse effects. Pharmacogenetics is based on all polymorphisms that determine genetic human diversity associated with variable response to anticancer drugs. PERSPECTIVES: Morbidity and mortality related to toxicity or inefficacy of these drugs could be reduced by analyzing the pharmacogenetic profile of patients before treatment. Results should be integrated in protocols for monitoring and assessment the dosage of drugs. PMID- 17624637 TI - [Liver involvement in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). Report of one case and review of the literature]. AB - INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia; mutations in at least three genes (ENG, ACVRL1 et MADH4), which are components of transforming growth factor (TGF)-beta, may lead to the clinical picture of HHT. HHT is a multisystemic angiodysplasia, resulting in multiple vascular malformations, involving notably the liver. EXEGESIS: We report the case of a patient with anicteric cholestasis, revealing HHT. Abdominal CT-scan revealed hepatic artery dilation and multiple arteriovenous fistula. At 2 year follow-up, the patient exhibited liver involvement-associated high output cardiac insufficiency. CONCLUSION: Liver involvement is frequent in HHT, occurring in 8-31% of patients; it may lead to life-threatening complications, such as high output cardiac failure, portal hypertension or severe cholangitis. Abdominal Doppler ultrasonography is a non-invasive accurate method, suitable for first-line imaging of the liver in patients with HHT; it should be done in all patients, in order to detect HHT-related hepatic vascular malformations. PMID- 17624638 TI - [Hyponatremia due to tramadol]. AB - We reported a 92-year-old woman with hyponatremia (117 mmol/l) occurring three days after the introduction of tramadol. Diagnosis of inappropriate antidiuretic hormone secretion was based on blood and urinary analysis and dosage of antidiuretic hormone. Natremia became normal after tramadol cessation and fluid restriction. Natremia must be measured when neurological abnormality occurs with tramadol treatment. PMID- 17624639 TI - [Activity tarification and national guidelines for the proper use of expensive and innovative drugs in internal medicine]. PMID- 17624640 TI - [Temporal artery biopsy may remain positive even after long-term corticosteroid treatment: report of two cases]. AB - INTRODUCTION: Temporal arteritis is the most common systemic vasculitis of the elderly. It is diagnosed with the combination of a clinico-biological syndrome and typical histologic features recognized on temporal artery biopsy (TAB). Cortisteroid therapy is quickly recommended, before the TAB is performed or before the histologic results confirm the diagnosis. It is recommended to perform TAB as soon as possible after the treatment has begun in order to avoid a presumed improvement or normalisation of the histological features. EXEGESIS: We report the cases of two patients, a 76-year-old woman and a 78-year-old man who had persistent clinical and histological features of temporal arteritis 5 years and one year respectively after corticosteroid therapy was initiated. CONCLUSION: Histological changes in the temporal artery biopsy may persist for as long as five years in a patient receiving a corticosteroid treatment for temporal arteritis. Even when largely delayed after the beginning of the treatment, temporal artery biopsy may prove to be important in diagnosing persistent temporal arteritis. PMID- 17624641 TI - [Stiff person syndrome associated with thymoma. Efficacy of thymectomy]. AB - INTRODUCTION: Stiff person syndrome is a rare autoimmune neurologic disorder characterized by axial muscular rigidity and intermittent painful spasms. Three distinct forms are described: auto-immune, paraneoplastic and idiopathic. EXEGESIS: We report the case of a 51-year-old man with an history of Stiff Person Syndrome with typical clinical, electrophysiological and immunological findings. Anti-glutamic acid decarboxylase antibodies were present, as well as anti amphiphysin antibodies, commonly reported in the paraneoplastic syndrome. CT scan revealed a thymoma. Surgical resection was followed by reduction of the neurologic symptoms, without lowering the auto antibodies titer. CONCLUSIONS: The association between Stiff Person Syndrome and thymoma is exceptional. Thymectomy is an effective treatment and may act without change of the autoantibodies titer. Patients with Stiff Person Syndrome should be systematically tested for thymoma. PMID- 17624642 TI - Wicked spell or magic bullet? A review of the clinical supervision literature 2001-2007. AB - Clinical supervision has become an established part of nursing. Implemented in various different ways it has attracted attention from the research, educator and practice communities. The literature reported and analysed in this paper describes work that may benefit professional practice but there continue to be questions about application and method. Two new messages arise from the literature. The first underscores the responsibility of health care organisations to sustain and develop clinical supervision and the second points to the potential benefit that clinical supervision may have on patient outcomes. PMID- 17624643 TI - Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity. AB - BACKGROUND & AIMS: Vitamin D deficiency has been recently associated with the metabolic syndrome. However, it is not known whether this possible association of vitamin D deficiency with the metabolic syndrome is still present at very high degrees of obesity, as in morbidly obese patients. METHODS: Transversal, observational study that included 73 consecutive morbidly obese patients (body mass index 40 kg/m(2)). In every patient, anthropometric variables were recorded, fasting blood was assayed for 25-hydroxyvitamin D concentrations, lipid profiles, glucose and insulin levels, and insulin resistance was estimated by homeostasis model assessment. RESULTS: Vitamin D deficiency was present in 37 of the 73 patients (50.7%). As defined by revised Adult Treatment Panel III criteria, 46 of the 73 obese patients (63%) had the metabolic syndrome. Vitamin D deficiency was more prevalent in morbidly obese patients presenting with the metabolic syndrome, compared with those who did not achieve the criteria for this syndrome (60.9% vs. 33.3% respectively, P = 0.023). When serum concentrations of 25-hydroxyvitamin D were categorized in tertiles, there was an association of the prevalence of the metabolic syndrome with the former (P = 0.038). Serum high-density lipoprotein cholesterol concentrations were lower (37.0+/-7.8 mg/dl vs. 44.9+/-8.7 mg/dl, P = 0.003), and triglycerides levels were higher (163.3+/-81.5 mg/dl vs. 95.1+/-24.2 mg/dl, P = 0.001) in the vitamin D-deficient group. CONCLUSION: Vitamin D deficiency is associated with the metabolic syndrome in morbidly obese patients. PMID- 17624644 TI - Radionuclides from past uranium mining in rivers of Portugal. AB - During several decades and until a few years ago, uranium mines were exploited in the Centre of Portugal and wastewaters from uranium ore milling facilities were discharged into river basins. To investigate enhancement of radioactivity in freshwater ecosystems, radionuclides of uranium and thorium series were measured in water, sediments, suspended matter, and fish samples from the rivers Vouga, Dao, Tavora and Mondego. The results show that these rivers carry sediments with relatively high naturally occurring radioactivity, and display relatively high concentrations of radon dissolved in water, which is typical of a uranium rich region. Riverbed sediments show enhanced concentrations of radionuclides in the mid-section of the Mondego River, a sign of past wastewater discharges from mining and milling works at Urgeirica confirmed by the enhanced values of (238)U/(232)Th radionuclide ratios in sediments. Radionuclide concentrations in water, suspended matter and freshwater fish from that section of Mondego are also enhanced in comparison with concentrations measured in other rivers. Based on current radionuclide concentrations in fish, regular consumption of freshwater species by local populations would add 0.032 mSv a(-1) of dose equivalent (1%) to the average background radiation dose. Therefore, it is concluded that current levels of enhanced radioactivity do not pose a significant radiological risk either to aquatic fauna or to freshwater fish consumers. PMID- 17624645 TI - Exploring the effect of hospital admission on contraction patterns and labour outcomes using women's perceptions of events. AB - OBJECTIVE: this study investigated the phenomenon of spontaneous labour contractions becoming less frequent on admission to hospital, which is observed anecdotally but is not evident in the literature. Anxiety in response to hospitalisation has been proposed to be responsible by initiating the biochemical response termed 'fight or flight'. DESIGN: A non-experimental prospective design and a combination of quantitative and qualitative analysis. Data were collected using self-report labour diaries, postnatal questionnaires and hospital records of labour. Univariate analysis using t-test and chi(2)-test was performed to examine relationships between variables, and content analysis was undertaken on qualitative data regarding reactions to hospitalisation. SETTING: hospital and community maternity services provided by a National Health Service hospital in Southern England in 1997. PARTICIPANTS: about 87 women at least 37-week gestation, uncomplicated singleton pregnancy anticipating spontaneous labour with a live fetus. MEASUREMENTS AND FINDINGS: labour diaries were analysed from 26 births. In three home births and 11 hospital births, labour contractions became more frequent, but in the remaining 12 labours, contractions decreased after admission to hospital. Women whose contractions slowed were not more anxious, but they rarely had cervical dilatation over 5cm and usually assumed a recumbent position in hospital. Artificial rupture of membranes was performed more frequently in these women, they used more pain relief and had a higher incidence of complicated childbirth; however, these differences were not statistically significant. KEY CONCLUSIONS: labour contractions can increase or decrease in frequency following admission to hospital, and the change of frequency may be associated with stage of cervical dilatation and posture rather than anxiety. IMPLICATIONS FOR PRACTICE: routine intervention to speed up labour on the basis of admission observations is called into question, and women should be made aware that slowing of contractions can occur as a normal part of changing the labour environment. Further research is needed to determine the physiological parameters of spontaneous labour and the role of posture in labour progress is needed. PMID- 17624646 TI - Fluxes of inorganic and organic arsenic species in a Norway spruce forest floor. AB - To identify the role of the forest floor in arsenic (As) biogeochemistry, concentrations and fluxes of inorganic and organic As in throughfall, litterfall and forest floor percolates at different layers were investigated. Nearly 40% of total As(total) input (5.3g Asha(-1)yr(-1)) was retained in Oi layer, whereas As(total) fluxes from Oe and Oa layers exceeded the input by far (10.8 and 20g Asha(-1)yr(-1), respectively). Except dimethylarsinic acid (DMA), fluxes of organic As decreased with depth of forest floor so that <10% of total deposition (all <0.3g Asha(-1)yr(-1)) reached the mineral soil. All forest floor layers are sinks for most organic As. Conversely, Oe and Oa layers are sources of As(total), arsenite, arsenate and DMA. Significant correlations (r>/=0.43) between fluxes of As(total), arsenite, arsenate or DMA and water indicate hydrological conditions and adsorption-desorption as factors influencing their release from the forest floor. The higher net release of arsenite from Oe and Oa and of DMA from Oa layer in the growing than dormant season also suggests microbial influences on the release of arsenite and DMA. PMID- 17624648 TI - Panax ginseng effects on DNA damage, CYP1A1 expression and histopathological changes in testes of rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - The effects of Panax ginseng extracts on DNA damage, expression of cytochrome P450 (CYP) 1A1 and reproductive toxicity were evaluated in the testis of rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxinthe (TCDD). Fifty rats were divided into five groups according to treatment with 2,3,7,8-TCDD and P. ginseng extracts. Single cell gel electrophoresis assays were performed to evaluate DNA damage that occurred in the lymphocytes of rats. Histological changes in the seminiferous tubules of the testis were determined using Johnsen's scoring system and Real Time-PCR was performed to evaluate the mRNA expression of CYP1A1. Significant pathological effects were observed in the 2,3,7,8-TCDD treated rats including a reduced seminiferous tubular diameter, an increased number of damaged tubules (maturation arrest, eosinophilic degeneration and spermatid giant cells) and increased Johnsen's score. DNA damage and the expression of CYP1A1 mRNA were significantly increased in rat testes. There were no significant differences between the control and animals treated with P. ginseng extracts. However, a significantly decreased level of DNA damage, decreased CYP1A1 expression and reduced pathological effects were observed in the 2,3,7,8-TCDD with P. ginseng extracts treated groups when compared with the TCDD treated group. In summary, our study demonstrates that 2,3,7,8-TCDD induces the pathological and genotoxical damage in rat testes, while P. ginseng extract treatment exhibits a therapeutic capacity to reduce these effects via reduction of CYP1A1 mRNA. PMID- 17624649 TI - Antioxidant activities of the flaxseed lignan secoisolariciresinol diglucoside, its aglycone secoisolariciresinol and the mammalian lignans enterodiol and enterolactone in vitro. AB - The flaxseed lignan secoisolariciresinol diglucoside (SDG) and mammalian lignans enterodiol (ED) and enterolactone (EL) were previously shown to be effective antioxidants against DNA damage and lipid peroxidation. Others reported inhibition of activated cell chemiluminescence by supra-physiological concentrations of secoisolariciresinol (SECO), ED and EL. Thus, we evaluated the antioxidant efficacy of potential physiological concentrations of SDG, SECO, ED and EL against 1,1-diphenyl-2-picrylhydrazyl (DPPH()), and 2,2'-azo-bis(2 amidinopropane) dihydrochloride (AAPH)-initiated peroxyl radical plasmid DNA damage and phosphatidylcholine liposome lipid peroxidation. SDG and SECO were effective (p<0.01) antioxidants against DPPH() at 25-200muM; whereas, ED and EL were inactive. Efficacy of lignans and controls against AAPH peroxyl radical induced DNA damage was: SDG>SECO=17alpha-estradiol>ED=EL>genistein>daidzein. Lignan efficacy against AAPH-induced liposome lipid peroxidation was: SDG>SECO=ED=EL. Plant lignan antioxidant activity was attributed to the 3-methoxy 4-hydroxyl substituents of SDG and SECO, versus the meta mono-phenol structures of ED and EL. Benzylic hydrogen abstraction and potential resonance stabilization of phenoxyl radicals in an aqueous environment likely contributed to the antioxidant activity of the mammalian lignans. These represent likely extra- and intracellular antioxidant activities of flax-derived lignans at concentrations potentially achievable in vivo. PMID- 17624650 TI - Protection from inorganic mercury effects on the in vivo dopamine release by ionotropic glutamate receptor antagonists and nitric oxide synthase inhibitors. AB - The possible role of ionotropics glutamate receptors on the HgCl(2)-induced dopamine (DA) release from rat striatum was investigated by using in vivo brain microdialysis technique after administration of selective NMDA and AMPA/Kainate receptors antagonists dizocilpine (MK-801), D (-)-2-amino-5-phoshonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moreover, we have also studied the effects of nitric oxide synthase (NOS) inhibitors L-nitro arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on HgCl(2)-induced DA release. Intraestriatal infusion of 1mM HgCl(2) increased striatal DA to 1717.2+/ 375.4% respect to basal levels. Infusion of 1mM HgCl(2) in 400 microM MK-801 pre treated animals produced an increase on striatal DA levels 61% smaller than that induced in non-pre-treated animals. In the case of AP5, this treatment reduced 92% the increase produced by HgCl(2) as compared to non-pre-treated rats. Nevertheless, the administration of CNQX did not produce any effect on HgCl(2) induced dopamine release. Intrastriatal infusion of 1mM HgCl(2) in 100 microM L NAME pre-treated animals produced an increase on extracellular DA levels 82% smaller than produced by HgCl(2) alone. In addition, the pre-treatment with 7-NI reduced 90% the increase produced by infusion of HgCl(2) alone in rats. Thus, HgCl(2)-induced DA release could be produced at last in part, by overstimulation of NMDA receptors with NO production, since administration of NMDA receptor antagonists and NOS inhibitors protected against HgCl(2) effects on DA release. PMID- 17624651 TI - Effect of an acute 900MHz GSM exposure on glia in the rat brain: a time-dependent study. AB - Because of the increasing use of mobile phones, the possible risks of radio frequency electromagnetic fields adverse effects on the human brain has to be evaluated. In this work we measured GFAP expression, to evaluate glial evolution 2, 3, 6 and 10 days after a single GSM exposure (15min, brain averaged SAR=6W/kg, 900MHz signal) in the rat brain. A statistically significant increase of GFAP stained surface area was observed 2 days after exposure in the frontal cortex and the caudate putamen. A smaller statistically significant increase was noted 3 days after exposure in the same areas and in the cerebellum cortex. Our results confirm the Mausset-Bonnefont et al. study [Mausset-Bonnefont, A.L., Hirbec, H., Bonnefont, X., Privat, A., Vignon, J., de Seze, R., 2004. Acute exposure to GSM 900MHz electromagnetic fields induces glial reactivity and biochemical modifications in the rat brain. Neurobiol. Dis. 17, 445-454], showing the existence of glial reactivity after a 15min GSM acute exposure at a brain averaged SAR of 6W/kg. We conclude to a temporary effect, probably due to a hypertrophy of glial cells, with a temporal and a spatial modulation of the effect. Whether this effect could be harmful remains to be studied. PMID- 17624652 TI - Different mechanisms of modulation of gap junction communication by non-genotoxic carcinogens in rat liver in vivo. AB - This is a comparative study of the mechanisms by which three different rodent non genotoxic carcinogens modulate connexin-mediated gap junction intercellular communication in male rat liver in vivo. In the case of the peroxisome proliferating agent Wy-14,643, a non-hepatotoxic dose of 50mg/kg led to a marked loss of inter-hepatocyte dye transfer associated with a loss of both Cx32 and Cx26 protein expression. In contrast, p,p'-dichlorodiphenyltrichloroethane (DDT) at a non-hepatotoxic dose (25mg/kg) was not found to alter Cx32 or Cx26 expression or to produce a measurable Cx32 serine phosphorylation but did give a small, significant reduction of cell communication. Carbon tetrachloride (CCl(4)) did not affect cell communication (despite a small significant reduction of Cx32 content) at a non-hepatotoxic dose. Both loss of communication and Cx32 expression was observed only at a dose that caused hepatocyte toxicity as evidenced by increased serum alanine aminotransferase activity. Overall, the findings emphasise that loss of gap junctional communication in vivo can contribute to carcinogenesis by non-genotoxic carcinogens through different primary mechanism. In contrast to Wy-14,643 and DDT, the results with CCl(4) are consistent with a requirement for hepatotoxicity in its carcinogenic action. PMID- 17624653 TI - Identification of proteins undergoing expression level modifications in WI-38 SV40 fibroblasts overexpressing methionine sulfoxide reductase A. AB - Methionine sulfoxide reductase A overexpressing WI-38 SV40 human fibroblasts have been previously shown to exhibit higher resistance to oxidative stress by decreasing intracellular reactive oxygen species content and oxidative damage to proteins [C.R. Picot, I. Petropoulos, M. Perichon, M. Moreau, C. Nizard, B. Friguet, Overexpression of MsrA protects WI-38 SV40 human fibroblasts against H(2)O(2)-mediated oxidative stress, Free Radic Biol Med 39 (2005) 1332-1341]. In order to get further insight into the molecular mechanisms underlying this resistance to oxidative stress, proteins that are differentially expressed in methionine sulfoxide reductase A overexpressing cells were identified by 2D gel and Western blot quantitative analyses. Five proteins were shown to be differentially expressed and were identified by mass spectrometry, some of them were related to either cellular protection against oxidative stress, apoptosis or premature ageing. PMID- 17624647 TI - Social neuroscience of child and adolescent depression. AB - The social neuroscience of child and adolescent depression is inherently multidisciplinary. Depressive disorders beginning early in life can have serious developmental and functional consequences. Psychopathology research has described depression's defining clinical and contextual features, and intervention research has characterized its response to treatment and prevention programs. Neuroendocrine, electrophysiological, and neuroimaging studies have identified core neurobiological aspects of early-onset mood disorders. These areas are reviewed using a developmental social neuroscience perspective for integrating disparate observations. The paper introduces a dynamic adaptive systems framework, and it discusses hedonic capacity, stress sensitivity, ruminative self focus, and attentional impairments as fundamental components of mood disorders. PMID- 17624654 TI - RNase P RNA mediated cleavage: substrate recognition and catalysis. AB - The universally conserved endoribonuclease P consists of one RNA subunit and, depending on its origin, a variable number of protein subunits. RNase P is involved in the processing of a large variety of substrates in the cell, the preferred substrate being tRNA precursors. Cleavage activity does not require the presence of the protein subunit(s) in vitro. This is true for both prokaryotic and eukaryotic RNase P RNA suggesting that the RNA based catalytic activity has been preserved during evolution. Progress has been made in our understanding of the contribution of residues and chemical groups both in the substrate as well as in RNase P RNA to substrate binding and catalysis. Moreover, we have access to two crystal structures of bacterial RNase P RNA but we still lack the structure of RNase P RNA in complex with its substrate and/or the protein subunit. Nevertheless, these recent advancements put us in a new position to study the way and nature of interactions between in particular RNase P RNA and its substrate. In this review I will discuss various aspects of the RNA component of RNase P with an emphasis on our current understanding of the interaction between RNase P RNA and its substrate. PMID- 17624655 TI - The Sp6 locus uses several promoters and generates sense and antisense transcripts. AB - The SP/KLF transcription factor family contains over 25 members sharing a DNA binding domain composed of three zinc fingers of the C(2)H(2) type. We previously identified the sixth member of the SP subfamily (Sp6). The 5' end of the Sp6 transcript was not cloned and was predicted bioinformatically. A mouse molar tooth cDNA was then isolated differing from the Sp6 sequence by its 5' end, and was named epiprofin. Sp6 and epiprofin are currently used as synonyms. Here, we show that the Sp6 transcript possesses a first exon distinct from the epiprofin one: the Sp6 gene thus uses two promoters, generating two transcript variants which differ in their first exon. Furthermore, we identified an Sp6 opposite strand transcript (Sp6os) and examined, by quantitative RT-PCR experiments, the presence and the abundance of these two transcripts in mouse tissues. We also mapped the mouse locus by FISH to chromosome 11D. PMID- 17624656 TI - A screening model for fate and transport of biodegradable polyesters in soil. AB - A numerical model for predicting the fate and transport of biodegradable polyester residues in soil, following successive applications of mulch film, was developed and applied. The polymer, applied on surface soil, was assumed to be converted into by-products (monomers), according to a first order kinetics with constant K(1deg). The monomers released were assumed to sorb on soil organic matter (according to a first-order kinetics with constant K(s)), to be leached with the seepage water, through vertical advection and hydrodynamic dispersion, and biodegraded (according to a first-order kinetics with constant K(b)). Results suggested that, to assess a possible build-up of mulch film (as a polymer) on the surface soil, the degradation constant K(1deg) relating the polymer conversion to by-products should be known, whereas the biodegradation constant K(b) indicates there is no danger of groundwater pollution. Likewise, on the basis of by-product concentration in deep soil, soil pollution should not occur. PMID- 17624657 TI - Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? AB - OBJECTIVES: We compared long-term outcome in patients with initial pT1G3 bladder cancer (BC) treated with early versus deferred cystectomy (CX) for recurrent pT1G3 or muscle-invasive BC after an initial bladder-sparing approach. The aim of this study was to compare survival rates and to analyse the influence of the recognised risk factors multifocality, tumour size, and carcinoma in situ (CIS) in initial transurethral resection of the bladder. METHODS: Between 1995 and 2005, a total of 105 patients were diagnosed with initial pT1G3 BC featuring>or=2 risk factors. Forty-five percent had multiple tumours, 73% tumours>3 cm in size, and 46% CIS. All patients were offered early CX. Fifty-one percent of patients opted for early and 49% underwent deferred CX for recurring BC. Risk factors were distributed evenly between the groups. RESULTS: Upstaging in the CX specimen was found in 30% of cases. No risk factor was related to upstaging. The 10-yr cancer specific survival rate was 78% in early CX and 51% in deferred CX (p<0.01). No risk factor predicted cancer-related death in early CX. In survival analysis, CIS was related to a lower cancer-specific survival rate in deferred CX (p<0.001). CONCLUSIONS: Early as opposed to deferred CX seems to prolong the cancer-specific survival rate in high-risk pT1G3 BC. Patients with CIS should be considered for early CX owing to reduced cancer-specific survival in case of deferred CX. PMID- 17624658 TI - Glucocorticoids, metabolism and metabolic diseases. AB - Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids (GC) and their cognate, intracellular receptor, the glucocorticoid receptor (GR) have been characterized as critical components of the delicate hormonal control system that determines energy homeostasis in mammals. Whereas physiological levels of GCs are required for proper metabolic control, excessive GC action has been tied to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Highlighted by its importance for human health, the investigation of molecular mechanisms of GC/GR action has become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the GC-GR pathway has been proven to be of substantial value for the identification of novel therapeutic options in the treatment of severe metabolic disorders. Therefore, this review focuses on the role of the GC-GR axis for metabolic homeostasis and dysregulation, emphasizing tissue-specific functions of GCs in the control of energy metabolism. PMID- 17624659 TI - The role of erythropoietin in central and peripheral nerve injury. AB - Erythropoietin (Epo) is a cytokine which controls red cell production. Apart from the red cell surface, erythropoietin's receptor (Epo-R) is also expressed in a large variety of normal tissues. Erythropoietin, as well as its receptor, is present in the central and peripheral nervous system. As erythropoietin having direct and indirect effect on nerve cells, enhances antioxidotic enzyme production, antagonizes glutamate's cytotoxic action, metabolizes free radicals, normalizes cerebral blood flow, affects neurotransmitters release and stimulates neoangiogenesis. After injury of the central as well as the peripheral nervous system, Epo presents an anti-apoptotic action. In combination with its anti apoptotic effect, Epo, by reducing the inflammatory response plays a crucial role in neuroprotection in many types of injury in the central and the peripheral nervous system. Epo's administration contributes to the recovery of mechanical allodynia and may be effective in peripheral nerve regeneration after neurorrhaphy. PMID- 17624660 TI - Non-traumatic brachial plexopathies, clinical, radiological and neurophysiological findings from a tertiary centre. AB - OBJECTIVE: To establish the clinical characteristics, aetiology, neuro physiological characteristics, imaging findings and other investigations in a cohort of patients with non-traumatic brachial plexopathy (BP). METHODS: A 3-year retrospective study of patients with non-traumatic BP identified by electromyography (EMG) and nerve conduction studies (NCS). Clinical information was retrieved from patients' medical charts. RESULTS: Twenty-five patients were identified. Causes of BP included neuralgic amyotrophy (NA) (48%), neoplastic (16%), radiation (8%), post infectious (12%), obstetric (4%), rucksack injury (4%), thoracic outlet syndrome (4%) and iatrogenic (4%). Patients with NA presented acutely in 50%. The onset was subacute in all others. Outcome was better for patients with NA. All patients with neoplastic disease had a previous history of cancer. MRI was abnormal in 3/16 patients (18.8%). PET scanning diagnosed metastatic plexopathy in two cases. CONCLUSIONS: NA was the most common cause of BP in our cohort and was associated with a more favourable outcome. The authors note potentially discriminating clinical characteristics in our population that aid in the assessment of patients with brachial plexopathies. We advise NCS and EMG be performed in all patients with suspected plexopathy. Imaging studies are useful in selected patients. PMID- 17624661 TI - Analysis of incidence and risk factors for progression in patients with intracranial steno-occlusive lesions by serial magnetic resonance angiography. AB - OBJECTIVES: Conventional angiography and transcranial Doppler ultrasonography have usually been used for serial observation of cerebral atherosclerotic diseases. This study used magnetic resonance (MR) angiography to monitor serial changes in steno-occlusive lesions of the major intracranial arteries to elucidate the incidence of progression and investigate the risk factors for progression. PATIENTS AND METHODS: The 151 consecutive patients, 78 males and 73 females aged 42-92 years (mean 71.1+/-10.2 years), were followed up by serial MR angiography for 5-34 months (mean 14.4+/-5.78 months). Progression was defined as increased stenosis or occlusion, or new stenotic lesion. Age, sex, duration of MR angiography follow up, hypertension, diabetes mellitus, hyperlipidemia, hyperuricemia, current smoking, and atrial fibrillation were chosen as risk factors for multiple logistic analysis. RESULTS: Twenty-three of the patients (15.2%) had progression, caused by total occlusion in 10, increased stenosis in 10, and new stenosis in 3, 15 patients had regression, and 113 patients had no change. Diabetes (odds ratio: 6.771, p value: 0.0004) and current smoking (odds ratio: 7.574, p value: 0.0019) were determined as significant risk factors for progression. CONCLUSIONS: Patients with intracranial steno-occlusive lesion and either diabetes or smoking habit should be carefully followed up by serial MR angiography. PMID- 17624662 TI - High magnesium or potassium hair accumulation is not associated with ischemic stroke risk reduction: a pilot study. AB - OBJECTIVES: Various studies suggest that deficiency of magnesium and potassium may be associated with increased risk of ischemic stroke. However, single time point serum measurements may not be suitable for assessing long-term tissue levels. PATIENTS AND METHODS: We investigated Mg and K levels in hair of patients with acute ischemic stroke. The elements hair accumulation analysis might provide historical information on their concentrations over a longer period of time and probably reflects the corresponding nutritional condition. The concentrations of Mg and K in hair of 48 men with acute ischemic stroke and a control group were measured using spectroscopic methods. RESULTS: The mean Mg and K concentrations in hair of patients were significantly higher than in the controls. CONCLUSIONS: This analysis does not seem to confirm the results of the previous studies suggesting that Mg or K high levels (or their diet supplementation) might protect humans against ischemic stroke. PMID- 17624663 TI - High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. AB - We surveyed IL-21 receptor (IL-21R) in leukemia and lymphoma and found that follicular lymphoma cells showed exceptionally high IL-21R expression. Notably, IL-21 showed divergent effects depending on the cell origin: growth stimulation in Burkitt lymphoma cell lines and adult T cell leukemia/lymphoma cell lines but induction of apoptosis in B lymphoma cell lines with t(14;18)(q32;q21), a marker karyotype of follicular lymphoma. IL-21 activated caspase-8 and -3 and reduced mitochondrial membrane potential. More importantly, IL-21 decreased Bcl-2 expression but increased Bax expression. These results support a new therapeutic approach using the IL-21/IL-21R system in follicular lymphoma. PMID- 17624664 TI - Induction of cytotoxic T cell response against HCA661 positive cancer cells through activation with novel HLA-A *0201 restricted epitopes. AB - HCA661 is a cancer-testis (CT) antigen frequently expressed in human hepatocellular carcinoma (HCC). To search for immunogenic peptides of HCA661, bioinformatics analysis and CD8(+) T cell IFN-gamma ELISPOT assay were employed, and two HLA-A *0201 restricted peptides, H110 and H246, were identified. These two HCA661 peptides are naturally processed in dendritic cells (DCs) and when used for DCs loading, they are sufficient to prime autologous CD8(+) T cells to elicit cytotoxic response against HCA661(+) human cancer cells. The HCA661 peptides, H110 and H246, are hence attractive candidates for human cancer immunotherapy. PMID- 17624665 TI - Analysis of results from the operation of a pilot plasma gasification/vitrification unit for optimizing its performance. AB - Plasma gasification/vitrification is an innovative and environmentally friendly method of waste treatment. A demonstration plasma gasification/vitrification unit was developed and installed in Viotia region in order to examine the efficiency of this innovative technology in dealing with hazardous waste. The preliminary results from the trial runs of the plasma unit, as well as the study of the influence of certain parameters in the system performance are presented and analyzed in this paper, contributing to the improvement of the operation performance. Finally, data on the final air emissions and the vitrified ash toxicity characteristic leaching procedure (TCLP) results are provided in order to assess the environmental performance of the system. The produced slag was found to be characterized by extremely low leaching properties and can be utilized as construction material, while the values of the polluting parameters of the air emissions were satisfactory. PMID- 17624666 TI - Risk analysis of a biomass combustion process using MOSAR and FMEA methods. AB - Thermal and chemical conversion processes that convert in energy the sewage sludge, pasty waste and other pre-processed waste are increasingly common, for economic and ecological reasons. Fluidized bed combustion is currently one of the most promising methods of energy conversion, since it burns biomass very efficiently, and produces only very small quantities of sulphur and nitrogen oxides. The hazards associated with biomass combustion processes are fire, explosion and poisoning from the combustion gases (CO, etc.). The risk analysis presented in this paper uses the MADS-MOSAR methodology, applied to a semi industrial pilot scheme comprising a fluidization column, a conventional cyclone, two natural gas burners and a continuous supply of biomass. The methodology uses a generic approach, with an initial macroscopic stage where hazard sources are identified, scenarios for undesired events are recognized and ranked using a grid of SeverityxProbability and safety barriers suggested. A microscopic stage then analyzes in detail the major risks identified during the first stage. This analysis may use various different tools, such as HAZOP, FMEA, etc.: our analysis is based on FMEA. Using MOSAR, we were able to identify five subsystems: the reactor (fluidized bed and centrifuge), the fuel and biomass supply lines, the operator and the environment. When we drew up scenarios based on these subsystems, we found that malfunction of the gas supply burners was a common trigger in many scenarios. Our subsequent microscopic analysis, therefore, focused on the burners, looking at the ways they failed, and at the effects and criticality of those failures (FMEA). We were, thus, able to identify a number of critical factors such as the incoming gas lines and the ignition electrode. PMID- 17624667 TI - Metal biosorption capability of Cupriavidus taiwanensis and its effects on heavy metal removal by nodulated Mimosa pudica. AB - A novel metal biosorption system consisting of the symbiotic combination of an indigenous metal-resistant rhizobial strain, Cupriavidus taiwanensis TJ208, and its host plant Mimosa pudica has been developed for the removal of heavy-metal pollutants. Free-living C. taiwanensis TJ208 cells were able to adsorb 50.1, 19.0, and 19.6 mg/g of Pb, Cu, and Cd, respectively. After nodulation via inoculation with strain TJ208, the metal uptake ability of M. pudica markedly increased, as the nodulated M. pudica displayed a high metal uptake capacity (qmax) of 485, 25, and 43 mg/g, respectively, which is 86, 12, and 70% higher than that of nodule-free plants. Moreover, with TJ208 nodules, the M. pudica plant also displayed a 71, 81, and 33% enhancement in metal adsorption efficiency (eta) for Pb, Cu, and Cd, respectively. The nodulation appeared to give the greatest enhancing effect on the uptake of Pb, which is consistent with the preference of metal adsorption ability of TJ208. This seems to indicate the crucial role that the rhizobial strain may play in stimulating metal uptake of the nodulated plant. Furthermore, the results show that metal accumulation in the nodulated plant mainly occurred in the roots, accounting for 65-95% of total metal uptake. In contrast, the nodules and the shoots only contributed to 3-12 and 2-23% of total metal uptake, respectively. Nevertheless, the specific adsorption capacity of nodules is comparable to that of the roots. Hence, this work demonstrates the feasibility and effectiveness of using the nodulated plants to promote phyto-removal of heavy metals from the polluted environment as well as to restrict the metal contaminants in the unharmful region of the plant. PMID- 17624668 TI - Characterization of phenol degradation by Rhizobium sp. CCNWTB 701 isolated from Astragalus chrysopteru in mining tailing region. AB - To screen high strength phenol degrading bacteria, we selected 108 rhizobial strains isolated from nodules of eight wild legumes species in the mining tailing region of Shaanxi province, northwest of China, and cultivated them in a basal salt (BS) medium supplemented with different phenol concentrations as a sole carbon source. The results showed that some of the strains could use phenol as sole carbon source. In order to study the characteristics of phenol degradation, the strain CCNWTB701 isolated from Astragalus chrysopteru was used as well, due to the fact that it was very efficient in phenol degradation. The phenol degradation was around 99.5 and 78.3%, with an initial concentration of 900 and 1000 mg/l phenol in 62 and 66 h, respectively. Kinetic studies indicated that the strain had a high KS (743.1 microM) and an extremely high KSI (10,469 microM) in Haldane's model. The phylogenetic analysis based on 16S rRNA gene sequences showed that CCNWTB701 belonged to the Rhizobium genus, and it was closely related to Rhizobium mongolense and Rhizobium gallicum. PMID- 17624669 TI - The adsorption kinetics and removal of cationic dye, Toluidine Blue O, from aqueous solution with Turkish zeolite. AB - Clinoptilolite, a natural zeolite, was investigated as an inexpensive and effective adsorbent for the adsorption of Toluidine Blue O (TBO) from its aqueous solution. The effect of parameters such as the initial concentration of TBO, the solution of pH, contact time, temperature and particle size on the TBO adsorption was examined. The adsorption rate data were analysed according to the first and second-order kinetic models. Kinetic studies show that adsorption of TBO on clinoptilolite was fitted to the second-order adsorption model with two-step diffusion process. The activation energies for TBO adsorption on clinoptilolite for the first and second diffusion processes were 8.72 kJ mol(-1) and 19.02 kJ mol(-1), respectively. The adsorption isotherm was well fitted to both the Langmuir and Freundlich models. The maximum adsorption capacity of clinoptilolite for TBO was 2.1x10(-4) mol g(-1) at solution pH of 11.0. PMID- 17624670 TI - New approach for the dynamical simulation of CBED patterns in heavily strained specimens. AB - A new method for the dynamical simulation of convergent beam electron diffraction (CBED) patterns is proposed. In this method, the three-dimensional stationary Schrodinger equation is replaced by a two-dimensional time-dependent equation, in which the direction of propagation of the electron beam, variable z, stands as a time. We demonstrate that this approach is particularly well-suited for the calculation of the diffracted intensities in the case of a z-dependent crystal potential. The corresponding software has been developed and implemented for simulating CBED patterns of various specimens, from perfect crystals to heavily strained cross-sectional specimens. Evidence is given for the remarkable agreement between simulated and experimental patterns. PMID- 17624671 TI - Establishment of a panel of reference Trypanosoma evansi and Trypanosoma equiperdum strains for drug screening. AB - The animal pathogenic protozoan, Trypanosoma evansi, leads to a wasting disease in equines, cattle and camels, commonly known as Surra. It is extensively distributed geographically with a wide range of mammalian hosts and causes great economical loss. Trypanosoma equiperdum causes a venereal disease called Dourine in horses and donkeys. Chemotherapy appears to be the most effective form of control for T. evansi, whereas infections caused by T. equiperdum are considered incurable. Due to emerging drug resistance, efficient control of T. evansi is severely threatened, emphasising the urgent need to find new alternative drugs. A drug profile for a panel of T. evansi and T. equiperdum strains has been established for the four standard drugs currently used in treatment. The (3)H hypoxanthine incorporation assay was used to obtain 50% inhibitory concentration (IC(50)) values for each standard drug against the various strains. The results indicate the presence (and in some cases, the emergence) of drug resistance in several strains. This panel of characterised strains with known drug sensitivities and resistances will be of great value for the screening of new active compounds, in comparison with the four standard drugs currently available. PMID- 17624672 TI - Evaluation of the diagnostic accuracy of the modified agglutination test (MAT) and an indirect ELISA for the detection of serum antibodies against Toxoplasma gondii in sheep through Bayesian approaches. AB - The diagnostic accuracies of the modified agglutination test (MAT) and indirect ELISA test for the detection of serum antibodies against Toxoplasma gondii in sheep were evaluated through Bayesian approaches on two populations of sheep created from three different groups of animals (T. gondii-aborted ewes, colostrums-deprived newborn lambs, and ewe-lambs and adult ewes with unknown T. gondii infection status). Tests showed a high degree of agreement (kappa statistic = 0.93; 95% confidence interval = 0.87, 0.98) and a significant specificity (Sp) correlation (gamma(Sp) = 0.26; 95% credibility interval = 0.017, 0.61). When prior information was used for all unknown parameters the posterior medians for the sensitivity (Se) and Sp of the MAT and ELISA were, respectively, 92.6% (95% credibility interval = 85.2, 96.9), 95.5% (89.9, 98.7), 90.5% (83.4, 95.6), and 97.8% (94.2, 99.5). These estimates remained similar when uninformative priors were included. The Se estimates of the MAT and ELISA were higher than those obtained on pigs in other study using the same approach (Se = 80.6% and Sp = 89.5% for the MAT, and Se = 71.5% and Sp = 85.5% for the ELISA [Georgiadis, M.P., Wesley, O.J., Gardner, I.A., Singh, R., 2003. Correlation adjusted estimation of sensitivity and specificity of two diagnostic tests. Appl. Stat. 52, 63-78]. This finding supported the believe that test performances may vary when applied on different animal species. Thus, if these tests are planned to be used on animal species other than sheep or pigs, their diagnostic accuracy should be re-assessed to prevent biased inferences from their results. PMID- 17624673 TI - Efficacy of repeated trickle applications of oxalic acid in syrup for varroosis control in Apis mellifera: influence of meteorological conditions and presence of brood. AB - Oxalic acid field trails for the control of varroosis (Varroa destructor) were carried out in an apiary located on the Mt. Imittos (Attica, Greece). The colonies received four successive applications (approximately one every 16 days) with 4.2% oxalic acid (OA) and 60% sugar solution by trickling method with two alternative types of syringes (an automatic self-filling dosing and a single-use) from the broodright to broodless period. The results indicate that the first three applications (from 6th October to 25th November-broodright period) resulted in 65.3% cumulative mite mortality, while only the last application (after the 26th November-broodless period) resulted in 77.3% mite mortality. Very low outern temperatures reduce to the minimum the bee movability, which may result into a slower development of the OA efficacy. No poor colony growth or queen loss were observed even if the bee colonies were received the four successive OA applications with the last one taken place at a very low outern temperature (6.2 degrees C). The trickling method using an automatic-filling syringe seems to be a very quick way for applying oxalic acid in large apiaries (approximately 150hives/h). PMID- 17624674 TI - Control of the sheep scab mite Psoroptes ovis in vivo and in vitro using fungal pathogens. AB - As part of a research programme designed to identify biological agents for the control of sheep scab, the pathogenicity of the fungus Metarhizium anisopliae to Psoroptes mites in the presence of sheepskin and wool was examined in the laboratory. No inhibitory effects of skin and wool were observed and high levels of infection were recorded. Subsequently the pathogenicity of formulations of both M. anisopliae and Beauveria bassiana to Psoroptes ovis was studied in vivo. For this, 36 batches of 20 adult female Psoroptes mites were confined in 25 mm diameter chambers which were attached to the backs of 6 scab-naive sheep. In some treatments, mites were exposed to the fungal pathogens for 48 h in vitro prior to being placed on the host, while other treatments involved mites with no prior exposure placed directly onto the skin of a host treated with a fungal pathogen. After 48 h on the host, mites were removed, incubated individually and all fungal infections were recorded. Fungal infection was observed in all treatments, except untreated controls. However, B. bassiana infected a significantly greater number of mites than M. anisopliae with all the formulations examined. Infection rates were highest when mites were exposed to dry conidia (>90%) and lowest with M. anisopliae in diatomaceous earth. Overall, the infection rate was not affected by whether or not the mites were given prior exposure to the conidia, before being placed on the sheep. The results demonstrate that Psoroptes mites can become infected by entomopathogenic fungi on the skin of sheep and provides a first demonstration of the potential of this technology for the control of sheep scab. PMID- 17624675 TI - Heat analysis of biological tissue exposed to microwave by using thermal wave model of bio-heat transfer (TWMBT). AB - Thermal analyses of biological tissues exposed to microwaves were studied by using thermal wave model of bio-heat transfer (TWMBT). As a model, skin stratified as three layers with various thermal physical properties were simulated and thermal wave model of bio-heat transfer equations were solved by using finite difference method. Finally, the thermal variations were simulated in the cross section of the model. Comparative studies on the traditional Pennes' equations and thermal wave model of bio-heat transfer were performed and evaluated. Furthermore, temperature variations in the skin exposed to microwave were predicted depending on blood perfusion rate, thermal conductivity, frequency and power density of microwave, and exposure time. Thermal wave model of bio-heat transfer gives lower heat rise predictions than that of Pennes' equation, initially. When it approaches to steady state, it overlaps with the Pennes' equation. PMID- 17624676 TI - The timing of surgery for deep burns of the hands: early versus delayed surgery. PMID- 17624677 TI - Cross-cultural adaptation and validation of the Questionnaire for Pruritus Assessment for use in the French Canadian burn survivor population. AB - BACKGROUND: Severe pruritus after burn continues to be a clinical challenge. To address this challenge, thorough documentation of burn survivors' itch experience is required. A "Questionnaire for Pruritus Assessment" has been developed to capture the sensory and affective experiences associated with itch as well as its functional and quality of life implications, but to evaluate the Quebec burn survivor population, a Canadian French version is required. Thus, the purpose of this study was to generate a Canadian French cross-cultural adaptation of the questionnaire suitable for the burn survivor population. METHODS: Cross-cultural adaptation followed six steps: forward translation into Canadian French, back translations into English, resolution between the two versions, synthesis of the Canadian French versions, revision by a committee of experts, and testing of the pre-final version. RESULTS: The adaptation process resolved issues surrounding translation, content validity, burn survivor-specific modifications, and format, resulting in a Canadian French pre-final version that was pilot-tested among 32 burn survivors. Content validity of the Canadian French version was assessed by a committee of experts and the participants. The results showed good item completion and adequate distribution of scores without a ceiling or floor effect. CONCLUSIONS: This study resulted in a Canadian French version of the "Questionnaire for Pruritus Assessment" that can confidently be compared to other investigations utilizing the same tool. The adapted questionnaire also provides a valuable data collection means, enabling more thorough documentation of the burn survivor itch experience. PMID- 17624678 TI - Considerations for psychosocial support following burn injury--a family perspective. AB - As part of a larger study involving burned adults and parents of burned children, family members were asked for their views regarding the impact of burn on themselves and the family (N=50). The aim is to describe the range of psychosocial issues that psychosocial support programmes may need to address. This paper reports on the content analysis of specifically designed self completion questionnaires. The results reveal commonalities within support needs across the three study groups (siblings, children, and partners). These are recommended as key elements in a family support programme: (i) normalising of family member's reactions to the burn. (ii) Advice, support, and information regarding scar permanence, realistic outcome expectations, acceptance of altered appearance, and potential after-effects of burn. (iii) Support in understanding how a burned individual may change or respond following injury and advice regarding constructive methods of coping with altered family dynamics and after effects of burn. (iv) Advice to enable family members and their burned relative to effectively deal with potentially uncomfortable social encounters. PMID- 17624679 TI - An extraordinary chemical burn injury cause: buttercup a report of five cases. PMID- 17624680 TI - Arsenical-based cancer drugs. AB - Arsenic is a semi-metal or metalloid with two biologically important oxidation states, As(III) and As(V). As(III), in particular, reacts with closely spaced protein thiols, forming stable cyclic dithioarsinite complexes in which both sulfur atoms are bound to arsenic. It is this reaction that is mostly responsible for arsenics cytotoxicity. Arsenic compounds have been used as medicinal agents for many centuries for the treatment of diseases such as psoriasis, syphilis, and rheumatosis. From the 1700's until the introduction of and use of modern chemotherapy and radiation therapy in the mid 1900's, arsenic was a mainstay in the treatment of leukemia. Concerns about the toxicity of arsenical compounds led eventually to their abandonment for the treatment of cancer. The discovery in the 1980's that arsenic trioxide induces complete remission in a high percentage of patients with acute promyelocytic leukemia has awakened interest in this metalloid for the treatment of human disease. In particular, a new class or organoarsenicals are being trialed for the treatment of hematological malignancies and solid tumors. In this review, we discuss the arsenical-based compounds used in the past and present for the treatment of various forms of cancer. Mechanisms of action and selectivity and acute and chronic toxicities are discussed along with the prospects of this class of molecule. PMID- 17624681 TI - Neuroprotective effect of erythropoietin, and role of metallothionein-1 and -2, in permanent focal cerebral ischemia. AB - Metallothioneins (MTs) are small cysteine-rich proteins found widely throughout the mammalian body, including the CNS. MT-1 and -2 protect against reactive oxygen species and free radicals. We investigated the role of MT-1 and -2 using MT-1,-2 knockout (KO) mice. MT-1,-2 KO mice exhibited greater neuronal damage after permanent middle cerebral artery occlusion (MCAO) than wild-type mice. MT-2 mRNA was significantly increased at 6, 12, and 24 h after MCAO in the wild-type mouse brain [as detected by real-time reverse-transcription polymerase chain reaction (RT-PCR)], while MT-1 and MT-3 were decreased at 12 and 24 h. In an immunohistochemical study, MT expression displayed colocalization with glial fibrillary acidic protein (GFAP)-positive cells (astrocytes) in the penumbra area in wild-type mice. Since erythropoietin (EPO) has been reported to induce MT-1 and -2 gene expression in vitro, we examined its effect after permanent MCAO, and explored the possible underlying mechanism by examining MT-1 and -2 induction in vivo. In wild-type mice, EPO significantly reduced both infarct area and volume at 24 h after the ischemic insult. However, in MT-1,-2 KO mice EPO-treatment did not alter infarct volume (vs. vehicle-treatment). In wild-type mice at 6 h after EPO administration, real-time RT-PCR revealed increased MT-1 and -2 mRNA expression in the cerebral cortex (without MCAO). Further, MT-1 and -2 immunoreactivity was increased in the cortex of EPO-treated mice. These findings indicate that MTs are induced, and may be neuroprotective against neuronal damage, after MCAO. Furthermore, EPO is neuroprotective in vivo during permanent MCAO, and this may be at least partly mediated by MTs. PMID- 17624682 TI - Associations between Cloninger's temperament dimensions and acute tobacco withdrawal. AB - This study examined associations between three temperament dimensions measured by the Temperament and Character Inventory-125 [Cloninger, C.R. (1992). The Temperament and Character Inventory-125 (TCI-125; Version 1.)] and tobacco abstinence effects. Smokers (N=203, >/= 15 cigarettes/day) attended two laboratory sessions, one following 12 h of abstinence and the other following ad libitum smoking (order counterbalanced). Participants completed measures of withdrawal symptoms, cigarette urges, and affect. Smokers high in Novelty Seeking reported greater abstinence-induced increases in several nicotine withdrawal symptoms, negative affect, and cigarette craving. Smokers high in Harm Avoidance reported greater abstinence-induced increases in negative affect and urges to smoke to relieve distress. Reward Dependence was not associated with abstinence effects. Novelty Seeking and Harm Avoidance showed independent predictive associations with negative affect and urges, and their associations with abstinence effects persisted when controlling for FTND scores. Smokers with different temperaments display different patterns of acute tobacco withdrawal, and may benefit from treatments matched to their particular abstinence profile. PMID- 17624683 TI - Do polyunsaturated fatty acids behave like an endogenous "polypill"? AB - Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin - called as polypill - was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites and other products prevent platelet aggregation, lower blood pressure, reduce LDL-C, and ameliorate the adverse actions of homocysteine. Thus, EFAs and their metabolites show all the actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules, have no significant side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and children; and have been shown to reduce the incidence cardiovascular diseases. I propose that a rational combination of omega-3 and omega-6 fatty acids is as beneficial as that of the "polypill"; and may even show additional benefit in the prevention of depression, schizophrenia, Alzheimer's disease, and enhance cognitive function. PMID- 17624684 TI - Modic changes, possible causes and relation to low back pain. AB - In patients with low back pain (LBP) it is only possible to diagnose a small proportion, (approximately 20%), on a patho-anatomical basis. Therefore, the identification of relevant LBP subgroups, preferably on a patho-anatomical basis, is strongly needed. Signal changes on MRI in the vertebral body marrow adjacent to the end plates also known as Modic changes (MC) are common in patients with LBP (18-58%) and is strongly associated with LBP. In asymptomatic persons the prevalence is 12-13%. MC are divided into three different types. Type 1 consists of fibro vascular tissue, type 2 is yellow fat, and type 3 is sclerotic bone. The temporal evolution of MC is uncertain, but the time span is years. Subchondral bone marrow signal changes associated with pain can be observed in different specific infectious, degenerative and immunological diseases such as osseous infections, osteoarthritis, ankylosing spondylitis and spondylarthritis. In the vertebrae, MC is seen in relation to vertebral fractures, spondylodiscitis, disc herniation, severe disc degeneration, injections with chymopapain, and acute Schmorl's impressions. The aim of this paper is to propose two possible pathogenetic mechanisms causing Modic changes. These are: A mechanical cause: Degeneration of the disc causes loss of soft nuclear material, reduced disc height and hydrostatic pressure, which increases the shear forces on the endplates and micro fractures may occur. The observed MC could represent oedema secondary to the fracture and subsequent inflammation, or a result of an inflammatory process from a toxic stimulus from the nucleus pulposus that seeps through the fractures. A bacterial cause: Following a tear in the outer fibres of the annulus e.g. disc herniation, new capilarisation and inflammation develop around the extruded nuclear material. Through this tissue it is possible for anaerobic bacteria to enter the anaerobic disc and in this environment cause a slowly developing low virulent infection. The MC could be the visible signs of the inflammation and oedema surrounding this infection, because the anaerobic bacteria cannot thrive in the highly aerobic environment of the MC type 1. PERSPECTIVES: One or both of the described mechanisms can - if proven - be of significant importance for this specific subgroup of patients with LBP. Hence, it would be possible to give a more precise and relevant diagnosis to 20-50% of patients with LBP and enable in the development of efficient treatments which might be antibiotics, special rehabilitation programmes, rest, stabilizing exercise, or surgical fixation, depending on the underlying cause for the MC. PMID- 17624685 TI - A novel extracellular peroxidase and nucleases from a milky sap of Chelidonium majus. AB - Using affinity chromatography, SDS-PAGE, peroxidase activity assay and mass spectrometry data, a new extracellular peroxidase (CMP) from Chelidonium majus milky sap was isolated and characterized. The protein has a molecular weight of about 40 kDa and belongs to secretory class III plant peroxidases. The peroxidase activity is also accompanied by DN-ase activities. A novel CMP combined with other proteins is probably involved in development and differentiation of the plant and defence against different pathogens. It suggests that the biological activity of C. majus whole plants and extracts may depend not only on its alkaloidal content but also on the presence of biologically active proteins. PMID- 17624686 TI - Country of origin, age of drinking onset, and drinking patterns among Mexican American young adults. AB - This study examines relationships between country of origin, age of drinking onset, and adverse drinking outcomes among young adult Mexican Americans in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Logistic regression models estimate associations between age of drinking onset, age of onset in relation to age at immigration, and adverse drinking outcomes, controlling for sex, age, employment, education, marital status, and income. Adjusted analyses indicate the odds of adverse drinking outcomes decreased as age of drinking onset increased. Mexican Americans who initiated drinking in Mexico had significantly lower odds of current or lifetime harmful drinking than U.S. born but the odds were not significantly different between foreign-born Mexican Americans who initiated drinking in the U.S. and U.S. born. Irrespective of whether drinking onset was in Mexico or the U.S., foreign-born Mexican Americans had lower odds of alcohol abuse than U.S. born. However, odds of dependence were not significantly different between foreign-born and U.S.-born Mexican Americans. While findings suggest that being foreign born may be protective, further research on social and cultural factors impacting drinking onset and related outcomes among young Mexican Americans may help inform prevention efforts. PMID- 17624687 TI - Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients. AB - BACKGROUND: Benzodiazepine abuse is common among methadone- and buprenorphine maintained patients; however interactions between these drugs under high dose conditions have not been adequately examined under controlled conditions. OBJECTIVE: To investigate the effects of co-administering diazepam with methadone or buprenorphine under high dose conditions. DESIGN: Double-blind, randomly ordered, 2 x 2 cross-over design in which the effects of diazepam dose (0mg versus 40 mg) and opioid dose (100% versus 150% normal dose) were examined over four sessions in methadone- and buprenorphine-maintained patients. PARTICIPANTS: Four methadone- and seven buprenorphine-prescribed patients without concurrent dependence on other substances or significant medical co-morbidity. MEASURES: Physiological (pulse rate, blood pressure, pupil size, respiratory rate and peripheral SpO2), subjective (ARCI, VAS ratings) and performance (reaction time, cancellation task and Digit Symbol Substitution Test, DSST) measures were taken prior to and for 6h post-dosing. RESULTS: High dose diazepam was associated with time-dependent increases in the intensity of subjective drug effects (strength of drug effect, sedation) and decreases in psychological performance (reaction time, DSST) for both methadone and buprenorphine patients. These effects were generally independent of the opioid dose administered. High dose opioid administration (150% normal dose) was associated with reductions in overall SpO2 levels and performance (reaction time, DSST) in the methadone patients, but had virtually no impact on pharmacodynamic responses in the buprenorphine group. CONCLUSION: High dose diazepam significantly alters subjective drug responses and psychological performance in patients maintained on methadone and buprenorphine. PMID- 17624688 TI - Psychosocial functioning and cocaine use during treatment: strength of relationship depends on type of urine-testing method. AB - Although improvement in psychosocial functioning is a common goal in substance abuse treatment, the primary outcome measure in most cocaine trials is urinalysis verified cocaine use. However, the relationship between cocaine use and psychosocial outcomes is not well documented. To investigate this relationship and identify the optimal urine-screen method, we retrospectively analyzed data from two 25-week randomized controlled trials of abstinence reinforcement (AR) in 368 cocaine/heroin users maintained on methadone. Cocaine use was measured thrice weekly by qualitative urinalysis, benzoylecgonine concentration (BE), and an estimate of New Uses of cocaine by application of an algorithm to BE. Social adjustment (SAS-SR), current diagnosis of cocaine dependence (DSM-IV criteria), and depression symptoms (Beck Depression Inventory) were determined at study exit. Cocaine use was significantly lower in AR groups than in controls. Across groups, in-treatment cocaine use was significantly associated with worse social adjustment, current cocaine dependence, and depression at exit. Significant differences were detected more frequently with New Uses than qualitative urinalysis or BE. Nevertheless, the amount of variance accounted for by the urine screens was typically <15%. Cocaine use during treatment, especially when measured with New Uses criteria, can predict psychosocial functioning, but cannot substitute for direct measures of psychosocial functioning. PMID- 17624689 TI - Variations in social contexts and their effect on adolescent inhalant use: a latent profile investigation. AB - The social contexts surrounding the use and abuse of inhalants are poorly understood. The aim of this study was to utilize latent profile analysis (LPA) to identify specific subgroups of adolescents based on social contextual effects surrounding inhalant use episodes in a sample of 279 adolescent inhalant users. Findings revealed that a three-class solution exhibited the best empirical and conceptual fit with the data. Identified classes represented a gradient of low, moderate, and high levels of contextual effects where approximately one third of adolescent inhalant users reported high levels of inhalant use in response to social contextual influences. Subsequent validation analysis showed that these gradient-based classes were directly correspondent with severity in measures of psychopathology, past drug use, variety of inhalants used, and measures of impulsivity and fearlessness. Results indicate heterogeneity in contextual effects on inhalant use and suggest that follow-up studies should examine the role that susceptibility and exposure to contextual effects has on inhalant use. PMID- 17624690 TI - Drug use related problems among nonmedical users of prescription stimulants: a web-based survey of college students from a Midwestern university. AB - This college-based study compared nonmedical users of prescription stimulants to other types of drug users regarding drug use related problems. A Web survey was self-administered in 2005 by a probability sample of 3639 full-time undergraduate students (68% response rate) at a large public Midwestern 4-year university in the United States. The survey consisted of measures to assess substance use and misuse, including a modified version of the Drug Abuse Screening Test (DAST-10). Nonmedical users of prescription stimulants were more likely than other drug users to report polydrug use. Nonmedical users of prescription stimulants had over four times greater odds than other drug users to experience three or more DAST-10 items in the past 12 months (AOR=4.61, 95% CI=3.28-6.48). Among nonmedical users of prescription stimulants, those who used prescription stimulants via intranasal and other non-oral routes of administration had greater odds than oral only users to experience three or more DAST-10 items in the past 12 months. The findings of the present study suggest that the majority of nonmedical users of prescription stimulants are polydrug users and should be screened for potential drug abuse or dependence, especially those who report non oral routes of administration. PMID- 17624691 TI - Rat homolog of PinX1 is a nucleolar protein involved in the regulation of telomere length. AB - Human PinX1 involves in regulation of telomere length. Here, we describe the function of a rat homolog of PinX1. Rat PinX1 (rPinX1) was cloned from WB-F344, a rat hepatic stem-like epithelial cell. It encodes a protein of 331 amino acids with 70% homology to human PinX1 and 91% homology to mouse. Northern analysis revealed that rPinX1 is expressed in both somatic and germ tissues, most abundantly in heart, liver and testis. Co-localization with a nucleolar protein, fibrillarin, showed that rPinX1 resides in the nucleolus. Analysis of truncated mutants revealed that an internal K,E/D region seems to be important for nucleolar localization. A stable cell line expressing rPinX1 was established in NIH3T3, a mouse-transformed embryonic fibroblast cell line, and stable cells were subcultured for more than 150 population doublings. The growth of stable rPinX1 cells slowed down at late passages, and a fraction of these cells exhibited increased size and stained positively for senescence-associated beta galactosidase. Overexpression of rPinX1 in NIH3T3 cells resulted in gradual telomere shortening over successive passages. However, the telomeric 3' overhang was not altered by PinX1 expression. This study demonstrates that a rat homolog of human PinX1 is a nucleolar protein, and that overexpression of rPinX1 induces cellular senescence and telomere shortening, but has no effect on 3' overhang length. The function of PinX1 in regulating telomere length is conserved in rodents, and this study may provide insight into the mechanism by which a nucleolar protein can regulate telomere length. PMID- 17624692 TI - The genomic structure of Brucella strains isolated from marine mammals gives clues to evolutionary history within the genus. AB - The genomic structure and the restriction maps were studied in 24 Brucella strains isolated from marine mammals. From SpeI restriction profiles, the strains could be ascribed to three clonal groups, each corresponding to a specific host. Cross contamination between exclusively terrestrial and exclusively marine hosts is unlikely suggesting the divergence of the different species of the genus Brucella which may have taken place 60 million years ago, concomitant with the radiation of their mammalian hosts (Artiodactyla) from other mammalian orders. PMID- 17624693 TI - Effects of Salmonella enterica subsp. enterica serovar Enteritidis vaccination in layer hens subjected to S. Enteritidis challenge and various feed withdrawal regimens. AB - Levels of Salmonella enterica subsp. enterica serovar Enteritidis infection and serum S. Enteritidis antibodies after experimental S. Enteritidis challenge and feed withdrawal were investigated in S. Enteritidis-vaccinated and unvaccinated hens. The results were used to determine whether formalin-inactivated S. Enteritidis vaccination can protect layer hens from S. Enteritidis challenge during feed withdrawal periods. S. Enteritidis infection rates were evaluated from cloacal swabs, eggs and organs. Serum antibody titers to deflagellated S. Enteritidis whole cells (DEWC) and S. Enteritidis FliC-specific 9-kDa polypeptide (SEp 9) were examined by commercial ELISA kits. Cloacal S. Enteritidis recovery rates were lower in the vaccinated than unvaccinated group. Recovery rates of S. Enteritidis from samples increased after feed withdrawal and decreased after re introduction of feed. S. Enteritidis counts in cloacal swabs were lower in the vaccinated than in the unvaccinated group (P<0.05). More S. Enteritidis-positive eggs were detected from the unvaccinated group. Before S. Enteritidis challenge, the DEWC ELISA titer of the vaccinated group was higher (P<0.05) than the unvaccinated group; subsequently, the S. Enteritidis DEWC ELISA titers of both groups increased gradually. In contrast, only the vaccinated group elicited high SEp-9 antibody titer during post-challenge and feed withdrawal. Additionally, vaccinated hens yielded negative S. Enteritidis isolation rates from egg contents. There is a correlation between negative S. Enteritidis isolation rates and high SEp 9 titers in vaccinated layer hens challenged with S. Enteritidis and subjected to feed withdrawal regimens. These findings suggest the S. Enteritidis vaccination of pullets may protect against S. Enteritidis infection during forced molting and that SEp 9 titer could be a potential indicator of antibody protection against S. Enteritidis infection. The potential of the SEp 9 peptide as an antigen for S. Enteritidis vaccination in the future is worth noting. PMID- 17624694 TI - Sequence and phylogenetic analysis of the 16S rRNA gene of Ehrlichia canis strains in dogs with clinical monocytic ehrlichiosis. AB - The purpose of this study was to characterize, at the molecular level, the Ehrlichia canis strains involved in naturally occurring canine monocytic ehrlichiosis (CME) in Greece, and to investigate if any sequence diversity exists between the 16S rRNA genes of those involved in the mild non-myelosuppressive or the severe myelosuppressive form of CME. To this end, amplification of the ehrlichial 16S rRNA gene was attempted by nested polymerase chain reaction (PCR) assays in bone marrow (BM) aspirates from 20 dogs tentatively diagnosed as having non-myelosuppressive (n=10, group A) or myelosuppressive (n=10, group B) CME. PCR assay using E. canis-specific primers revealed that 15 BM samples, including all group A and 5 group B dogs, were positive. Using universal PCR primers, a nearly full-length 16S rRNA gene could be amplified from 13 BM samples, including 9 group A and 4 group B dogs. The 16S rDNA analysis based on secondary structure revealed that all sequences of the Greek strains were identical to each other and indicated 100% identity among some American (Venezuelan and Brazilian), European (Greek), Middle Eastern (Turkish) and Asiatic (Thailand) strains. The results of this study suggest that the E. canis strains involved in the non-myelosuppressive and myelosuppressive forms of CME in Greece share an identical 16S rRNA genotype. PMID- 17624695 TI - Expression of the dermonecrotic toxin by Bordetella bronchiseptica is not necessary for predisposing to infection with toxigenic Pasteurella multocida. AB - This experiment was designed to determine whether a Bordetella bronchiseptica mutant that does not produce dermonecrotic toxin (DNT) is still capable of predisposing pigs to infection with toxigenic Pasteurella multocida. Three groups of pigs were initially inoculated intranasally with a wild type B. bronchiseptica that produces DNT, an isogenic mutant of B. bronchiseptica that does not produce DNT, or PBS. All pigs were then challenged intranasally with a toxigenic strain of P. multocida 4 days later. P. multocida was recovered infrequently and in low numbers from pigs initially inoculated with PBS, and no turbinate atrophy was present in these pigs. P. multocida was isolated in similar numbers from the pigs initially inoculated with either the wild type or the DNT mutant of B. bronchiseptica, and turbinate atrophy of a similar magnitude was also seen in pigs from both of these groups. Thus, although the DNT has been shown to be responsible for much of the pathology seen during infection with B. bronchiseptica by itself, infection with non-DNT-producing strains can still predispose to secondary respiratory infections with P. multocida. PMID- 17624697 TI - The diabetogenic effects of the combination of humic acid and arsenic: in vitro and in vivo studies. AB - Black foot disease (BFD) is a peripheral arterial occlusive disease found among the inhabitants of the southwest coast of Taiwan. Moreover, within the BFD endemic areas, diabetes mellitus occur at significantly higher rates than in other areas of Taiwan. A high concentration of humic acid (HA), and arsenic (As) are present in the artesian well water from BFD-endemic area. The aim of this paper is to study the diabetogenic effect of the combination of HA and AS. Treatment of HIT-T15 cells with HA, As, or both of them resulted loss of cell viability, apoptosis, depletion of ATP, increment of oxidative stress, activation of caspase 3, and dysfunction of insulin secretion. In addition, the plasma insulin of ICR mice, which were exposed to HA and As in drinking water for 12 weeks, was decreased in the 5, 7, and 12 weeks, and increased at early stage of exposure (3 weeks). The results reported herein reveal that HA and As exert HIT T15 cell dysfunction and inhibited insulin secretive effects. In addition, the sub-acute peri-pancreatitis and islet damage caused by the infiltration of inflammatory cells after exposure of HA and As in drinking water for 5 weeks. Our study has important implications in the diabetogenic effect of the HA and AS which may be mediated by ROS and further information of the toxicity mechanisms will provide under our progressive studies. PMID- 17624696 TI - Cytokines and other immunological biomarkers in children's environmental health studies. AB - Environmental exposures (e.g. pesticides, air pollution, and environmental tobacco smoke) during prenatal and early postnatal development have been linked to a growing number of childhood diseases including allergic disorders and leukemia. Because the immune response plays a critical role in each of these diseases, it is important to study the effects of toxicants on the developing immune system. Children's unique susceptibility to environmental toxicants has become an important focus of the field of immunotoxicology and the use of immune biomarkers in molecular epidemiology of children's environmental health is a rapidly expanding field of research. In this review, we discuss how markers of immune status and immunotoxicity are being applied to pediatric studies, with a specific focus on the various methods used to analyze T-helper-1/2 (Th1/Th2) cytokine profiles. Furthermore, we review recent data on the effects of children's environmental exposures to volatile organic compounds, metals, and pesticides on Th1/Th2 cytokine profiles and the associations of Th1/Th2 profiles with adverse health outcomes such as pediatric respiratory diseases, allergies, cancer and diabetes. Although cytokine profiles are increasingly used in children's studies, there is still a need to acquire distribution data for different ages and ethnic groups of healthy children. These data will contribute to the validation and standardization of cytokine biomarkers for future studies. Application of immunological markers in epidemiological studies will improve the understanding of mechanisms that underlie associations between environmental exposures and immune-mediated disorders. PMID- 17624698 TI - Liposomes modified with polycation used for gene delivery: preparation, characterization and transfection in vitro. AB - Gene therapy provides great opportunities for treating diseases from genetic disorders, infections and cancer. The development of efficient and safe gene transfer systems could be one of the most important factors for successful gene therapy. In the present study, an amphiphilic compound, polyethylenimine (PEI, MW 800)-cholesterol (PEI 800-Chol), firstly designed to modify the surface of liposomes, was synthesized. Polycation liposomes (PCLs) composed of soybean phospholipids (SPL), cholesterol (Chol) and PEI 800-Chol were prepared using film hydration method. The mean particle size of the PCLs was 133.0 nm and the zeta potential was 50.1+/-2.6 mV. Due to the PEI anchored onto the surface of liposomes, higher buffering capacity of PCLs was observed, indicating the potential for buffering in the acidic pH environment of the endosomes. Compared to Lipofectamine 2000, PCLs have equivalent transfection efficiency with significantly low cytotoxicity. Interestingly, the transfection activity of PCLs was not influenced in the presence of serum. Furthermore, we constructed another PCL composed of PEI 800-Chol and DOPE, and transfection efficiency increased notably. In conclusion, the PCLs described in this study have high transfection efficiency with low cytotoxicity, as well as the protection ability from serum, which suggests PCLs would be a potential non-viral gene delivery system. PMID- 17624700 TI - Biopharmaceutic evaluation of novel anthelmintic (1H-benzimidazol-5(6) yl)carboxamide derivatives. AB - Benzimidazole 2-carbamates, such as albendazole (ABZ) and mebendazole (MBZ), used for the treatment of helmintic infections, have low aqueous solubility and poor bioavailability, both of which lead to high interindividual variability when used for human systemic helmintiosis; therefore, it is necessary to search for new anthelmintics with better biopharmaceutical properties. In the present study the solubility, pKa, logP and apparent permeability in the Caco-2 cells system of four novel anthelmintic (1H-benzimidazol-5(6)-yl)carboxamide derivatives (compounds 1-4) with a 2-methylthyo group were evaluated. Also the pharmacokinetic parameters of compound 1 which in previous studies showed activity similar to ABZ against T. spirallis, was evaluated in BALB/c mice, as a representative molecule of the series. The novel anthelmintics, showed better solubility than ABZ in aqueous acid pH and in organic solvents. The logP, P(app) and Caco-2 data indicate that the 4 derivatives are highly permeable drugs, but it is possible that an efflux system could be involved in the transport of these compounds. Plasma levels of compound 1 and its sulfoxide (compound 5) were high after the first 5 min. This fact strongly suggests that compound 1 is rapidly metabolized in the small intestine. On the other hand, the sulfone metabolite (compound 6) levels were lower than those of compound 5. The half life and mean residence time (MRT) of compound 1 and its main metabolites indicate that their elimination is very rapid. More studies in mammalian species are necessary in order to understand the pharmacokinetic behavior of these novel compounds. PMID- 17624699 TI - Encapsulation of moxifloxacin within poly(butyl cyanoacrylate) nanoparticles enhances efficacy against intracellular Mycobacterium tuberculosis. AB - Macrophages in the lungs are the most important cell type supporting replication of Mycobacterium tuberculosis in humans. The objective of this study was to investigate whether the effect of moxifloxacin against M. tuberculosis residing in macrophages could be improved by encapsulation of the drug in the biodegradable nanoparticles, which are known to accumulate in macrophages upon intravenous administration. To accomplish this, moxifloxacin was encapsulated in poly(butyl cyanoacrylate) (PBCA) nanoparticles. Encapsulated moxifloxacin accumulated in macrophages approximately three-fold times more efficiently than the free drug, and was detected in the cells for at least six times longer than free moxifloxacin at the same extracellular concentration. Inhibition of intracellular M. tuberculosis growth with encapsulated moxifloxacin was achieved at the concentration of 0.1microg/ml, whereas the same effect with free MX required a concentration of 1microg/ml. Nanoparticles observed within the macrophage cytoplasm were distributed throughout the cytoplasm, sometimes in the vicinity of intracellular bacteria. PMID- 17624701 TI - Diffusion properties of model compounds in artificial sebum. AB - Sebaceous glands secrete an oily sebum into the hair follicle. Hence, it is necessary to understand the drug partition and diffusion properties in the sebum for the targeted delivery of therapeutic agents into the sebum-filled hair follicle. A new method was developed and used for determination of sebum flux of topical therapeutic agents and other model compounds. The drug transport through artificial sebum was conducted using sebum loaded filter (Transwell) as a membrane, drug suspensions as donor phases and HP-beta-CD buffer solution as a receiver phase. The experiment was performed at 37 degrees C for 2h. The results of the drug transport studies indicate that the flux (J(sebum)) through the artificial sebum is compound dependent and a bell-shaped curve was observed when logJ(s) versus alkyl side chain length of the compounds that proved to be different from the curves obtained upon plotting logJ skin versus clogP for the same compounds, indicating the possibility to select appropriate compounds for sebum targeted delivery based on the differences in the skin flux and sebum transport profiles of the molecules. PMID- 17624702 TI - Protein concentration and pH affect the apparent P-glycoprotein-ATPase activation kinetics. AB - Reliable predictions of the role of P-glycoprotein in the pharmacokinetics are needed already at the early stage of drug development. In order to obtain meaningful in vitro-in vivo scaling factors, it is essential to know the factors affecting the in vitro results. In this study, the apparent P-glycoprotein-ATPase activation kinetics were determined using the cell membrane fraction of human MDR1-transfected insect cells. The apparent affinities to P-glycoprotein of basic verapamil and quinidine were higher at pH 7.4 than at pH 6.8. However, this shift in pH did not have a significant effect on the apparent affinity of acidic monensin. The protein concentration used in the assay did not affect the apparent activator affinities, but was inversely related to the maximum activation achieved. Thus, pH and protein concentration should be taken into account when interpreting the Pgp-ATPase data. PMID- 17624703 TI - Evaluation of in vitro brain penetration: optimized PAMPA and MDCKII-MDR1 assay comparison. AB - Parallel artificial membrane permeability assay (PAMPA) is arising in ADMET screening as a powerful tool to determine the passive permeability of new potential chemical entities. In an attempt to set up a sensitive high throughput method to assess passive blood-brain barrier (BBB) penetration we focused our attention on the effect of solvent and the influence of phospholipids on the permeability in PAMPA. Moreover, the high throughput nature of the assay was maximized by decreasing the incubation time and performing the assay in a cassette mode. UPLC system coupled with a mass spectrometer enormously reduces the analytical time, contemporaneously increasing the sensitivity of the method. P(app) values obtained from PAMPA were compared to permeability values from MDCKII-MDR1 assay. Evaluation of the two in vitro models with in vivo data was performed to test the predicting capacity of the two methods. Their contemporary assessment was shown to be an helpful tool in understanding the prevalent mechanism of penetration through the BBB. PMID- 17624705 TI - Discrimination of pencil markings on paper using elemental analysis: an initial investigation. AB - The characterisation and comparison of pencil markings on paper is an area of questioned document analysis that has previously not received much attention. Despite this, there would be value in an examiner being able to analyse two pencil markings and coming to a conclusion about whether they were from a similar or different source. Previous studies have analysed raw materials and bulk pencil cores for purposes of characterisation and differentiation, but to date, no studies have successfully analysed pencil markings non-destructively off a paper substrate. In this work, pencils from a number of manufacturers were analysed by inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Analysis of data using multivariate techniques (principal component analysis), showed that ToF-SIMS can successfully be used to analyse such pencil markings to deduce whether two markings can be differentiated, in terms of inorganic elemental composition. It was possible to discriminate between pencil markings from different manufacturers, and it was also indicated that pencils from the same manufacturer, but discrete batches, can be significantly different. PMID- 17624704 TI - Inhibition of Escherichia coli heat-labile enterotoxin-induced diarrhea by Chaenomeles speciosa. AB - Enterotoxigenic Escherichia coli (ETEC) is responsible for millions of deaths in developing countries. Heat-labile enterotoxin (LT), the virulence factor of ETEC, induces diarrhea by initially binding to the G(M1) on the surface of intestinal epithelial cells and consequently leading to the massive loss of fluid and ions from cells. Fruit of Chaenomeles (FC), the dried fruit of Chaenomeles speciosa, has been used for diarrhea in China. However, the anti-diarrheal mechanism of FC is still unclear. In this study, we demonstrated that FC extract (FCE) inhibited the LT-induced diarrhea in mice by blocking the binding of the B subunit of LT (LTB) to G(M1). The ethyl acetate (EA) soluble fraction was the most active fraction of FC that significantly abolished the LTB and G(M1) interaction. Furthermore, the oleanolic acid, ursolic acid, and betulinic acid from EA fraction, blocked the toxin binding effects, resulting in the suppression of LT induced diarrhea. Moreover, by docking techniques, these compounds fitted LTB well via hydrogen bonds and hydrophobic contacts with amino acid residues of LTB. In conclusion, our findings suggested that oleanolic acid, ursolic acid, and betulinic acid were the active constituents from FC and might be considered as lead therapeutic agents in the treatment of LT-induced diarrhea. PMID- 17624706 TI - Development and validation of the Cozart DDS oral fluid collection device. AB - The testing of oral fluid for drugs of abuse has increased significantly over recent years and is now commonplace in drug rehabilitation clinics, the workplace, prisons and custody suites. The global problem of identifying drugged drivers has also led to an increase in oral fluid testing at the roadside. The main requirements for the implementation of roadside drug testing are a rapid sample collection time, collection of a known sample volume and recovery of drugs from the collection device. We report here the development of the Cozart DDS oral fluid collector, an oral fluid collector that combines rapid and adequate sample collection with satisfactory drug recovery. Oral fluid was collected from drug users (n=134) and drug-free individuals (n=137), using the Cozart DDS oral fluid collector. The mean time for the completion of collection (full coloration of the sample presence indicator) was 34 s for drug-free individuals and 44 s for drug users. The average volume collected was 0.34 mL (n=271). No chemical stimulant (to induce salivation) was used to achieve the collection times observed in either the drug-free or the drug-taking sample populations. Drugs were extracted from the collector using the Cozart DDS buffer and drug recovery was determined by Cozart enzyme immunoassays. The recovery studies showed that for amphetamine, Delta(9)THC, cocaine, methadone, methamphetamine, morphine and temazepam over 90% of the drug in the sample was eluted from the collector. The Cozart DDS oral fluid collector provides a reliable mechanism for the collection of oral fluid at the roadside that achieves the rapid collection times required. PMID- 17624707 TI - Sex determination from the distal part of the femur in a French contemporary population. AB - Until now, determining the sex of a recently deceased individual using the measurement of the bicondylar breadth of the femur (also known as condylar width, epicondylar breadth and distal epiphyseal breadth) raised some concerns as to accuracy because no sample of contemporary French subjects was available. In this study, a sample of 88 female and male femurs taken from recently deceased elderly French people was studied. The bones were collected from subjects who had donated their bodies to the Medical School of Nice. The mean value of the male bicondylar breadth was found to be greater than that of females (84.3mm versus 74.8mm), confirming the sexual dimorphism of this parameter. Furthermore, the results showed a 95.4% accuracy rate for sexing individuals. To date, in the French population, as in some other samples, epicondylar breadth is the single most accurate measurement of sex determination, ahead even of head diameter. A discriminant function is presented to allow sex determination from remains of the distal femur. With regard to the data available in the literature, sexual dimorphism is probably the result of both genetic and environmental factors. The comparison of our results with those of other populations shows that there are inter-population variations of the bicondylar breadth, and also intra-population variations that account for the differences in the accuracy rate of this variable for the purposes of sex determination. These findings underscore the need to re evaluate bone measurements within various contemporary populations. PMID- 17624708 TI - Visual function of a patient with advanced adrenoleukodystrophy: comparison of luminance and color contrast sensitivities. AB - We assessed achromatic luminance and isoluminant chromatic contrast sensitivity functions of a 20-year-old male. He showed severe motor and intellectual disabilities after advanced adrenoleukodystrophy, which started at the age of 7. Optokinetic nystagmus (OKN) to drifting gratings was used to assess his contrast sensitivities. Although the achromatic luminance contrast sensitivities were lower over the entire range of spatial frequencies tested than those of the healthy adults, they were preserved to the level comparable to healthy 7-year-old children, except for the frequency of 1 and 4 cycles/degree. In contrast, both of the red-green and blue chromatic contrast sensitivities were remarkably lower in all frequency range compare to healthy children and adults. These results indicate that it is possible for even an advanced case of ALD to show residual visual capacity that was preserved to a remarkable extent. PMID- 17624709 TI - Adipogenic signaling in rat white adipose tissue: modulation by aging and calorie restriction. AB - Alterations in adipogenesis could have significant impact on several aging processes. We previously reported that calorie restriction (CR) in rats significantly increases the level of circulating adiponectin, a distinctive marker of differentiated adipocytes, leading to a concerted modulation in the expression of key transcription target genes and, as a result, to increased fatty acid oxidation and reduced deleterious lipid accumulation in other tissues. These findings led us to investigate further the effects of aging on adipocytes and to determine how CR modulates adipogenic signaling in vivo. CR for 2 and 25 months, significantly increased the expression of PPARgamma, C/EBPbeta and Cdk-4, and partially attenuated age-related decline in C/EBPalpha expression relative to rats fed ad libitum (AL). As a result, adiponectin was upregulated at both mRNA and protein levels, resulting in activation of target genes involved in fatty acid oxidation and fatty acid synthesis, and greater responsiveness of adipose tissue to insulin. Moreover, CR significantly decreased the ratio of C/EBPbeta isoforms LAP/LIP, suggesting the suppression of gene transcription associated with terminal differentiation while facilitating preadipocytes proliferation. Morphometric analysis revealed a greater number of small adipocytes in CR relative to AL feeding. Immunostaining confirmed that small adipocytes were more strongly positive for adiponectin than the large ones. Overall these results suggest that CR increased the expression of adipogenic factors, and maintained the differentiated state of adipocytes, which is critically important for adiponectin biosynthesis and insulin sensitivity. PMID- 17624710 TI - Pulmonary infections following bone marrow transplantation: high-resolution CT findings in 35 paediatric patients. AB - PURPOSE: The purpose of this study was to assess the high-resolution CT findings of paediatric patients who had pulmonary infections following bone marrow transplantation (BMT), and to evaluate the differential diagnosis through high resolution CT of the various pathogens responsible for pulmonary infections after BMT. PATIENTS AND METHODS: The study included 35 consecutive patients who had documented pulmonary infection, high-resolution CT of the chest performed within 24h of the beginning of symptoms, and proven diagnosis within 1 week of the onset of symptoms. The pulmonary infections were due to viruses (n=16), bacteria (n=9), fungi (n=9), and protozoa (n=1). Two radiologists analyzed the CT scans and reached final decisions regarding the findings by consensus. RESULTS: Four patients with confirmed pneumonia had normal high-resolution CT scans. Regarding the viral infections, the most frequent features were areas of ground-glass attenuation (43.7%) and small centrilobular nodules (31.2%). Airspace consolidation (88.9%), small centrilobular nodules (22.2%) and ground-glass attenuation (22.2%) were the most frequent findings in patients with bacterial pneumonia following BMT. Large nodules were seen in 66.7% of the patients with fungal pneumonia, and in only one case of virus infection. The "halo sign" (n=5) was seen only in patients with fungal pneumonia. CONCLUSION: In conclusion, the main causes of pulmonary infection in paediatric patients following BMT share similar high-resolution CT findings. Large nodules and "halo sign" are more common in patients with fungal infections. PMID- 17624711 TI - Identification and characterization of new impurity in didanosine. AB - Didanosine is an antiviral drug. During the preparation of didanosine in our lab, six process related known impurities and one unknown impurity were detected in HPLC analysis at levels ranging from 0.05 to 0.8%. The same unknown impurity was also observed in commercial batches. This new impurity was isolated by preparative HPLC and co-injected with didanosine sample to confirm the retention times in HPLC. This impurity was characterized as, 9-(2,3,5-trideoxy-beta-D glycero-pentofuranosyl)-9H-purin-6-one (2',3',5'-trideoxyinosine). Structural elucidation of this impurity by spectral data (1H NMR, 13C NMR, MS and IR) has been discussed. PMID- 17624712 TI - Effect of gestational ethanol exposure on long-term memory formation in newborn chicks. AB - Fetal alcohol syndrome (FAS), a condition occurring in some children of mothers who have consumed alcohol during pregnancy, is characterized by craniofacial malformations, and physical and mental retardation. It is significant that even children with history of gestational ethanol exposure but relatively unaffected overall IQ performance, often exhibit learning difficulties and behavioral problems, suggestive of impaired memory formation. Hence, the specific aim of this study was to examine memory formation in chicks exposed to ethanol during early gestation toward the understanding of neurobehavioral disturbances in FAS. Chicks were exposed to alcohol on gestational days 1-3 by injection of ethanol into the airspace of freshly fertilized eggs. The effects of prenatal ethanol on physical growth and development, and memory formation were studied. The one-trial passive avoidance learning paradigm in 1-day-old chicks was used to study memory formation in these chicks. It was observed that chick embryos exposed to 10% ethanol on gestational days 1-3 had significant reduction in all body parameters when compared with appropriate controls. Further, ethanol-exposed chick embryos had significantly impaired (P<.05) long-term memory (LTM) formation after training, though short-term or intermediate-term memory formation was unimpaired. Thus, the findings of the current study demonstrate the detrimental effects of ethanol exposure during early pregnancy on developing chick embryos in general and on memory formation in particular. Hence, it is suggested that impairment in LTM could be a fundamental mechanism for learning disorders and neurobehavioral abnormalities observed in FAS. PMID- 17624713 TI - Ratio of metastatic lymph nodes: impact on staging and survival of gastric cancer. AB - AIMS: No consensus exists on the level and number of lymph nodes to be dissected and examined for accurate staging of patients with resectable gastric cancer. The aim of this study was to examine the prognostic value and staging accuracy of the metastatic lymph nodes ratio (NR). METHODS: The postoperative survival of 247 patients with gastric cancer who underwent gastrectomy was analyzed. Lymph nodes status was assigned according to three different classifications: 6th UICC/AJCC TNM; JGCA; NR (NR0: 0%; NR1: < or =20%; NR2: >20%). Staging accuracy of the three classifications was compared according to patients survival. RESULTS: A significant difference in survival was observed in patients with NR1 versus NR2. At multivariate analysis only NR along with pT and grading were found to be independent prognostic factors. Stage migration was present in 84 cases (51%) with JGCA classification, in 30 (19%) with 6th UICC/AJCC TNM classification and in only 18 cases (11%) when NR was applied. CONCLUSIONS: Our data showed that NR is a simply reproducible and highly reliable staging system with a strong ability to predict patients' outcome. Compared to other nodal staging classifications, NR is less influenced from the number of the lymph nodes dissected and examined, reducing the stage migration phenomenon. PMID- 17624714 TI - Expression analysis of proteases of Mycobacterium leprae in human skin lesions. AB - Proteases are commonly involved in bacterial pathogenesis and their inhibition has represented a successful therapeutic approach to treat infectious diseases. However, there is little information on the role of proteases in the pathogenesis of Mycobacteria. Five of these genes, three coding for putative secreted proteases, were selected in the present study to investigate their expression in Mycobacterium leprae isolated from skin biopsies of multibacillary leprosy patients. Via nested-PCR, it was demonstrated that mycP1 or ML0041, htrA2 or ML0176, htrA4 or ML2659, gcp or ML0379 and clpC or ML0235 are transcribed in vivo during the course of human infection. Moreover, the expression of Gcp in leprosy lesions was further confirmed by immunohistochemistry using a specific hyperimmune serum. This observation reinforces the potential role of mycobacterial proteases in the context of leprosy pathogenesis. PMID- 17624715 TI - The human placenta--an alternative for studying foetal exposure. AB - Pregnant women are daily exposed to a wide selection of foreign substances. Sources are as different as lifestyle factors (smoking, daily care products, alcohol consumption, etc.), maternal medication or occupational/environmental exposures. The placenta provides the link between mother and foetus, and though its main task is to act as a barrier and transport nutrients and oxygen to the foetus, many foreign compounds are transported across the placenta to some degree and may therefore influence the unborn child. Foetal exposures to environmental and medicinal products may have impact on the growth of the foetus (e.g. cigarette smoke) and development of the foetal organs (e.g. methylmercury and thalidomide). The scope of this review is to give insight to the placental anatomy, development and function. Furthermore, the compounds physical properties and the transfer mechanism across the placental barrier are evaluated. In order to determine the actual foetal risk from exposure to a chemical many studies regarding the topic are necessary, including means of transportation, toxicological targets and effects. For this purpose several in vivo and in vitro models including the placental perfusion system are models of choice. PMID- 17624716 TI - Taurine, a conditionally essential amino acid, ameliorates arsenic-induced cytotoxicity in murine hepatocytes. AB - Arsenic is a potent environmental toxin. Present study has been designed to evaluate the protective role of taurine (2-aminoethanesulfonic acid) against arsenic induced cytotoxicity in murine hepatocytes. Sodium arsenite (NaAsO(2)) was chosen as the source of arsenic. Incubation of hepatocytes with the toxin (1 mM) for 2 h reduced the cell viability as well as intra-cellular antioxidant power. Increased activities of alanine transaminase (ALT) and alkaline phosphatase (ALP) due to toxin exposure confirmed membrane damage. Toxin treatment caused reduction in the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx). In addition, the same treatment reduced the level of glutathione (GSH), elevated the level of oxidized glutathione (GSSG) and increased the extent of lipid peroxidation. Incubation of hepatocytes with taurine, both prior to and in combination with NaAsO(2), attenuated the extent of lipid peroxidation and enhanced the activities of enzymatic as well as non enzymatic antioxidants. Besides, taurine administration normalized the arsenic-induced enhanced levels of the marker enzymes ALT and ALP in hepatocytes. The cytoprotective activity of taurine against arsenic poisoning was found to be comparable to that of a known antioxidant, vitamin C. Combining all, the results suggest that taurine protects mouse hepatocytes against arsenic induced cytotoxicity. PMID- 17624717 TI - Facial attractiveness ratings and perfectionism in body dysmorphic disorder and obsessive-compulsive disorder. AB - Individuals with body dysmorphic disorder (BDD) suffer from a preoccupation about imagined or slight appearance flaws. We evaluated facial physical attractiveness ratings and perfectionistic thinking among individuals with BDD (n=19), individuals with obsessive-compulsive disorder (OCD; n=21), and mentally healthy control participants (n=21). We presented participants with photographs displaying faces varying in facial attractiveness (attractive, average, unattractive) and asked them to rate them in terms of their physical attractiveness. We further examined how the participants evaluated their own physical attractiveness, relative to independent evaluators (IEs). As predicted, BDD participants perceived their own attractiveness as significantly lower than did the IEs, and they rated photographs from the category "Attractive" as significantly more attractive than did the other groups. Furthermore, both clinical groups were characterized by more perfectionistic thinking than controls. These findings mostly support cognitive-behavioral models of BDD that suggest that individuals with BDD exhibit perfectionistic thinking and maladaptive attractiveness beliefs. PMID- 17624718 TI - Inhibitory effects of lipopolysaccharide on hypothalamic nuclei implicated in the control of food intake. AB - The arcuate nucleus (Arc) and the lateral hypothalamic area (LHA), two key hypothalamic nuclei regulating feeding behavior, express c-Fos, a marker of neuronal activation in fasted animals. This is reversed by refeeding. In the present study we tested whether an anorectic dose of lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, also inhibits fasting-induced c-Fos expression in these hypothalamic nuclei. This would suggest that they are involved in anorexia during bacterial infections as well. We also studied whether LPS modulates the activity of orexin-A positive (OX+) LHA neurons. Food deprived BALB/c mice were injected with LPS or saline and were sacrificed 4 or 6h later. Four hours after injection, LPS reduced the number of c-Fos positive cells in the Arc and in the LHA, but had no effect on c-Fos in OX+ neurons. Six hours after injection, LPS reduced c-Fos expression in the LHA, both in the OX- and OX+ neurons, but not in the Arc. These results show that LPS modulates neuronal activity in the Arc and LHA similar to feeding-related stimuli, suggesting that the observed effects might contribute to the anorectic effect of LPS. Thus, physiological satiety signals released during refeeding and anorexia during bacterial infection seem to engage similar neuronal substrates. PMID- 17624719 TI - Yukmijihwang-tang protects against cyclophosphamide-induced reproductive toxicity. AB - A side effect of cyclophosphamide (CP), an alkylating agent widely used to treat tumors and autoimmune disorders, is the alteration of male reproductive function. Yukmijihwang-tang (YJT) is a multi-herbal medicinal formula that has been used in traditional Asian medicine to treat male reproductive problems. In this study, we investigated the effects of YJT on CP-induced reproductive toxicities in rat testes. Eight-week-old male Wistar rats were divided into three groups: vehicle treated (control), CP-treated and CP+YJT-treated groups. CP was administered for the first 7 days (20 mg/kg/day, p.o.), and YJT was administered for 56 days consecutively (1.0 g/kg/day, p.o.). The CP-treated group showed significant decreases in the weight of the testes, epididymal sperm count and sperm motility compared to the control group, while the CP+YJT-treated group had significant increases for these variables compared to the CP-treated group. The enhancement of lipid peroxidation by CP in the rat testes was reduced by YJT treatment. CP diminished the expression of cAMP-responsive element modulator (CREM), a transcription factor that is highly expressed in male germ cells and is crucial to post-meiotic germ cell differentiation. YJT restored CREM at both the mRNA and protein levels. These results suggest that YJT has a protective effect against CP induced reproductive toxicities by inhibiting the increases in lipid peroxidation and enhancing CREM expression. PMID- 17624720 TI - Aflatoxin treatment brings about generation of multinucleate giant spermatids (symplasts) through opening of cytoplasmic bridges: light and transmission electron microscopic study in Swiss mouse. AB - Aflatoxins are dietary mycotoxins, which are a health hazard. Sub-symptomatic exposure to aflatoxins is known to produce male reproductive toxic effects with several manifestations. With a view to find if aflatoxins would produce multinucleate giant cells or symplasts in the seminiferous epithelium, we treated male Swiss mice with aflatoxin B(1) for 35 days and subjected the testis to light and transmission electron microscopic analysis. We found abundant symplastic spermatids in the seminiferous epithelium of treated mice. The origin of these cells was traced to opening of cytoplamic bridges. Due to widening of cytoplasmic bridge, the cytoplasm of spermatid(s) in a clone entered a cytoplasm-rich spermatid, followed by the nucleus/nuclei. Subsequently, the bridge(s) collapsed resulting in spherical symplasts. The study, in addition to revealing yet another manifestation of aflatoxin-induced disruption of spermatogenesis, also provides first direct evidence for opening of cytoplasmic bridges as the mechanism underlying origin of spermatid symplasts. PMID- 17624721 TI - Development and validation of microarray-based assay for epidemiological study of MRSA. AB - We have developed a microarray-based assay for the genotyping of Staphylococcus aureus strains. A DNA microarray consisting of 221 genes with 390 oligonucleotide probes was designed to identify characteristic genes or gene alleles of S. aureus. The 221 genes were chosen on the basis of the following criteria: (i) genes used as control for the microarray system, (ii) virulence genes, (iii) resistance genes and their regulators, and (iv) genes constituting genomic islands, e.g., SCCmec. The microarray system was established by determining the method to prepare targets by random-primer labeling with chromosomal DNA and the conditions for hybridization. We verified the system by using DNAs of seven strains, the genome of which has been fully sequenced. Furthermore, the presence of 32 genes and the types of SCCmec elements and coagulase genes carried by another 27 strains were examined and compared with the results of PCR. As a result, the presence or absence of 182 genes out of the 221 genes was verified. Our data showed the usefulness of the oligonucleotide microarray based assay in identifying important marker sets, such as toxin genes, resistance genes, SCCmec elements, and coagulase genes, for the molecular epidemiology of S. aureus. PMID- 17624722 TI - Distribution and morphology of cholinergic, putative catecholaminergic and serotonergic neurons in the brain of the Egyptian rousette flying fox, Rousettus aegyptiacus. AB - Over the past decade much controversy has surrounded the hypothesis that the megachiroptera, or megabats, share unique neural characteristics with the primates. These observations, which include similarities in visual pathways, have suggested that the megabats are more closely related to the primates than to the other group of the Chiropteran order, the microbats, and suggests a diphyletic origin of the Chiroptera. To contribute data relevant to this debate, we used immunohistochemical techniques to reveal the architecture of the neuromodulatory systems of the Egyptian rousette (Rousettus aegypticus), an echolocating megabat. Our findings revealed many similarities in the nuclear parcellation of the cholinergic, putative catecholaminergic and serotonergic systems with that seen in other mammals including the microbat. However, there were 11 discrete nuclei forming part of these systems in the brain of the megabat studied that were not evident in an earlier study of a microbat. The occurrence of these nuclei align the megabat studied more closely with primates than any other mammalian group and clearly distinguishes them from the microbat, which aligns with the insectivores. The neural systems investigated are not related to such Chiropteran specializations as echolocation, flight, vision or olfaction. If neural characteristics are considered strong indicators of phylogenetic relationships, then the data of the current study strongly supports the diphyletic origin of Chiroptera and aligns the megabat most closely with primates in agreement with studies of other neural characters. PMID- 17624723 TI - Age-related changes in long-term average spectra of children's voices. AB - This paper forms part of a larger study into the nature of singing development in children. The focus here is on an investigation of age-related changes in long term average spectra (LTAS). Three hundred and twenty children in age groups 4-11 years learned a song. Each child was then digitally recorded singing alone. LTAS curves were calculated from the recordings of each voice and perceived age was estimated by a panel of independent judges. Progressive statistically significant changes were observed in the LTAS as a function of increasing age of the children. These took the form of increases in spectral energy in all frequencies below 5.75 kHz, with concomitant reductions of energy in frequency regions above this point. Increases with age were also found in overall intensity levels of the vocal products. Four experienced listeners audited the voice samples and made estimates of the children's ages. The level of accuracy of age-estimates was remarkably high for children in the youngest age groups, but was reduced with voice samples from older children. Maturation and developing competence of the vocal system, both in growth of lung capacity and at a laryngeal level, are implicated in the generation of age-related spectral changes. Perceived child singer age appears to be less closely related to spectral characteristics (as defined within LTAS) with increasing age of children. PMID- 17624724 TI - Increasing the closed quotient improves voice quality after type I thyroplasty in patients with unilateral vocal cord paralysis: analysis using SPEAD program. AB - The aim of this study was to determine the importance of the closed quotient in the improvement of voice quality after medialization thyroplasty by measuring acoustic parameters at the sentence level. The clinical records of patients who received type I thyroplasty were reviewed retrospectively. All of the patients underwent the perceptual, acoustic, and aerodynamic evaluation before the surgery and on the 60th postoperative day. The perceptual and acoustic measurements were obtained from a recording of a passage read aloud by the patients. Acoustic and aerodynamic parameters were investigated. A paired t test was used to compare presurgery and postoperative results. A correlation analysis was also used to discern which parameters were most correlated with improvement of postoperative voice quality. Statistically significant improvements were observed in subglottic pressure (Psub), maximum phonation time, and mean flow rate. Average fundamental frequency and average closed quotients were found to be the parameters that were most associated with an improvement of postoperative breathiness. The /G/ grade of GRBAS scale quality was found to be most associated with Psub and shimmer (P<0.05). An increase of the contact area of both vocal folds induced improvement in aerodynamic parameters and led to the stabilization of vocal fold vibration. This effect resulted in improvement of the acoustic parameters (shimmer, jitter, signal-to-noise ratio, voice range profile) and voice quality. PMID- 17624725 TI - Vocal symptoms and allergy--a pilot study. AB - Allergic rhinitis and asthma are common among university students. Inhalant allergies have been considered to be a risk factor contributing to voice disorders. The purpose of this pilot study was to determine if students with confirmed respiratory allergies have frequently occurring vocal symptoms. A questionnaire concerning the prevalence of vocal symptoms was distributed to 49 students attending a 3-year allergen immunotherapy program and to 54 students without known allergy. The results indicated that subjects with allergy report significantly more vocal symptoms than subjects without allergy. Allergy should be considered as an underlying factor for vocal symptoms, especially for persons who work in or study for vocally demanding occupations. PMID- 17624726 TI - Matrix Metalloproteinases (MMP-2 and MMP-9) and cyclooxygenase-2 (COX-2) expressions in vocal fold polyps. AB - The objective of this study was to investigate the roles of matrix metalloproteinases (MMP-2, MMP-9) and cyclooxygenase-2 (COX-2) in the pathogenesis of vocal fold polyps (VFPs). In this study, 20 VFPs and 8 normal vocal fold (VF) specimens were obtained from subjects undergoing surgery. Staining intensities were semiquantitatively assessed and statistically analyzed. Significant increases were observed in the expressions of MMP-2, MMP-9, and COX-2 in stromal spindle cells (P=0.00) and vascular wall (P=0.04, P=0.00, P=0.00) of VFPs compared with normal VFs. MMP-2 expression in surface epithelium basal cells (P=0.00) of VFPs showed enhancement compared with normal vocal folds, whereas MMP 9 and COX-2 expressions showed no significant differences. Our study showed that gelatinases and COX-2 may play a role in the development of VFPs. This is the first study to document the expression of gelatinases and COX-2 in VFPs. PMID- 17624727 TI - Machine learning approach to color constancy. AB - A number of machine learning (ML) techniques have recently been proposed to solve color constancy problem in computer vision. Neural networks (NNs) and support vector regression (SVR) in particular, have been shown to outperform many traditional color constancy algorithms. However, neither neural networks nor SVR were compared to simpler regression tools in those studies. In this article, we present results obtained with a linear technique known as ridge regression (RR) and show that it performs better than NNs, SVR, and gray world (GW) algorithm on the same dataset. We also perform uncertainty analysis for NNs, SVR, and RR using bootstrapping and show that ridge regression and SVR are more consistent than neural networks. The shorter training time and single parameter optimization of the proposed approach provides a potential scope for real time video tracking application. PMID- 17624728 TI - An abbreviated carotid intima-media thickness scanning protocol to facilitate clinical screening for subclinical atherosclerosis. AB - BACKGROUND: Carotid intima-media thickness (CIMT) testing can assist with cardiovascular risk prediction; however, the requirement for rigorous, time consuming protocols has limited it use in clinical practice. METHODS: Bilateral images of the common carotid artery (CCA), bulb, and internal carotid artery segments were obtained using a comprehensive scanning protocol. Three abbreviated scanning protocols were evaluated for their ability to identify patients with increased CIMT (> or = 75th percentile). RESULTS: Of 261 subjects, 134 (51.3%) had increased left or right CCA CIMT (CCA protocol), 136 (52.1%) had carotid plaque (plaque protocol), and 190 (72.7%) had plaque or at least one increased CCA CIMT (combination protocol). The area under the receiver-operator characteristic curves for the CCA (0.738) and combination protocols (0.692) were higher than the plaque protocol (0.625, P < .05). The combination protocol was 100% sensitive. CONCLUSIONS: Compared with a comprehensive scanning protocol, plaque screening with measurement of far wall CCA CIMT identifies all patients with increased CIMT. PMID- 17624729 TI - Unruptured giant aneurysm of sinus of valsalva. AB - An apparently healthy young adult was referred for echocardiography because of a cardiac 2/6 diastolic murmur, heard during physical examination in the context of our competitive sports screening program. PMID- 17624730 TI - A large pediculated myxoma of the left ventricle causing outflow obstruction in a young man. AB - We report a case of a large mobile myxoma of the left ventricle that caused obstruction of the outflow tract. Transthoracic and transesophageal echocardiography defined the extent and location of the mass providing crucial information for surgical treatment, which was successful. PMID- 17624731 TI - Left atrial appendage collapse as a sole feature of cardiac tamponade after cardiac surgery: a case report. AB - We report on a postoperative patient with cardiac tamponade caused by posteriorly localized pericardial effusion. In this case, transthoracic echocardiography only suggested mild left atrial compression. However, transesophageal echocardiography demonstrated significant collapse of the left atrial appendage that completely disappeared after pericardial drainage. The left atrial appendage collapse should be a valuable diagnostic sign in this setting. Transesophageal echocardiography would surely be valuable in diagnosing postoperative cardiac tamponade as a result of localized effusion when clinical symptoms and transthoracic echocardiographic findings are atypical. PMID- 17624732 TI - Erk5 is activated and acts as a survival factor in mitosis. AB - Erk5 is a recently discovered MAPK claimed to be responsible for some of the roles attributed to Erk1/2; here we report that it is activated in mitosis in comparison to G1/S. When Erk5 is inactivated pharmacologically or largely ablated by RNAi, cell survival in mitosis is diminished. We have previously shown Bim, a BH3-only protein of the Bcl-2 family, to be phosphorylated in mitosis, in a MEK dependent manner (M. Graos, A. D. Almeida, S. Chatterjee, Biochem. J. 388 (2005) 185). Inactivation of Erk5 in mitosis causes dephosphorylation of Bim. Bim is in the mitochondria in mitosis and when dephosphorylated interacts with Bax, inducing caspase activation. We also show that in mitosis Bim co immunoprecipitates with Erk5 and Erk5 phosphorylates GST-Bim in in vitro kinase reaction. Taken together, our results identify a new target of the still largely mysterious Erk5 and suggest that Erk5 in mitosis may be a decisive step for the survival of proliferating cells. PMID- 17624733 TI - Levetiracetam attenuates spontaneous spike-and-wave discharges in DBA/2J mice. AB - Recent evidence highlights levetiracetam (LEV) as an advantageous treatment of absence epilepsy (AE). Thus, we investigated the effects of this drug in DBA/2J mice, a murine model of AE. Similarly to ethosuximide (200 mg/kg, intraperitoneal, i.p.) and sodium valproate (250 mg/kg, i.p.), two classic antiabsence agents, LEV (50-200 mg/kg, i.p.) reduced the occurrence of spike-and wave discharges, AE's typical electroencephalographic patterns. Our results confirm LEV's efficacy in AE treatment. PMID- 17624734 TI - Valproate selectively reduces EEG activity in anterior parts of the cortex in patients with idiopathic generalized epilepsy. A low resolution electromagnetic tomography (LORETA) study. AB - PURPOSE: To localize the cortical area where the anticonvulsive drug valproate (VPA) exerts its effect in patients with idiopathic generalized epilepsy (IGE). METHODS: In a prior study we investigated 15 IGE patients in the untreated condition and compared their low resolution electromagnetic tomography (LORETA) results to a normal control group. The investigation of these patients was continued in the present study. All the 15 patients were treated with VPA and were followed by the authors. EEG was recorded after 3 months of VPA treatment in the seizure-free patients. A total of 2min of 19-channels, common reference recorded, waking-relaxed background activity (without paroxysmal and other, non stationary elements) was analyzed. "Activity" (current density, amper/meters squared) was given in four frequency bands (delta, theta, alpha, beta). Band related group differences between the present LORETA results (treated condition) and the prior LORETA results (untreated condition) were computed for all the 2394 voxels by t-tests for interdependent datasets. The statistically significant (p<0.01, uncorrected) differences of activity were projected to real cortical anatomy using the Talairach Brain Atlas. RESULTS: Statistically significant differences between the untreated and treated condition emerged in the delta and theta bands. VPA decreased delta and theta activity in the entire frontal cortex, insula, anterior temporal cortex and hippocampus, and in the anterior part of the parietal cortex. CONCLUSIONS: VPA decreased activity in parts of the cortex that display ictogenic properties and contribute to seizure generation in IGE. Furthermore, the anatomical distribution of the drug effect exactly corresponded to the VPA-related accumulation of neuroprotective proteins reported in experimental papers. PMID- 17624735 TI - Is Rolandic epilepsy associated with abnormal findings on cranial MRI? AB - Rolandic epilepsy (RE) is designated an idiopathic epilepsy syndrome, and hence no lesional abnormalities are expected on MRI exam. Recent reports suggest that MRI abnormalities are not only common, but may be specific for temporal lobe epilepsy, and lateralized to the side of EEG discharges. However, no controlled study has been performed to test the hypothesis of association between MRI abnormalities and Rolandic epilepsy. We performed an unmatched case-control study to test the hypothesis of association between MRI abnormalities and Rolandic epilepsy, using 25 typical RE cases and 25 children with migraine. Two independent examiners rated the MRIs for abnormalities. Examiners were blinded to the study hypothesis and identity of case and control exams. Fifty-two percent of RE exams contained at least one abnormality: peri/hippocampal abnormality (one case), non-localized congenital malformation (seven cases), subcortical parenchymal hyperintensities (two cases), periventricular parenchymal hyperintensities (one case), dilated perivascular spaces (six cases). There was no difference between the number or type of abnormalities in cases and controls. No type of abnormality lateralized to the hemisphere from which the EEG spikes emanated. The odds ratio of association between MRI abnormalities and RE was 0.87, 95% CI: 0.18-4.33 after adjusting for potential demographic and technical factors. We conclude that routine cranial MRI abnormalities are common in RE, but no more common than in controls, and not specific for RE. PMID- 17624737 TI - Validation of epilepsy diagnoses in the Danish National Hospital Register. AB - PURPOSE: To validate the diagnosis of epilepsy in the Danish National Hospital Register. METHODS: We randomly selected 200 patients registered with epilepsy in the Danish National Hospital Register between 1977 and 2002 and validated the diagnosis according to the guidelines developed by the International League Against Epilepsy. RESULTS: We reviewed the medical records of 188 (94%) persons from 57 departments at 41 hospitals. The epilepsy diagnoses were confirmed in 153 patients, providing a positive predictive value for epilepsy of 81% (95% confidence interval (95% CI): 75-87%). Among the 35 patients who did not fulfill the criteria for epilepsy, 14 were admitted after a single, unprovoked seizure. Among patients registered with epilepsy the positive predictive value of seizure disorder was 89% (95% CI: 83-93%). Among patients classified with epilepsy syndromes, the positive predictive value for syndrome classification was 60% (95% CI: 44-74%) for epilepsy with complex focal seizures and 35% (95% CI: 22-51%) for primary generalized epilepsy. CONCLUSION: The validity of the epilepsy diagnoses in the Danish National Hospital Register has a moderate to high positive predictive value for epilepsy, but a relatively low predictive value for epilepsy syndromes. PMID- 17624736 TI - In vitro status epilepticus but not spontaneous recurrent seizures cause cell death in cultured hippocampal neurons. AB - It is established that the majority but not all of the seizure-induced cell death is associated with status epilepticus while spontaneous recurrent seizures associated with epilepsy do not cause neuronal death. Extracellular effects and compensatory changes in brain physiology complicate assessment of neuronal death in vivo as the result of seizures. In this study we utilized a well-characterized in vitro hippocampal neuronal culture model of both continuous high-frequency epileptiform discharges (status epilepticus) and spontaneous recurrent epileptiform discharges (acquired epilepsy) to investigate the direct effects of continuous and episodic electrographic epileptiform discharges on cell death in a carefully controlled extracellular environment. The results from this study indicate that continuous high-frequency epileptiform discharges can cause neuronal death in a time-dependent manner. Episodic epileptiform seizure activity occurring for the life of the neurons in culture was not associated with increased neuronal cell death. Our data confirm observations from clinical and some animal studies that spontaneous recurrent seizures do not initiate cell death. The hippocampal neuronal culture model provides a powerful in vitro tool for carefully evaluating the effects of seizure activity alone on neuronal viability in the absence of various confounding factors and may provide new insights into the development of novel therapeutic agents to prevent neuronal injury during status epilepticus. PMID- 17624738 TI - Absence of Smad3 confers radioprotection through modulation of ERK-MAPK in primary dermal fibroblasts. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1), a key biological mediator following ionizing radiation, plays a role in a complex tissue reaction involved in local radiation-induced pathological damage. Knocking out Smad3 (S3KO), a downstream signaling intermediate in the TGF-beta pathway, in mice protects their skin from radiation damage as demonstrated by decreased epithelial acanthosis and dermal fibrosis as compared to Smad3 wild-type (S3WT) mice. OBJECTIVE: The present study was designed to investigate the molecular mechanisms contributing to increased radioprotection in the absence of Smad3. METHODS: Primary dermal fibroblasts derived from S3WT and KO mice were exposed to 5Gy ionizing radiation in vitro. Western blot analyses, immunocytochemistry, and reporter transfections were used to dissect the radiation-induced events. RESULTS: There was increased phosphorylation of ERK-MAPK, p53 and H2A.X in S3KO compared to the S3WT fibroblasts, implicating them in a key signaling cascade in response of these cells to radiation. Pro-fibrotic gene expression was decreased in S3KO fibroblasts post-irradiation. CONCLUSION: The absence of Smad3 may decrease radio-responsiveness by increasing activation of DNA damage sensing mechanisms and decreasing induction of pro-fibrotic genes. PMID- 17624739 TI - Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases. AB - Skin undergoes self-renewal throughout life. Terminally differentiated keratinocytes, namely the corneocytes, are continually shed from the surface of the skin, whereas immature cells produce progeny that proceed through the differentiation process. Notch signaling controls a number of cellular processes including cell fate decision, proliferation, differentiation and survival/apoptosis. Hence, Notch and its ligands are expressed in multiple tissues including the skin, where they are abundantly expressed in the epidermis. Notch activation results in the promotion of growth arrest and the onset of differentiation, therefore suggesting that specific Notch activation may regulate skin homeostasis by balancing these processes, i.e. Notch signaling functions as a molecular switch that controls the transition of cells between skin layers during the epidermal differentiation process. Recent advances in the study of Notch signaling have confirmed that there is cross-talk between the Notch signaling pathway and a variety of other signaling molecules including Sonic hedgehog (Shh), beta-catenin and the p53 family member, p63. The absence of Notch activity allows Wnt and Shh signaling to persist in a tissue where they are normally repressed. In addition, Notch counteracts the action of p63 to maintain immature cell characteristics. However, aberrant Notch signaling results in the development of psoriasis and skin cancers such as squamous cell carcinoma, basal cell carcinoma and malignant melanoma. Future efforts to further define how Notch controls cell proliferation and differentiation may lead to the application of Notch in new therapies for various skin diseases. PMID- 17624740 TI - Limitations of current medical treatments for depression: disturbed circadian rhythms as a possible therapeutic target. AB - The proportion of diagnosed depressives prescribed antidepressants has increased markedly over the last 20 years, mainly following the introduction of the selective serotonin reuptake inhibitors. However, currently available antidepressants have notable limitations, relating to their only moderate efficacy relative to placebo, relatively slow onset of action, possible withdrawal symptoms, and problems of compliance. Sleep disturbances are often used to identify newly presenting depressive patients, and may be part of a more general alteration of bodily rhythms. There are links between pharmacological treatments and circadian rhythms in depression, which might represent another, new option for the development of a therapeutic approach to depression treatment. Many antidepressants affect sleep, some are sedative, and others have been used specifically in severely insomniac depressives. Disturbances in circadian rhythms may be an integral part of depressive mechanisms, and normalising them via an innovative mechanism of antidepressant action may be a fruitful avenue in the search for improved antidepressant agents. PMID- 17624741 TI - Cis-regulation of the amphioxus engrailed gene: insights into evolution of a muscle-specific enhancer. AB - To gain insights into the relation between evolution of cis-regulatory DNA and evolution of gene function, we identified tissue-specific enhancers of the engrailed gene of the basal chordate amphioxus (Branchiostoma floridae) and compared their ability to direct expression in both amphioxus and its nearest chordate relative, the tunicate Ciona intestinalis. In amphioxus embryos, the native engrailed gene is expressed in three domains - the eight most anterior somites, a few cells in the central nervous system (CNS) and a few ectodermal cells. In contrast, in C. intestinalis, in which muscle development is highly divergent, engrailed expression is limited to the CNS. To characterize the tissue specific enhancers of amphioxus engrailed, we first showed that 7.8kb of upstream DNA of amphioxus engrailed directs expression to all three domains in amphioxus that express the native gene. We then identified the amphioxus engrailed muscle specific enhancer as the 1.2kb region of upstream DNA with the highest sequence identity to the mouse en-2 jaw muscle enhancer. This amphioxus enhancer directed expression to both the somites in amphioxus and to the larval muscles in C. intestinalis. These results show that even though expression of the native engrailed has apparently been lost in developing C. intestinalis muscles, they express the transcription factors necessary to activate transcription from the amphioxus engrailed enhancer, suggesting that gene networks may not be completely disrupted if an individual component is lost. PMID- 17624742 TI - Encapsulation of crosslinked subtilisin microcrystals in hydrogel beads for controlled release applications. AB - Enzymes are less stable in harsh conditions and hence to overcome this nature, several methodologies are being developed. It was found that crosslinked enzyme crystals are the most promising strategy for the stabilization of the enzymes [Emilia Abraham, T., Jegan Roy, J., Bindhu, L.V., Jayakumar, K.K., 2004. Crosslinked enzyme crystals of glucoamylase as a potent catalyst for biotransformations. Carbohydr. Res. 339, 1099-1104; Navia, M., St. Clair, N., 1997. Crosslinked enzyme crystals. Biosens. Bioelectron. 12, 7]. A cost effective methodology of crystallization of protease (Bacillus subtilis) with ammonium sulphate (65%, w/v) and then crosslinking the crystals with glutaraldehyde (4%, v/v) in isopropanol for 20min gave a stable and active enzyme. SEM studies showed that the protease is in small cubic shaped crystals of 1-2 microm size. Crosslinked enzyme crystal (CLEC) of protease has good stability in polar and nonpolar organic solvents, such as hexane, toluene, benzene and carbon tetrachloride and it had high thermal stability up to 60 degrees C and hence can be used as a catalyst for the biotransformation of compounds which are not soluble in aqueous medium. The CLECs were entrapped in the alginate:guar gum (3:1) composite beads which were resistant to low pH conditions in the stomach and hence was found to be useful for the oral drug delivery. This method can be used to deliver the protein and peptide drugs which require high concentrations at the delivery stage, and which normally degrades in the stomach before reaching the jejunum. Application of these pH-sensitive beads for the controlled release of subtilisin in in vitro was studied and found to be a viable strategy. PMID- 17624743 TI - [Management of acne in adolescents]. AB - Acne is an androgen-dependant inflammatory folliculitis with non-inflammatory lesions (open and closed comedos) and inflammatory papules, pustules and sometimes nodules. Topical retinoids, benzoyl peroxyde, antibiotics with anti inflammatory properties, antiandrogens in female acne (antiandrogens and antiandrogenic oral contraceptives), and isotretinoin are the major drugs used in the management of the affection. Acne has to be treated according to the type of acne, severity, age and sex. Acne may also be the major sign of ovarian (PCOS) or adrenal hyperandrogenism in either female teenagers or both sexes, respectively. PMID- 17624744 TI - Differential diagnosis of CT focal liver lesions using texture features, feature selection and ensemble driven classifiers. AB - OBJECTIVES: The aim of the present study is to define an optimally performing computer-aided diagnosis (CAD) architecture for the classification of liver tissue from non-enhanced computed tomography (CT) images into normal liver (C1), hepatic cyst (C2), hemangioma (C3), and hepatocellular carcinoma (C4). To this end, various CAD architectures, based on texture features and ensembles of classifiers (ECs), are comparatively assessed. MATERIALS AND METHODS: Number of regions of interests (ROIs) corresponding to C1-C4 have been defined by experienced radiologists in non-enhanced liver CT images. For each ROI, five distinct sets of texture features were extracted using first order statistics, spatial gray level dependence matrix, gray level difference method, Laws' texture energy measures, and fractal dimension measurements. Two different ECs were constructed and compared. The first one consists of five multilayer perceptron neural networks (NNs), each using as input one of the computed texture feature sets or its reduced version after genetic algorithm-based feature selection. The second EC comprised five different primary classifiers, namely one multilayer perceptron NN, one probabilistic NN, and three k-nearest neighbor classifiers, each fed with the combination of the five texture feature sets or their reduced versions. The final decision of each EC was extracted by using appropriate voting schemes, while bootstrap re-sampling was utilized in order to estimate the generalization ability of the CAD architectures based on the available relatively small-sized data set. RESULTS: The best mean classification accuracy (84.96%) is achieved by the second EC using a fused feature set, and the weighted voting scheme. The fused feature set was obtained after appropriate feature selection applied to specific subsets of the original feature set. CONCLUSIONS: The comparative assessment of the various CAD architectures shows that combining three types of classifiers with a voting scheme, fed with identical feature sets obtained after appropriate feature selection and fusion, may result in an accurate system able to assist differential diagnosis of focal liver lesions from non-enhanced CT images. PMID- 17624745 TI - An atlas of the pelvic lymph node regions to aid radiotherapy target volume definition. AB - AIMS: The implementation of advanced three-dimensional radiotherapy planning techniques requires accurate target volume localisation. We have previously developed guidelines to aid definition of the pelvic lymph node regions, and the aim of this study was to produce a CT atlas. MATERIALS AND METHODS: The guidelines were applied to a CT scan of a patient to receive adjuvant radiotherapy. RESULTS: Reference CT images of the pelvis were generated, illustrating the nodal regions and a typical target volume for adjuvant pelvic radiotherapy for gynaecological cancer. CONCLUSION: These images can be used as an aid for target volume definition of the pelvic nodal regions. PMID- 17624746 TI - Adjuvant chemotherapy in non-small cell lung cancer -- how feasible is it in a non-trial population? PMID- 17624747 TI - Experience of the use of trabectedin (ET-743, Yondelis) in 21 patients with pre treated advanced sarcoma from a single centre. AB - AIMS: Trabectedin (ET-743, Yondelis) is a marine-derived alkaloid that has two actions. It binds in the minor groove of DNA resulting in a conformational change; thus potentially altering interactions with transcription factors and other DNA binding proteins and it also interacts with the transcription-coupled nucleotide excision repair machinery to induce lethal double-stranded DNA breaks. In recent phase II trials it has shown considerable activity in the treatment of sarcomas. Here the use of trabectedin in patients with advanced refractory sarcoma from a single institution is presented. MATERIALS AND METHODS: Twenty-one patients with advanced refractory sarcoma from a single UK centre were treated with trabectedin on a named patient compassionate basis programme. All patients had received prior treatment with an anthracycline, and 95% had received ifosfamide. RESULTS: The patients received a median of four cycles of treatment. Objective partial responses were seen in three patients (14%) and a further eight patients (38%) achieved durable stable disease for a median duration of 4.5 months. The estimated 3- and 6-month progression-free survival was 58.8 and 17.6%, respectively. Six patients experienced early disease progression, and four patients died while on treatment. One death was due to treatment-related toxicity. Overall the drug was relatively well tolerated, with hepatic and haematological toxicities most commonly encountered. Both necessitated delays and/or dose reductions in a proportion of patients. Other significant toxicities were nausea, vomiting and asthenia. CONCLUSION: The disease responses and durable nature of disease stabilisation seen in a proportion of our patients support the continued investigational use of this drug in the treatment of advanced soft tissue sarcomas. PMID- 17624748 TI - Localization of cyclooxygenase-2 in mice testis and assessment of its possible role through suppressing its expression using nimesulide: a preferential cyclooxygenase-2 inhibitor. AB - Present generation non-steroidal anti-inflammatory drugs (NSAID) are potent inhibitors of the enzyme cyclooxygenase-2 (COX-2). Even though they exhibit reduced incidence of gastrotoxicity, severe nephrotoxicity and other side effects have been widely reported with respect to usage of these drugs. Since COX-2 levels are not only upregulated by inflammation but also by other stimuli such as cytokines, growth factors, mitogens and steroid hormones, we investigated the localization of COX-2 and activity of both COX-1 and COX-2 in mice testis. To correlate the localization of COX-2 with its function we suppressed COX-2 expression with the aid of nimesulide a preferential COX-2 inhibitor. We found COX-2 was constitutively expressed in the Leydig cells of mice testis suggesting a role on testosterone synthesis. Suppression of COX-2 resulted in increased concentration of most of polyunsaturated fatty acids especially arachidonic acid (AA). Prostaglandin (PG) levels which showed an initial decline during nimesulide treatment had a reversible effect during prolonged treatment. These findings state that cyclooxygenase is constitutively expressed in mice testis and continuous inhibition of COX-2 interferes in maturation of sperm. PMID- 17624749 TI - T cell memory in malaria. AB - The observation that individuals living in malaria endemic areas fail to develop sterilizing immunity to malaria infection has led to the assumption that malaria specific immune responses are sub-optimal. Recently, T cell receptor (TCR) transgenic mice specific for the sporozoite and blood stages of the malaria parasite have been developed. Studies using these models have found that, unexpectedly, T cell memory in malaria is not noticeably defective. However, if T cell memory is 'normal' why are people not better protected? We suggest this is because protective immunity and T cell memory do not always correlate; moreover, T cells alone may simply not be able to provide the type of antibody-mediated sterilizing immunity induced by traditional vaccines. PMID- 17624750 TI - Clara cell 16 protein in COPD sputum: a marker of small airways damage? AB - RATIONALE: The development of chronic obstructive pulmonary disease (COPD) in smokers and their susceptibility to infections is not fully understood. Recent evidences suggest that Clara cells play a part in host defense, immunomodulatory response and airways remodelling through the production of specific factors such as Clara cell 16 (CC-16). This protein has never been related to patients' lung function tests, blood gases parameters and diseases severity. OBJECTIVES: To evaluate a possible correlation between CC-16 expression in sputum, measured by a new methodological approach, and the degree of severity in patients with moderate and severe COPD. We also analyzed possible correlations between CC-16 and cytological sputum population, arterial blood gases and lung function. MAIN FINDINGS: We analyzed 20 patients, mean age 72.95, classified on the basis of the global initiative for chronic obstructive lung disease guidelines (GOLD 2006). The samples were processed for cytological analysis and CC-16 levels were assessed by Western blot. We found lower levels of CC-16 in severe COPD compared to moderate ones (p<0.027). No statistically significant differences were found between CC-16 expression and sputum cellularity (except for macrophages), arterial blood gases, and spirometric parameters. Multiple linear regression analysis of CC-16 versus functional and cytological parameters showed no significance. CONCLUSIONS: We found a significantly different expression of CC-16 in COPD patients, according to their stage of severity, as defined by the GOLD 2006 guidelines. Considering CC-16 properties in innate immunity, a possible link between protein expression, innate immune system, and COPD infectious exacerbations may be hypothesized but further investigation are needed. PMID- 17624751 TI - Assessment of the burden of caregiving for patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: To determine the effect of chronic obstructive pulmonary disease (COPD) on the quality of life of caregivers. DESIGN AND METHODS: A cross sectional study was carried out with forty-two COPD patients and their primary caregivers. Patients were assessed with the medical outcome survey short form (SF 36), the physical and mental component summary (PCS and MCS), Saint George's respiratory questionnaire (SGRQ), 6-min walking test, and spirometric and blood gas measurements. Caregivers were assessed using the medical outcome survey short form (SF-36), the physical and mental component summary (PCS and MCS), the 5 point Likert scale for measuring caregiver/patient relationships and the caregiver burden scale (CB scale). RESULTS: The majority of caregivers were female (85.3%), married (59%) and had low levels of income and schooling. The mean age was 51.6+/-16 years. Mean caregiver PCS and MCS scores were 45.9+/-10 and 46+/-12, while the mean total burden score was 1.79+/-0.6. The regression analysis showed caregiver/patient relationship quality, caregiver MCS scores and patient PCS scores to be important predictors of burden and explained 63% of the variance. CONCLUSIONS: COPD causes a significant impact on the quality of life of caregivers. The two most important predictors of COPD burden are the relationship between caregivers and patients and caregiver MCS scores. PMID- 17624752 TI - Evaluation of a simple, potentially individual device for exhaled breath temperature measurement. AB - RATIONALE: Inflammation is a universal pathological reaction and is characterized among other things by increased heat production. The question stays whether the contribution of the inflamed lung tissues to the overall exhaled breath temperature (EBT) can be reliably detected and used in everyday clinical practice. METHODS: We have designed a simple device for assessment of EBT and explored its performance under standard indoor conditions. We made our measurements in the morning hours, documenting the ambient conditions (room temperature, humidity, atmospheric pressure), and physiological characteristics of the tested subjects (heart rate, blood pressure, otic and axillary temperature). We assessed its day-to-day reproducibility in 17 healthy volunteers and its ability to discriminate between the same subjects without respiratory disease and uncontrolled asthmatics (n=14). We also compared the EBT of the 14 asthmatics before and after anti-inflammatory treatment. RESULTS: No association was found between EBT and any of the ambient conditions: room temperature, atmospheric pressure and humidity. While otic and axillary temperatures, which were measured in parallel, maintained high correlation between each other (Spearman's rho=0.71, p<0.01), EBT did not show meaningful association with any of them. The EBT (degrees C) of asthmatics (median 35.45, range 34.12-36.09) was higher than that of controls (34.84, 32.29-35.84), (p=0.009, Mann-Whitney U test). Anti-inflammatory treatment brought down the EBT of the asthmatics (34.78, 33.23-36.06), (p=0.001, Wilcoxon Signed Ranks test), while significantly improving their spirometry too. CONCLUSIONS: Measurements of EBT with the device we constructed are not significantly influenced by changes within the accepted range of a standard indoor environment. EBT represents a different characteristic of the human organism than otic and axillary temperatures. EBT is increased in uncontrolled asthmatics and decreases under anti-inflammatory treatment. PMID- 17624753 TI - Trafficking and regulation of neuronal voltage-gated calcium channels. AB - The importance of voltage-gated calcium channels is underscored by the multitude of intracellular processes that depend on calcium, notably gene regulation and neurotransmission. Given their pivotal roles in calcium (and hence, cellular) homeostasis, voltage-gated calcium channels have been the subject of intense research, much of which has focused on channel regulation. While ongoing research continues to delineate the myriad of interactions that govern calcium channel regulation, an increasing amount of work has focused on the trafficking of voltage-gated calcium channels. This includes the mechanisms by which calcium channels are targeted to the plasma membrane, and, more specifically, to their appropriate loci within a given cell. In addition, we are beginning to gain some insights into the mechanisms by which calcium channels can be removed from the plasma membrane for recycling and/or degradation. Here we highlight recent advances in our understanding of these fundamentally important mechanisms. PMID- 17624755 TI - Impact of DOM from composted "alperujo" on soil structure, AM fungi, microbial activity and growth of Medicago sativa. AB - Water-soluble extracts from compost may represent an alternative nutrient and organic matter source for crop production under drip irrigation. Dissolved organic matter (DOM), extracted from composted "alperujo", the main by-product from the Spanish olive oil industry, was applied to soil alone or in combination with either Glomus intraradices Schenck and Smith or a mixture of G. intraradices, Glomus deserticola (Trappe, Bloss. and Menge) and Glomus mosseae (Nicol and Gerd.) Gerd. and Trappe. Response measurements included mycorrhizal colonisation, nutrient uptake and growth of Medicago sativa and microbiological and physical properties in the rhizosphere. Dissolved organic matter was added to soil at concentrations of 0, 50, 100 or 300mgCkg(-1) substrate. During the four months of the experiment, the plants were harvested three times. Both mycorrhizal inoculation treatments significantly increased soil aggregate stability. Only the mycorrhizal inoculations increased microbial biomass C and protease and phosphatase activities and decreased water-soluble C, particularly the mixture of arbuscular mycorrhizal fungi. At the third harvest, the greatest increase in growth of M. sativa was observed in the inoculated plants with shoot biomass being 38% greater than for plants grown in the soil amended with the highest dose of DOM and 57% greater than for control plants. The addition of DOM was not sufficient to restore soil structure and microbial activity and did not affect the mycorrhizal development of introduced populations of arbuscular mycorrhizal fungi, but, depending on the dose, its fertiliser efficiency for improving plant growth was apparent. PMID- 17624756 TI - Fertilization of maize with compost from cattle manure supplemented with additional mineral nutrients. AB - An alternative approach for cattle manure management on intensive livestock farms is the composting process. An industrial-scale composting plant has been set up in northwest Spain for producing compost from cattle manure. Manure composting involved an increase in pH, electrical conductivity (EC), cation exchange capacity (CEC) and NO3(-)--N concentration, and a decrease in temperature, moisture content, organic matter (OM) content, NH4+--N concentration and C/N ratio. Cu, Zn and Ni concentrations increased due to the reduction of pile mass during the composting process. The resulting compost was applied to a field to study the viability of applying this compost combined with a nitrogen mineral fertilizer as a replacement for the mineral fertilization conventionally used for maize (Zea mays L.). The thermophilic phase of the composting process was very prolonged in the time, which may have slowed down the decomposition of the organic matter and reduced the nitrification process, leading to an over-short maturation phase. The humification and respirometric indexes, however, determined immediately after compost application to the soil, showed it to be stable. Compost application did not decrease the grain yield. A year later, soil pH, OM content and CEC were higher with the compost treatment. Total P, K, Ca and Na concentrations in compost-amended plots were higher than in mineral-fertilized ones, and no significant differences between treatments were found in soil concentrations of NH4+--N,NO3- --N, available P, Mg and B. Compost caused no heavy metal pollution into the soil. Therefore, this compost would be a good substitute for the mineral fertilizers generally used for basal dressing in maize growing. PMID- 17624757 TI - Architects' perspectives on construction waste reduction by design. AB - The construction, demolition and excavation waste arising in England was estimated at 91 million tonnes in 2003. The current thinking on construction waste minimisation is heavily focussed on several issues relating to physical construction waste and recycling guides. Indeed, much had been published on ways to improve on-site waste management and recycling activities but very few attempts made to address the effect of design practices on waste generation. However, there is a consensus in the literature that the architect has a decisive role to play in helping to reduce waste by focussing on designing out waste. This paper examines previous studies on architects' approach towards construction waste minimisation; and by means of a postal questionnaire, investigates: the origins of waste; waste minimisation design practices in the UK; and responsibilities and barriers within the UK architectural profession. The findings reveal that waste management is not a priority in the design process. Additionally, the architects seemed to take the view that waste is mainly produced during site operations and rarely generated during the design stages; however, about one-third of construction waste could essentially arise from design decisions. Results also indicate that a number of constraints, namely: lack of interest from clients; attitudes towards waste minimisation; and training all act as disincentives to a proactive and sustainable implementation of waste reduction strategies during the design process. PMID- 17624758 TI - Differential adhesion in morphogenesis: a modern view. AB - The spreading of one embryonic tissue over another, the sorting out of their cells when intermixed and the formation of intertissue boundaries respected by the motile border cells all have counterparts in the behavior of immiscible liquids. The 'differential adhesion hypothesis' (DAH) explains these liquid-like tissue behaviors as consequences of the generation of tissue surface and interfacial tensions arising from the adhesion energies between motile cells. The experimental verification of the DAH, the recent computational models simulating adhesion-mediated morphogenesis, and the evidence concerning the role of differential adhesion in a number of morphodynamic events, including teleost epiboly, the specification of boundaries between rhombomeres in the developing vertebrate hindbrain, epithelial-mesenchymal transitions in embryos, and malignant invasion are reviewed here. PMID- 17624759 TI - Patterning signals and proliferation in Drosophila imaginal discs. AB - Recent studies indicate that signaling pathways with well-known roles in patterning also directly regulate cell proliferation. During the differentiation of the retina, Hedgehog, Decapentaplegic, Notch and the EGF receptor regulate proliferation spatially through transcriptional regulation of string, dacapo, and as yet unidentified regulators of Retinoblastoma and Cyclin E/Cdk2 activities. In the developing wing, a novel response to discontinuities in Decapentaplegic signaling combines with concentration-dependent effects to achieve a uniform proliferation pattern in response to a Decapentaplegic gradient. Damage to growing tissues is repaired by transient Decapentaplegic and Wingless secretion from dying cells to induce compensatory proliferation. Diverse spatial patterns of fate specification and of proliferation can arise through distinct combinations of signaling pathways. Reminiscent of pattern formation, cell cycle effects of each signaling pathway differ in distinct developmental fields, making use of a variety of target genes. PMID- 17624760 TI - The insulin-like growth factor 1 receptor in cancer: old focus, new future. AB - The importance of insulin-like growth factor 1 receptor (IGF-1R) signalling in malignant behaviour of tumour cells is well established. Currently, development of drugs targeting the IGF-1R as anticancer treatment is emerging. Several IGF-1R targeting strategies are being investigated in phases I and II clinical trials. Interactions of IGF-1R with insulin receptor, however, might complicate efficiency and tolerability of such drugs. This review describes mechanisms, recent developments and potential limitations of IGF-1R antibodies and tyrosine kinase inhibitors. PMID- 17624761 TI - Health-related quality of life, anxiety and depression among adolescents and young adults with cancer: a prospective longitudinal study. AB - The present study sets out to add to knowledge about the development over time of health-related quality of life (HRQL), anxiety and depression among survivors of adolescent cancer. The aim was to investigate if and how the HRQL, anxiety and depression of a group of adolescents with cancer differ from those of a reference group shortly after diagnosis, and subsequently at 6, 12 and 18 months after diagnosis. Adolescents diagnosed with cancer and a reference group randomised from the general population completed the Hospital Anxiety and Depression Scale (HADS) and the two subscales Mental Health and Vitality in the Short Form 36 (SF 36) in telephone interviews. The results indicate a steady increase in psychological well-being from the time of diagnosis, when the cancer patients' ratings were significantly worse than those of the general population, and onwards. The differences gradually disappeared and then were reversed, resulting in the cancer group reporting significantly better HRQL and lower levels of anxiety and depression than the reference group when 1.5 years had passed since diagnosis. The adolescents faced with cancer show signs of adaptation to trauma, which can be understood in relation to the theoretical framework of posttraumatic growth as well as response shift. Future research should continue to follow this development over time, to investigate if the positive effects of the cancer experience will wear off, or if it has facilitated a permanent positive outcome. PMID- 17624762 TI - Controversies of aromatase localization in human breast cancer--stromal versus parenchymal cells. AB - Aromatase is a key enzyme of estrogen production through conversion from serum androgens in estrogen-dependent postmenopausal breast cancer. Aromatase has been reported to be predominantly located in intratumoral stromal cells and adipocytes but not in parenchymal or carcinoma cells in breast cancer tissue. It is, however, true that there have been controversies regarding intratumoral localization of aromatase in human breast carcinoma, especially whether intratumoral production of estrogens through aromatase occurs in parenchymal or stromal cells. Results of several studies suggested that aromatase present in parenchymal carcinoma cells plays more important roles in the growth and invasion of breast carcinomas than that in stromal cells through providing higher levels of estrogens to carcinoma cells. Aromatase inhibitors are increasingly being used in place of tamoxifen after results of various clinical trials demonstrated that aromatase inhibitors are more effective in increasing survival and recurrence of estrogen-dependent breast cancer patients. Therefore, it is important to clarify the estrogen supplying pathway by aromatase inside of breast carcinoma tissues in order to evaluate the possible efficacy of aromatase inhibitor treatment. In this review, the controversies regarding these intratumoral localization patterns in human breast carcinoma will be briefly summarized. PMID- 17624763 TI - Structure/function of human type 1 3beta-hydroxysteroid dehydrogenase: An intrasubunit disulfide bond in the Rossmann-fold domain and a Cys residue in the active site are critical for substrate and coenzyme utilization. AB - The human type 1 (placenta, breast tumors) and type 2 (gonads, adrenals) isoforms of 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) are key enzymes in steroidogenic pathways leading to the production of all active steroid hormones. Kinetic analyses of purified 3beta-HSD1 show that the Michaelis-Menten constants (Km) for substrates and cofactor are decreased dramatically (three- to eight fold) by the addition of beta-mercaptoethanol (BME), which suggest that a disulfide bond may be critical to ligand utilization. Western immunoblots and SDS PAGE of purified 3beta-HSD1 in the presence or absence of BME showed a lack of intersubunit disulfide bonds in the dimeric enzyme. The Rossmann-fold domain of 3beta-HSD1 contains two Cys residues, Cys72 and Cys111, which are capable of forming an intrasubunit disulfide bond based on their proximity in our structural model. Our structural model also predicts that Cys83 may affect the orientation of substrate and cofactor. To test these predictions, the C72S, C72F, C111S, C111A, C83S and C83A mutants of 3beta-HSD1 were produced, expressed, and purified. BME failed to diminish the Km values of substrate and cofactor for C72S, C72F, C111S and C111A but produced a 2.5 decrease in Km values for C83A ligands similar to wild-type 3beta-HSD. Thus, our results support the presence of an intrasubunit disulfide bond between Cys72 and Cys111 that participates in the tertiary structure of the Rossmann-fold domain. Although C83S had no enzyme activity, the C83A mutant enzyme exhibited two- to five-fold higher Km values for substrate and cofactor but had similar K(cat) values compared to wild-type 3beta HSD. These data characterize the roles of Cys residues in 3beta-HSD and validate the predictions of our structural model. PMID- 17624764 TI - Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. AB - Improving endocrine responsiveness and preventing the development of resistance is the goal of many current strategies that are looking to combine aromatase inhibitors with novel drugs that target various pathways in estrogen receptor (ER) positive breast cancer. Pre-clinical models of acquired resistance to aromatase inhibitors have suggested an increase in several signaling pathways including peptide growth factor signaling (EGFR, HER2) and activation of the mTOR signaling pathway. These may result in associated 'cross-talk' activation of ER dependent gene transcription, such that dual blockade of ER together with other signaling pathways has become a logical approach to improve endocrine responsivness. Clinical strategies with aromatase inhibitors are looking to prevent activation of these pathways either through combination with the selective ER downregulator fulvestrant, or with various signal transduction inhibitors (STIs) including monoclonal antibodies (trastuzumab), small molecule tyrosine kinase inhibitors (TKIs) against EGFR or HER2 (lapatinib, gefitinib) and mTOR antagonists (temsirolimus). Early clinical data have emerged this year for some of these approaches with mixed results. This article reviews the rationale for these strategies, and discusses the lessons that need to be learnt if we are to successfully integrate these new drugs with aromatase inhibitors in the clinic. PMID- 17624765 TI - Aromatase inhibition by bioavailable methylated flavones. AB - Previous studies have shown chrysin, 7-hydroxyflavone and 7,4'-dihydroxyflavone to be the most potent flavonoid inhibitors of aromatase. However, very poor oral bioavailability is a major limitation for the successful use of dietary flavonoids as chemopreventive agents. We have recently shown that methylated flavones, including 5,7-dimethoxyflavone, 7-methoxyflavone and 7,4' dimethoxyflavone, are much more resistant to metabolism than their unmethylated analogs and have much higher intestinal absorption. In this study, we examined these fully methylated flavones as potential aromatase inhibitors for the prevention and/or treatment of hormone-dependent cancers. Whereas 5,7 dimethoxyflavone had poor effect compared to its unmethylated analog chrysin, 7 methoxyflavone and 7,4'-dimethoxyflavone were almost equipotent to their unmethylated analogs with IC(50) values of 2-9 microM. Thus, some fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents. PMID- 17624766 TI - 7alpha- and 7beta-hydroxy-epiandrosterone as substrates and inhibitors for the human 11beta-hydroxysteroid dehydrogenase type 1. AB - The human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes both the NADP(H)-dependent oxido-reduction of cortisol and cortisone and the inter conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) through a 7 oxo-DHEA intermediate. As shown with human liver and intestine fractions, 7alpha hydroxy-epiandrosterone (7alpha-hydroxy-EpiA) and 7beta-hydroxy-EpiA were readily inter-converted with no evidence for a 7-oxo-EpiA intermediate. Whether this inter-conversion resulted from action of the 11beta-HSD1 or from an unknown epimerase is unresolved. Furthermore, whether these steroids could inhibit the cortisol-cortisone oxido-reduction remains a question. The recombinant human 11beta-HSD1 was used to test these questions. NADP(+) supplementation only provided the production of 7beta-hydroxy-EpiA out of 7alpha-hydroxy-EpiA with a V(max)/K(M) ratio at 0.1. With NADPH supplementation, both 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA were formed in low amounts from 7beta-hydroxy-EpiA and 7alpha-hydroxy-EpiA, respectively. These inter-conversions occurred without a trace of the putative 7-oxo-EpiA intermediate. In contrast, the 7-oxo-EpiA substrate was efficiently reduced into 7alpha-hydroxy-EpiA and 7beta-hydroxy EpiA, with V(max)/K(M) ratios of 23.6 and 5.8, respectively. Competitive and mixed type inhibitions of the 11beta-HSD1-mediated cortisol oxidation were exerted by 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA, respectively. The 11beta HSD1-mediated cortisone reduction was inhibited in a competitive manner by 7-oxo EpiA. These findings suggest that the active site of the human 11beta-HSD1 may carry out directly the epimeric transformation of 7-hydroxylated EpiA substrates. The low amounts of these steroids in human do not support a physiological importance for modulation of the glucocorticoid status in tissues. PMID- 17624767 TI - Gas chromatographic-mass spectrometric study of the degradation of phenolic compounds in wastewater olive oil by Azotobacter Chroococcum. AB - Compounds present in wastewater olive oil (WWOO) which can be used in metabolic pathways of Azotobacter chroococcum (A. chroococcum) have been investigated. Some compounds such as syringic acid, p-coumaric acid and syringaldehyde do not favour microorganism growing up. However, it has been shown that in batch culture, polyphenolic compounds (PCs) such as protocatetic acid and p-hydroxybenzoic acid do facilitate the growing up of microorganism. What is more, the maximum concentration in which bacteria can grow was 0.3% (w/v) for both polyphenols. At higher concentrations, substrate inhibition was observed; which is characterized by decreasing growth rates. Therefore, A. chroococcum can grow up using PCs as an individual source of carbon and energy supply but it is also dependent on the type of the compound and on its concentration. A gas chromatography coupled mass spectrometry method has been used for the study of the degradation of simple phenolic compounds. PMID- 17624768 TI - Pretreatment of milk thistle seed to increase the silymarin yield: an alternative to petroleum ether defatting. AB - Milk thistle (Silybum marianum L.) seed meal is extracted for the flavonolignans, silychristin, silydianin, silybinin A, silybinin B, isosilybinin A and isosilybinin B, which are collectively known as the silymarin complex. To obtain the flavonolignans, the meal is usually treated with successive washes of petroleum ether to remove the lipids, followed by extraction of the flavonolignans with ethanol. This work examines the possible replacement of petroleum ether and ethanol by water or other aqueous solutions in these processes. To replace petroleum ether, pretreatments with 1.2% NaOH (w/w), 1.5% H2SO4 (w/w), 2% NaHCO3 (w/w), 0.14% cellulase and water were investigated. Of these pretreatments, 1.5% H2SO4 and water produced similar flavonolignan yields as petroleum ether. Results established that pretreating the milk thistle seed meal with 1.5% H2SO4 (w/w) at 50 degrees C for 18 h could replace the petroleum ether pretreatment. In addition, it was shown that similar amounts of flavonolignan could be recovered with a 1.5% H2SO4/water (100 degrees C) extraction as with a petroleum ether/ethanol extraction. Although cellulase pretreatment was not examined extensively, significant advances in cellulase effectiveness and cost have occurred in the past few years by companies such as Genencor International and Novozymes. These advances should help to make enzyme use for cellulose conversion, as well as extraction pretreatment, technically and economically feasible. PMID- 17624769 TI - Biodegradation of pyrene by Mycobacterium frederiksbergense in a two-phase partitioning bioreactor system. AB - Biodegradation of pyrene by Mycobacterium frederiksbergense was studied in a two phase partitioning bioreactor (TPPB) using silicone oil as non-aqueous phase liquid (NAPL). The TPPB achieved complete biodegradation of pyrene; and during the active degradation phase, utilization rates of 270, 230, 139, 82 mg l(-1)d( 1) for initial pyrene loading concentrations (in NAPL) of 1000, 600, 400 and 200 mg l(-1), respectively, were obtained. The degradation rates achieved using M. frederiksbergense in TPPB were much higher than the literature reported values for an ex situ PAH biodegradation system operated using single and pure microbial species. The degradation data was fitted to simple Monod, logistic, logarithmic, three-half-order kinetic models. Among these models, only exponential growth form of the three-half-order kinetic model provided the best fit to the entire degradation profiles with coefficient of determination (R2) value >0.99. From the experimental findings, uptake of pyrene by the microorganism in TPPB was proposed to be a non-interfacial based mechanism. PMID- 17624770 TI - Optimization for the production of exopolysaccharide from Fomes fomentarius in submerged culture and its antitumor effect in vitro. AB - A medicinal mushroom Fomes fomentarius, was isolated from the fruiting body of a wild F. fomentarius and identified by ITS-5.8S rDNA sequencing analysis. Then, the optimization of submerged culture conditions and nutritional requirements of mycelial biomass and exopolysaccharide (EPS) production from F. fomentarius was studied using orthogonal matrix method. Under the optimal culture condition, the maximum EPS concentration reached 3.64 g l(-1), which is about four times higher than that at the basal medium. Furthermore, the EPS from F. fomentarius has a direct antiproliferative effect in vitro on SGC-7901 huaman gastric cancer cells in a dose- and time-dependent manner. Moreover, it was about three times that EPS at noncytocxity concentration of 0.25 mg ml(-1) could sensitize doxorubicin(Dox) induced growth inhibition of SGC-7901 cells after 24h treatment. PMID- 17624771 TI - Comparative study of biosorption of heavy metals using different types of algae. AB - Sorption capacity of six different algae (green, red and brown) was evaluated in the recovery of cadmium, nickel, zinc, copper and lead from aqueous solutions. The optimum sorption conditions were studied for each monometallic system. The optimum pH was 6 for the recovery of Cd, Ni and Zn, and less than 5 for Cu and Pb. The best results were obtained with the lowest biomass concentration used (0.5 g/L). Experimental data fitted a Langmuir model very well according to the following sequence of the sorption values: Pb>Cd> or =Cu>Zn>Ni. The brown algae achieved the lowest metal concentration levels in solution; the best results were obtained with Fucus spiralis. Finally, a software computer program was used to simulate the process by comparison of theoretical with experimental results and show minimum differences between both types of data. PMID- 17624772 TI - Effects of municipal waste compost and sewage sludge on proton binding behavior of humic acids from Portuguese sandy and clay loam soils. AB - The effects of amendment with municipal solid waste compost (MSWC) and sewage sludge (SS) on acid-base properties of soil humic acids (HAs) were investigated. For this purpose, HAs were isolated from MSWC and SS and two different Portuguese soils, one sandy and the other clay loam, either unamended or amended with MSWC or SS at a rate of 60 t ha(-1), and analysed by potentiometric titrations at various ionic strengths (0.01, 0.05, 0.1 and 0.3M) over the pH range from 3.5 to 10.5. All titration data were fitted with the NICA-Donnan model and the variations of model parameters between the various HA samples were discussed. The HAs from MSWC and SS had lower acidic functional group contents and higher proton binding affinities than the control soil HAs. Amending soils with MSWC and SS determined a decrease of acidic functional group contents and an increase on proton binding affinities of soil HAs. These effects were more evident in SS amended soil HAs than in MSWC-amended soil HAs, and in clay loam soil HA than in sandy soil HA. PMID- 17624773 TI - Design, synthesis and biological evaluation of 1,4-benzodiazepine-2,5-dione-based HDAC inhibitors. AB - New histone deacetylase inhibitors have been synthesized and evaluated for their activity against non-small lung cancer cell line H661. These compounds have been designed with diversely substituted 1,4-benzodiazepine-2,5-dione moieties as cyclic peptide mimic cap structures, and a hydroxamate side chain. Biological evaluations demonstrated that benzodiazepine-based HDACi bearing an aromatic substituent at the N1 position exhibited promising antiproliferative and HDAC inhibitory activities. PMID- 17624774 TI - Design, synthesis, and biological evaluation of tricyclic heterocycle-tetraamine conjugates as potent NMDA channel blockers. AB - We have developed a new class of N-methyl-d-aspartate (NMDA) channel blockers having a conjugate structure that consists of a nitrogenous heterocyclic head and a tetraamine tail. Among them, dihydrodibenzazepine-homospermine conjugate (8) exhibited potent antagonistic activity at NR1/NR2A or NR1/NR2B NMDA subtype receptors compared with the lead compound, AQ343 (1), or memantine, as well as weak cytotoxicity. Its superior biological profiles compared with known compounds point to its potential use as therapeutic agents for neurological disorders. PMID- 17624775 TI - Anthranilamide inhibitors of factor Xa. AB - SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays. PMID- 17624776 TI - Synthesis and in vitro antibacterial activity of novel methylamino piperidinyl oxazolidinones. AB - Design and synthesis of a few novel methylamino piperidinyl substituted oxazolidinones are reported. Their antibacterial activities have been evaluated in a MIC assay against broader panel of both susceptible and resistant Gram positive strains. (S)-N-{3-[3-Fluoro-4-(methyl-{1-[3-(5-nitrofuran-2-yl) acryloyl]-piperidin-4-yl}-amino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4i has shown comparable antibacterial activity to linezolid and eperezolid in the MIC assay, additionally compound 4i showed good antibacterial activity with an in vitro MIC value of 2-4 microg/mL against linezolid resistant Staphylococcus aureus (linezolid 16 microg/mL). PMID- 17624777 TI - Synthesis and structure-activity relationship of novel indene N-oxide derivatives as potent peroxisome proliferator activated receptor gamma (PPARgamma) agonists. AB - A series of novel indene N-oxide derivatives were prepared by various synthetic methods and evaluated for their ability to activate PPARgamma. The best PPARgamma agonist in this series was 9h, which showed an EC(50) value of 15 nM. PMID- 17624778 TI - Amyotrophic lateral sclerosis with mutation of the Cu/Zn superoxide dismutase gene (SOD1) in a patient with Down syndrome. AB - Familial amyotrophic lateral sclerosis can be related to mutations in the Cu/Zn superoxide dismutase gene (SOD1) located on chromosome 21q22.1. This is the first report of a SOD1 mutation in a patient with Down syndrome. A 34-year-old woman with Down syndrome developed a lower motor neuron disease that led to death in two years. Autopsy findings confirmed the diagnosis. DNA examination identified a missense mutation at nucleotide 134 of exon 5 of the SOD1 gene resulting in the aminoacid substitution serine-134-asparagine (S134N). A real time PCR detected the mutation in two out of three alleles. The 70-year-old mother of the patient carries the same mutation but has not yet developed the disease. The missense mutation of SOD1 gene in two of the three alleles could have increased its toxic effects in the Down syndrome patient leading to an earlier onset and rapid progression of the disease. PMID- 17624779 TI - Interval breast cancers in screening: the effect of mammography review method on classification. AB - Surveillance of interval cancers (IC) lacks standardisation of review methodologies. We investigated the extent to which 'informed' or 'blinded' review may affect IC classification. This is a retrospective study of 100 validated screening mammograms (20 IC, 80 negative screens) independently reviewed by six radiologists. Three sequenced review methods with increasing information were used: (1) blinded (no IC information, case mix), (2) partially informed, and (3) fully informed. IC 'screening error' (SE) reports averaged 24% (10-40), 33% (20 55), and 42% (35-50) for phases 1, 2, and 3, while 'minimal signs' (MS) reports averaged 6% (5-15), 10% (10-20), and 20% (15-30), respectively. Negative mammograms classification was MS in 18% (7-39) or SE in 19% (11-29), respectively. MS or SE classification was more likely for method 2 (OR=1.78, p=0.033) and method 3 (OR=3.91, p=0.000) relative to method 1, but no reader effect was evident. Inter-observer agreement in classifying at method 1 was slight (k 0.20), lowest (k 0.06) for MS, and fair (k 0.25) for negative and SE categories. More 'informed' review is more likely to yield an IC classification as MS or SE. Due to expected variability, review methods need standardisation to improve screening quality. Our data support blinded review of IC in mammography screening. PMID- 17624780 TI - Health care professionals' knowledge and attitudes regarding substance use and substance users. AB - In Ireland one in four (28%) of those attending hospital emergency departments have substance abuse-related injury/illness and one in eight (13%) present in a state of clinical intoxication. Health care professionals working in emergency departments are frequently exposed to patients with substance use problems and are in ideal positions to provide early diagnosis and treatment. The success rate in detecting these patients is however disturbingly low (25-50%) and as a result many substance use problems are misdiagnosed or remain undetected. International studies that focus on primary care and addiction within the mental health sector suggest that health care professionals' knowledge and attitudes regarding substance use and substance users may negatively influence the care that these patients receive. There is a dearth of empirical research, internationally, and particularly in Ireland that addresses health care professionals' knowledge and attitudes in relation to substance use and substance users with no empirical evidence to ascertain in particular, emergency department doctors' and nurses' knowledge and attitudes. PMID- 17624781 TI - Emergency care staff can improve survival rates from sepsis. AB - Patients die from sepsis. Reports of mortality as high as 50% are associated with patients who have severe sepsis. Often the signs and symptoms are unmanaged within the emergency care environment. This paper discusses the Surviving Sepsis Campaign and outlines a number of management steps that practitioners caring for patients within emergency care can use to reduce mortality. The sepsis resuscitation bundle is discussed in depth as its goals can be achieved within the emergency department. A number of relevant web sites are provided that guide interested readers to other information on the Surviving Sepsis Campaign. PMID- 17624782 TI - Gait initiation in lower limb amputees. AB - OBJECTIVE: To study limitations in function and adjustment strategies in lower limb amputees during gait initiation. DESIGN: Observational cohort study. SETTING: University Medical Center. PARTICIPANTS: Amputees with a unilateral transfemoral or transtibial amputation, and able-bodied subjects. MAIN OUTCOME MEASURES: Leading limb preference, temporal variables, ground reaction forces, and centre of pressure shift. RESULTS: Amputees demonstrated a decrease in peak anterior ground reaction force, a smaller or absent posterior centre of pressure shift, and a lower gait initiation velocity. The main adjustments strategies in amputees were more limb-loading on the non-affected limb, prolonging the period of propulsive force production in the non-affected limb and initiating gait preferably with the prosthetic limb. CONCLUSION: Since an intact ankle joint and musculature is of major importance in gait initiation, functional limitations and adjustment strategies in transfemoral and transtibial amputees were similar. Improving prosthetic ankle properties and initiating gait with the prosthetic limb may facilitate the gait initiation process in amputees. PMID- 17624783 TI - Effects of extended effortful activity on spatio-temporal parameters of gait in individuals with stroke. AB - Neuromuscular dyscontrol during gait following stroke may be further compromised by increased susceptibility to fatigue. Our purpose was to examine how extended effortful activity affected spatio-temporal gait parameters after stroke. The influence of sub-maximal exercise was assessed among 26 stroke survivors who performed the Six-Minute Walk Test with distance recorded every 2 min. Walking distance decreased 5.8 (S.D. 6.9) m in the second 2-min interval and another 2.3 (S.D. 9.9) m in the final 2 min (p=0.0005). Secondly, we evaluated spatio temporal gait parameters prior to and immediately following a standardized maximal exercise test on a cycle ergometer in 36 stroke survivors. In contrast to the expected reduction in walking speed, maximal exercise led to a 5.5 (S.D. 11.5) cm/s increase in preferred gait speed (p=0.007) and a 4.5 (S.D. 7.7) steps/min increase in cadence (p=0.0004), but did not affect gait symmetry. Subsequent division of participants by preferred pedaling cadence revealed that individuals with lower preferred cadence had the greatest increase in preferred speed, cadence and paretic leg step length (p<0.01). These unexpected results suggest that potential fatigue-induced effects on gait may have been masked by immediate positive influences of movement rate on walking speed. Such activity specific effects may have clinical applications for stroke patients and other populations with gait deviations. PMID- 17624784 TI - Muscle compensatory mechanisms during able-bodied toe walking. AB - The purpose of this study was to use muscle-actuated forward dynamic simulations to quantify individual muscle contributions to body support (vertical ground reaction force) and propulsion (horizontal ground reaction force) and the mechanical energetics of the body segments during toe and heel-toe walking performed by able-bodied subjects to identify possible compensatory mechanisms necessary to toe walk. The simulations showed that an increased magnitude of plantar flexor power output in early stance, which was necessary to maintain the equinus posture during toe walking, contributed to body support and acted to brake (decelerate) the center-of-mass in the horizontal direction. This in turn required a reduction in the contributions to support from the vastii, gluteus maximus and biarticular hamstring muscles and decreased contributions to braking from the vastii and to a lesser extent the gluteus maximus. In late stance, the soleus contributed less to body support and forward propulsion during toe walking, which when combined with the increased braking by the plantar flexors in early stance, required a prolonged contribution to forward propulsion from the hamstrings from mid- to late stance. The multiple compensatory mechanisms necessary to toe walk have important implications for distinguishing between underlying pathology and necessary compensatory mechanisms, as well as for identifying the most appropriate treatment strategy for equinus gait. PMID- 17624785 TI - The pathways to tumor suppression via route p38. AB - Besides its well-known functions in inflammation and other stresses, the p38 mitogen-activated protein kinase pathway also negatively regulates cell proliferation and tumorigenesis. Inactivation of the p38 pathway enhances cellular transformation and renders mice prone to tumor development with concurrent disruption of the induction of senescence. Conversely, persistent activation of p38 inhibits tumorigenesis. Mechanistic insights into this additional p38 function are starting to emerge. For example, p38 has been shown to have a crucial role in oncogene-induced senescence, replicative senescence, DNA-damage responses and contact-inhibition. In addition, the role of the p38 pathway in proliferative control and tumor suppression is mediated by its impact on several cell-cycle regulators. These findings reveal a tumor-suppressing function of the p38 pathway, and indicate that components of the p38 pathway are potential targets for novel cancer therapies. PMID- 17624786 TI - Gene regulation under low oxygen: holding your breath for transcription. AB - Oxygen is both an environmental and developmental signal that governs important cellular pathways. Therefore, hypoxia (or low oxygen tensions) is part of both physiological and pathological processes. To deal with hypoxic conditions, cells and organisms have evolved exquisite mechanisms for adaptation and survival. The cellular responses are reliant on controlled transcriptional and post transcriptional events, where certain genes are positively regulated and others either remain inactive or are actively repressed. It has been known for some time that, during hypoxia, transcription is mainly regulated by the hypoxia inducible factor (HIF). However, recently it has been demonstrated that additional transcription factors are also activated and that non-HIF-dependent processes are involved in the hypoxic stress response. Therefore, gene expression following hypoxia is the result of combined effects on transcription, translation and adjustment mechanisms such as the induction of microRNAs and changes in chromatin. PMID- 17624787 TI - Synthesis and biological evaluation of cepharadiones A and B and related dioxoaporphines. AB - Described herein is the first total synthesis and structural confirmation of cepharadione A, a naturally occurring DNA damaging agent. Also reported is the synthesis of cepharadione B, a closely related natural product, as well as the biological evaluation of both natural products. Finally, the preparation and biological evaluation of novel dioxoaporphine analogues is described. PMID- 17624788 TI - Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists. AB - 1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1 (azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3 b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists. PMID- 17624789 TI - LNA nucleotides improve cleavage efficiency of singular and binary hammerhead ribozymes. AB - Variants of trans-acting hammerhead ribozymes were modified with Locked Nucleic Acid (LNA) nucleotides to reduce their size, to improve access to their RNA target and to explore combinational properties of binary constructs. Using low Mg(2+) concentrations and low substrate and ribozyme concentrations, it was found that insertion of LNA monomers into the substrate binding arms allowed these to be shortened and results in a very active enzyme under both single and multiple turnover conditions. Incorporation of a mix of LNA and DNA residues further increased the multiple turnover cleavage activity. At high Mg(2+) concentrations or high substrate and ribozyme concentrations, the enhancing effect of LNA incorporation was even more prominent. Using LNA in the stem of Helix II diminished cleavage activity, but allowed deletion of the tetra-loop and thus separating the ribozyme into two molecules with each half binding to the substrate. Efficient, binary hammerhead ribozymes were pursued in a combinatorial approach using a 6-times 5 library, which was analysed concerning the best combinations, buffer conditions and fragment ratios. PMID- 17624790 TI - Synthesis and evaluation of water-soluble docetaxel prodrugs-docetaxel esters of malic acid. AB - The synthesis of docetaxel esters of malic acid is described. These compounds were found to have greatly improved water solubility and are stable in solution at neutral pH. The C2' modified compounds 2a-c and 3a-c behave as prodrugs, that is, docetaxel is generated upon exposure to human plasma, whereas the C7 and C2',7,10- l modified derivatives do not. 2'-dl-Malyl docetaxel sodium salt demonstrated enhanced antitumor activity in vitro when compared to docetaxel and showed the inhibitory effect on tumor growth in vivo. PMID- 17624791 TI - 2-Styrylchromones: novel strong scavengers of reactive oxygen and nitrogen species. AB - 2-Styrylchromones are a small group of naturally occurring chromones, vinylogues of flavones (2-phenylchromones). Natural and synthetic 2-styrylchromones have been tested in different biological systems, showing activities with potential therapeutic applications. In particular, the potential and hitherto understudied antioxidant behavior of these compounds has been raised as a matter of interest. Thus the present work consisted in the study of the in vitro scavenging activities for reactive oxygen species (ROS) and reactive nitrogen species (RNS) of various 2-styrylchromone derivatives and structurally similar flavonoids. Some of the studied 2-styrylchromones proved to be extremely efficient scavengers of the different ROS and RNS, showing, in some cases, IC(50)s under 1 microM. The hydroxylation pattern of 2-styrylchromones, especially in the B-ring but also in the A ring, modulates the activity of these compounds, the catecholic derivatives being the most effective scavengers. The styryl pattern also contributes to their observed outstanding antioxidant activity. In conclusion, the scavenging activities for ROS/RNS of 2-styrylchromone derivatives, here shown for the first time, provide novel and most promising compounds to be applied as antioxidants. PMID- 17624792 TI - Synthesis of ferulic ester dimers, functionalisation and biological evaluation as potential antiatherogenic and antiplasmodial agents. AB - Oxidative dimerization of ferulic acid methyl ester afforded dihydrobenzofuran derivative and new linear compound identified by X-ray crystallography. The gallate derivatized dihydrobenzofuran analogue was obtained and all compounds were evaluated for potential antiatherogenic, antiplasmodial (best IC(50)=0.8 microM) and cytotoxic activities. PMID- 17624793 TI - Morphologic changes in the urethral epithelium in an ethanol-drinking rat strain (UChA and UChB). AB - The extreme use of ethanol causes metabolic and pathologic changes in testes and urogenital system in different animal species. The enzyme alcohol dehydrogenase (ADH) catalyses the conversion of ethanol into carcinogenic metabolite acetaldehyde which is partly excreted into the urine. However, papers relating the chronic ethanol consumption to the urethral morphology are unknown. This work evaluates the toxic effect of the chronic ethanol ingestion on the urethral epithelium of UChA and UChB rats. Conventional techniques of histology, histochemistry, immunohistochemistry and ultrastructural analysis were used. The analysis showed the presence of lipid drops and intercellular spaces in the epithelial cells in the urethra of UChA and UChB rats compared to control rats. Urethral neuroendocrine cell were observed and characterized for presenting vesicles containing electron-dense granules associated with nervous fibers. We conclude that the chronic consumption of ethanol induces the presence lipid drops in the epithelial cells of the urethra of UChA and UChB rats. The NE cells of the urethra of UChA and UChB rats did not show alterations under chronic effect of the ethanol. PMID- 17624794 TI - Optimization of production yields, radionuclidic purity and hotcell shielding of SPECT and PET radionuclides produced by proton irradiation in variable energy 30 MeV cyclotrons--Part 67Ga. AB - Optimization of the production parameters (incident and exit proton energy, thickness of the (68)Zn target layer, decay time to start chemical processing of an irradiated target after the end of bombardment) and of the thickness of the lead shield of the processing hotcell for the cyclotron production of (67)Ga by the (68)Zn(p,2n) threshold reaction are accomplished by powerful divide et impera and binary search algorithms with the Pharmacopoeia radionuclidic purity of the (67)Ga-citrate radiopharmaceutical at a reference time and the locally accepted dose rate level for the controlled area as boundary conditions. Two sets of equations are presented (one associated with the maximum production rate, the other with the use of a minimum target layer thickness) that allow the expression of the optimized production parameters, the radionuclide yields satisfying the Pharmacopoeia requirements at the start of distribution and the necessary shielding as a function of the required activity at the start of distribution and of the maximum allowable beam current on target. PMID- 17624795 TI - Adaptive response to salt involving carbohydrate metabolism in leaves of a salt sensitive tomato cultivar. AB - A salt-sensitive genotype of Solanum lycopersicum cv. Volgogradskij was submitted to a 6-day treatment with high salt (100, 200 mM NaCl), allowed to recover for 6 days and then submitted to a second period of salt stress in order to study changes in carbohydrate metabolism related to salt adaptation. The ion, soluble sugar and starch contents, as well as sucrose biosynthetic and sugar mobilizing enzyme activities and transcript levels were determined during the salt stress/recovery/stress cycle. Sodium ions were found to accumulate preferentially in old leaves. Young leaves accumulated lower levels of sodium ions but maintained control levels of potassium ions. Hexoses accumulated to higher levels and starch was better maintained in young compared to old leaves during the two salt treatments. Sucrose accumulated dramatically only in old leaves during the initial salt treatment. Sugar accumulation was not related to decreases in the activities of sugar mobilizing enzymes, acid (EC 3.2.1.25) and neutral (EC 3.2.1.26) invertases, sucrose synthase (EC 2.4.1.13) and hexokinase (EC 2.7.1.1). The activity of the biosynthetic enzyme sucrose phosphate synthase (EC 2.3.1.14) was linked to changes in sucrose levels but not with transcript levels. These results point to the importance of post-transcriptional regulation. Transcriptional regulation could nevertheless be seen in the down-regulation of ribulose bisphosphate carboxylase small subunit (EC 4.1.1.39) in old compared to young leaves, but this was not related to sugar levels. PMID- 17624796 TI - Higher accumulation of gamma-aminobutyric acid induced by salt stress through stimulating the activity of diamine oxidases in Glycine max (L.) Merr. roots. AB - Polyamines (PAs) are assumed to perform their functions through their oxidative product such as gamma-aminobutyric acid (GABA) formation. However, there is only limited information on the interrelation between PA degradation and GABA accumulation under salt stress. In order to reveal a quantitative correlation between PA oxidation and GABA accumulation, the effects of treatments with different NaCl concentrations, along with aminoguanidine (AG, a specific inhibitor of diamine oxidases (DAO; EC: 1.4.3.6)) and a recovery test from salt stress on endogenous free PAs, gamma-aminobutyric acid (GABA) accumulation and DAO activity were determined in roots of soybean [Glycine max (L.) Merr.] cultivar Suxie-1. The results showed that the levels of putrescine (Put), cadaverine (Cad), and spermidine (Spd) decreased significantly with increasing salt concentrations. This occurred because salt stress strongly promoted DAO activity to stimulate PA degradation. GABA accumulation increased with growing NaCl concentrations, about an 11- to 17-fold increase as compared with the control plants. AG treatment increased the accumulation of endogenous free PAs as a result of a strong retardation of DAO activity, but decreased GABA accumulation. The recovery for 6 days in 1/2 Hoagland solution from 100mM NaCl stress resulted in a decrease in DAO activity, a rebound of PA levels and a simultaneous reduction of GABA content. A close correlation was observed between the changes in DAO activity and GABA accumulation. The results indicated that higher GABA accumulation (about 39%) induced by salt stress could come from PA degradation, suggesting that PAs might perform their functions through GABA formation under salt stress. PMID- 17624797 TI - Lymphangiography in recurrent spontaneous chylothorax. PMID- 17624798 TI - Disinfection of drinking water contaminated with Cryptosporidium parvum oocysts under natural sunlight and using the photocatalyst TiO2. AB - The results of a batch-process solar disinfection (SODIS) and solar photocatalytic disinfection (SPCDIS) on drinking water contaminated with Cryptosporidium are reported. Cryptosporidium parvum oocyst suspensions were exposed to natural sunlight in Southern Spain and the oocyst viability was evaluated using two vital dyes [4',6-diamidino-2-phenylindole (DAPI) and propidium iodide (PI)]. SODIS exposures (strong sunlight) of 8 and 12h reduced oocyst viability from 98% (+/-1.3%) to 11.7% (+/-0.9%) and 0.3% (+/-0.33%), respectively. SODIS reactors fitted with flexible plastic inserts coated with TiO2 powder (SPCDIS) were found to be more effective than those which were not. After 8 and 16 h of overcast and cloudy solar irradiance conditions, SPCDIS reduced oocyst viability from 98.3% (+/-0.3%) to 37.7% (+/-2.6%) and 11.7% (+/ 0.7%), respectively, versus to that achieved using SODIS of 81.3% (+/-1.6%) and 36.0% (+/-1.0%), respectively. These results confirm that solar disinfection of drinking water can be an effective household intervention against Cryptosporidium contamination. PMID- 17624799 TI - Living with heart failure: partner perspectives. PMID- 17624800 TI - Structure-function relationships of the variable domains of monoclonal antibodies approved for cancer treatment. AB - Due to their exquisite specificity for a given epitope on the target antigen, recombinant monoclonal antibodies (rmAb) can deliver "targeted therapy" in oncology. This review focuses on the structural bases of "antigen specificity" to aid clinical researchers and pharmacologists in managing these new drugs. The fine structure of the Fv (Fragment variable) module (combination of VH and VL domains) from the five unconjugated antibodies currently approved for cancer treatment, namely rituximab, cetuximab, alemtuzumab, trastuzumab and bevacizumab, is presented and analysed. Co-crystal and functional studies are reviewed to define rmAb residues contributing to antigen binding site (paratope)-epitope interfaces. The genetic origin of these recombinant monoclonal antibodies, determined through the IMGT/3Dstructure-DB database and IMGT/V-QUEST (http://imgt.cines.fr), is presented, allowing the evaluation of homologies between antibodies and their closest germline human counterparts and hence their possible immunogenicity. Overall, the IMGT standards appear as a first and crucial step in the evaluation of recombinant antibodies. PMID- 17624801 TI - IL-16 signaling specifically induces STAT6 activation through CD4. AB - Biologic activities of IL-16 have been well described (e.g., chemotaxis of CD4+ cells, CD25 upregulation, secretion of IL-1b, IL-4 and TNF-a secretion) but very few signaling events have been described. To gain a better understanding of how the biologic activities of IL-16 are regulated following receptor engagement (CD4) we have analyzed the activation state of numerous STAT proteins in primary human peripheral blood mononuclear cells (PBMCs) and the human monocytic cell line THP-1 following IL-16 stimulation. Of the four STAT proteins tested, only STAT6 was activated (phosphorylated) in a dose-dependant manner by IL-16. The activation of STAT6 was completely abolished when IL-16 was pre-incubated with soluble CD4 (the IL-16 cell surface receptor), demonstrating the need for CD4 engagement in STAT6 activation. These results are the first to demonstrate a link between IL-16 and STAT6 activation. PMID- 17624802 TI - Quantitative determination of lipase activity by liquid chromatography-mass spectrometry. AB - We developed a novel in vitro lipase assay based on the quantitation of fatty acids by liquid chromatography-mass spectrometry. Oleic acids enzymatically released from triolein substrates were isolated from the reaction mixture by reverse-phase chromatography, ionized in negative mode electrospray mass spectrometry and quantitated with the aid of [(13)C]-oleic acid internal standard. The enzymatic activity was measured by monitoring oleic acid productions at multiple time points. This method overcomes the substrate and pH limitations of conventional techniques and thus serves as a generic lipase activity assay. PMID- 17624803 TI - Making the tumor-specific effectors ineffective. PMID- 17624804 TI - The potential of remote sensing for monitoring land cover changes and effects on physical geography in the area of Kayisdagi Mountain and its surroundings (Istanbul). AB - The effect of land cover change, from natural to anthropogenic, on physical geography conditions has been studied in Kayisdagi Mountain. Land degradation is the most important environmental issue involved in this study. Most forms of land degradation are natural processes accelerated by human activity. Land degradation is a human induced or natural process that negatively affects the ability of land to function effectively within an ecosystem. Environmental degradation from human pressure and land use has become a major problem in the study area because of high population growth, urbanization rate, and the associated rapid depletion of natural resources. When studying the cost of land degradation, it is not possible to ignore the role of urbanization. In particular, a major cause of deforestation is conversion to urban land. The paper reviews the principles of current remote sensing techniques considered particularly suitable for monitoring Kayisdagi Mountain and its surrounding land cover changes and their effects on physical geography conditions. In addition, this paper addresses the problem of how spatially explicit information about degradation processes in the study area rangelands can be derived from different time series of satellite data. The monitoring approach comprises the time period between 1990 and 2005. Satellite remote sensing techniques have proven to be cost effective in widespread land cover changes. Physical geography and particularly natural geomorphologic processes like erosion, mass movement, physical weathering, and chemical weathering features etc. have faced significant unnatural variation. PMID- 17624805 TI - Question 7: the first units of life were not simple cells. AB - Five common assumptions about the first cells are challenged by the pre-biotic ecology model and are replaced by the following propositions: firstly, early cells were more complex, more varied and had a greater diversity of constituents than modern cells; secondly, the complexity of a cell is not related to the number of genes it contains, indeed, modern bacteria are as complex as eukaryotes; thirdly, the unit of early life was an 'ecosystem' rather than a 'cell'; fourthly, the early cell needed no genes at all; fifthly, early life depended on non-covalent associations and on catalysts that were not confined to specific reactions. We present here the outlines of a theory that connects findings about modern bacteria with speculations about their origins. PMID- 17624806 TI - Late hyperenhancement in gadolinium-enhanced magnetic resonance imaging: comparison of hypertrophic cardiomyopathy patients with and without nonsustained ventricular tachycardia. AB - AIM: To assess the extent of hyperenhancement in hypertrophic cardiomyopathy (HCM) patients with nonsustained ventricular tachycardia (NSVT) in comparison to patients without NSVT. DESIGN: In HCM patients, NSVT in Holter monitoring is a risk factor for sudden cardiac death; however, its positive predictive value is low. Varying risk of sudden death related to NSVT may be dependent on the heterogeneous extent of the arrhythmogenic substrate, which seems to be visible as hyperenhancement in gadolinium-enhanced magnetic resonance imaging (MRI). METHODS: Hyperenhancement was assessed in 47 HCM patients (30 males and 17 females, mean age 42 +/- 12 years): 32 patients had NSVT, 15 patients had no NSVT. The extent of hyperenhancement was calculated by software and expressed as a mass. RESULTS: In HCM patients with NSVT 97% had some extent of hyperenhancement on MRI, ranging from 1 to 76 g. The mean mass of hyperenhanced myocardium was 19 +/- 18 g (8.1 +/- 7.6% of total left ventricular mass). In HCM patients without NSVT, a significantly lower percentage of patients (60%) had hyperenhancement (P < 0.05). However, the amount of hyperenhanced myocardium was not significantly different (13 +/- 19 g, 6.3 +/- 9.1% of total left ventricular mass; P < 0.05). CONCLUSIONS: Hyperenhancement was visible in almost all HCM patients with NSVT (97%) and in a significantly lower percentage of patients without NSVT (60%). Whether this finding explains the increased risk of sudden death in case of NSVT is not clear, since the extent of hyperenhancement was not significantly different between the two groups. PMID- 17624807 TI - High level accumulation of alpha-glucan in maize kernels by expressing the gtfD gene from Streptococcus mutans. AB - Glucosyltransferases (GTFs, EC.2.4.1.5) are bacterial enzymes that catalyze the polymerization of glucose residues from sucrose, leading to the production of high molecular weight glucan with alpha-1,3 /alpha-1,6 linkages. Such glucans, with many potential food and industrial applications, do not normally exist in higher plants. We fused a mutant form of the gtfD gene from Sreptococcus mutans with the maize (Zea mays L.) chloroplastic Brittle 1 transit peptide for amyloplast targeting. This construct, driven by the ubiquitin promoter, was introduced into maize by Agrobacterium-mediated transformation. We developed a novel HPLC-based method that enabled us differentially to distinguish transgene glucan from other endogenous polysaccharides in maize kernels. Using this method, we screened over 100 transgenic plants for the presence of GTF-produced glucan whose content varied between 0.8 and 14% of dry weight in the mature transgenic seeds. The mature transgenic plants were indistinguishable from wildtype plants in growth rate and morphology. Furthermore, starch granule size in the transgenic maize kernel was unaffected by the accumulation of the foreign polysaccharide. Mutation in Sh2, which encodes a subunit of ADP-glucose pyrophosphorylase, had no effect on glucan accumulation caused by gtfD expression. Our results indicated that high levels of novel carbohydrate polymer can be accumulated in crop plants through transgene technology. PMID- 17624808 TI - Detection of the causative agent of furunculusis, Aeromonas salmonicida in salmonids of the Krka River. AB - In this paper we describe the bacterial community associated with salmonids from the Krka River. Diversity analysis demonstrated that majority of the recovered bacteria were related to Aeromonadaceae group. Bacterial analysis also revealed the presence of Shigella spp. and Pseudomonas fluorescens. Isolation of Aeromonas salmonicida from trout, presents first isolation of this bacteria Croatian rivers. PMID- 17624809 TI - The distribution of acetohydroxyacid synthase in soil bacteria. AB - Most bacteria possess the enzyme acetohydroxyacid synthase, which is used to produce branched-chain amino acids. Enteric bacteria contain several isozymes suited to different conditions, but the distribution of acetohydroxyacid synthase in soil bacteria is largely unknown. Growth experiments confirmed that Escherichia coli, Salmonella enterica serotype Typhimurium, and Enterobacter aerogenes contain isozymes of acetohydroxyacid synthase, allowing the bacteria to grow in the presence of valine (which causes feedback inhibition of AHAS I) or the sulfonylurea herbicide triasulfuron (which inhibits AHAS II) although a slight lag phase was observed in growth in the latter case. Several common soil isolates were inhibited by triasulfuron, but Pseudomonas fluorescens and Rhodococcus erythropolis were not inhibited by any combination of triasulfuron and valine. The extent of sulfonylurea-sensitive acetohydroxyacid synthase in soil was revealed when 21 out of 27 isolated bacteria in pure culture were inhibited by triasulfuron, the addition of isoleucine and/or valine reversing the effect in 19 cases. Primers were designed to target the genes encoding the large subunits (ilvB, ilvG and ilvI) of acetohydroxyacid synthase from available sequence data and a approximately 355 bp fragment in Bacillus subtilis, Arthrobacter globiformis, E. coli and S. enterica was subsequently amplified. The primers were used to create a small clone library of sequences from an agricultural soil. Phylogenetic analysis revealed significant sequence variation, but all 19 amino acid sequences were most closely related to published large subunit acetohydroxyacid synthase amino acid sequences within several phyla including the Proteobacteria and Actinobacteria. The results suggested the majority of soil microorganisms contain only one functional acetohydroxyacid synthase enzyme sensitive to sulfonylurea herbicides. PMID- 17624810 TI - Question 8: from a set of chemical reactions to reproducing cells. AB - As a prerequisite for a reproducing cell, we first discuss how non-equilibrium states are sustained endogenously in a catalytic reaction network. Negative correlation between abundances of resource chemicals and of catalysts for their consumption is shown to lead to hindrance of relaxation to equilibrium. Mutual reinforcement among such sustainment of non-equilibrium state, spatial structure formation, and reproduction of a compartment is discussed as a mechanism to further suppress the relaxation to equilibrium. As a next step to protocell, consistency between cell reproduction and replication of constituent molecules is theoretically studied, which leads to a power-law on abundance of molecules as well as log-normal distribution over cells, which are shown to be universal, and also confirmed experimentally in the present cells. PMID- 17624811 TI - Question 9: minority control and genetic takeover. AB - As an issue of constructive biology, we study how molecules carrying heredity appear in a reproduction system that consists of mutually catalytic reactions. Molecules that are minority in number are shown to be preserved over generations, and control the behavior of the system. Life-critical information is then expected to be packed into such molecules and transferred over generations, leading to kinetic origin of genetic information. Relevance of this minority control to genetic takeover from loose reproduction is discussed, as a general consequence of any reproducing system with evolvability. Appropriate cell size to achieve both for reproduction and evolvability is also estimated based on this minority control mechanism. PMID- 17624812 TI - Medical humanities - arts and humanistic science. AB - The nature and scope of medical humanities are under debate. Some regard this field as consisting of those parts of the humanistic sciences that enhance our understanding of clinical practice and of medicine as historical phenomenon. In this article it is argued that aesthetic experience is as crucial to this project as are humanistic studies. To rightly understand what medicine is about we need to acknowledge the equal importance of two modes of understanding, intertwined and mutually reinforcing: the mode of aesthetic imagination and the mode of analytical reflection. PMID- 17624813 TI - Practical wisdom in medicine and health care. PMID- 17624814 TI - The effects of response bias on self-reported quality of life among childhood cancer survivors. AB - BACKGROUND: Several studies of long-term adjustment in childhood cancer survivors (CCS) report very positive outcomes, while other studies find significant adjustment problems. These inconsistencies have prompted some investigators to suggest survivors may be biased responders, prone to underreporting on self report measures. This study tested the hypothesis that CCS are elevated on self deception response bias (SDRB), and that SDRB is associated with higher ratings of quality-of-life (QOL). METHODS: One hundred and seven adult (mean age = 31.85) survivors of childhood cancers completed a demographic questionnaire, Short Form 12 (SF-12), Functional Assessment of Cancer Therapy-General (FACT-G), and Self Deception Enhancement scale (SDE), an SDRB measure. RESULTS: Survivors' QOL scores were similar to normative groups, but they evidenced much higher levels of response bias. SDE scores were significantly correlated with the FACT-G, and SF 12 Mental Health (but not Physical Health) scores even after accounting for demographic and treatment-related variables. CONCLUSIONS: CCS show a biased response style, indicating a systematic tendency to deny difficulties on QOL measures. This may complicate QOL studies by inflating survivors' reports of their socio-emotional functioning. Understanding how response bias develops may help us learn more about cancer survivors' adaptation to illness, and the effects of the illness experience on their perceptions of QOL. PMID- 17624815 TI - Measuring quality of health care from the user's perspective in 41 countries: psychometric properties of WHO's questions on health systems responsiveness. AB - OBJECTIVE: To evaluate, for different populations, psychometric properties of questions on "health systems responsiveness", a concept developed by World Health Organization (WHO) to describe non-clinical and non-financial aspects of quality of health care. DATA SOURCES/STUDY SETTING/DATA COLLECTION: The 2000-2002 WHO Multi-Country Study comprised 70 general population surveys. Forty-one surveys were interviewer-administered, from which we extracted respondent records indicating ambulatory and inpatient health services use (excluding long-term institutions) in the previous 12 months (50,876 ambulatory and 7,964 hospital interviews). STUDY DESIGN: We evaluated feasibility, reliability, and construct validity using 33 items with polytomous response options, comparing responses from populations identified by countries, sex, age, education, health and income. PRINCIPAL FINDINGS: Average item missing rates ranged from 0 to 16%. Domain specific alpha coefficients exceeded 0.7 in 7 (of 9) cases. Average intertemporal reliability was acceptable in 6 (of 10) sites, where Kappas ranged from 0.54 to 0.79, but low in 4 sites (K < 0.5). Kappa statistics were higher for male, educated and healthier populations than for female, less educated and less healthy populations. Factor solutions confirmed the domain structure of 7 domains (only 7 were operationalized for ambulatory settings). As in other studies, higher incomes and age was associated with more positive responsiveness reports and ratings. CONCLUSIONS: Quality issues addressed by WHO's questions are understood and reported adequately across diverse populations. More research is needed to interpret user-assessed quality of care comparisons across population groups within and between countries. PMID- 17624816 TI - Myocarditis: an unusual cause of postpartum fever in pregnancy complicated by antiphospholipid syndrome. AB - A pregnant woman with lupus anticoagulant and antiphospholipid syndrome developed atypical hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome requiring preterm delivery. Her postpartum course was marked by persistent fevers eventually found to be secondary to myocarditis. The diagnosis of myocarditis was confirmed by cardiac magnetic resonance but was not apparent on echocardiography. The myocarditis resolved with steroid therapy. PMID- 17624817 TI - Error reduction when prescribing neonatal parenteral nutrition. AB - A neonatal intensive care unit audit of 204 parenteral nutrition (PN) orders revealed a 27.9% PN prescribing error rate, with errors by pediatric residents exceeding those by neonatal nurse practitioners (NNPs) (39% versus 16%; P < 0.001). Our objective was to reduce the PN prescribing error rate by implementing an ordering improvement process. An interactive computerized PN worksheet, used voluntarily, was introduced and its impact analyzed in a retrospective cross sectional study. A time management study was performed. Analysis of 480 PN orders revealed that the PN prescribing error rate was 11.7%, with no difference in error rates between pediatric residents and NNPs (12.3% versus 10.5%). Use of the interactive computerized PN worksheet was associated with a reduction in the prescribing error rate from 14.5 to 6.8% for all PN orders ( P = 0.016) and from 29.3 to 9.6% for peripheral PN orders ( P = 0.002). All 12 errors that occurred in the 177 PN prescriptions completed using the computerized PN worksheet were due to avoidable data entry or transcription mistakes. The time management study led to system improvements in PN ordering. We recommend that an interactive computerized PN worksheet be used to prescribe peripheral PN and thus reduce errors. PMID- 17624818 TI - Tuberculosis and HIV coinfection: current state of knowledge and research priorities. PMID- 17624819 TI - Tuberculosis infection control in resource-limited settings in the era of expanding HIV care and treatment. AB - The opportunities for human immunodeficiency virus (HIV) care and treatment created by new treatment initiatives promoting universal access are also creating unprecedented opportunities for persons with HIV-associated immunosuppression to be exposed to patients with infectious tuberculosis (TB) within health care facilities, with the attendant risks of acquiring TB infection and developing TB disease. Infection control measures can reduce the risk of Mycobacterium tuberculosis transmission even in settings with limited resources, on the basis of a 3-level hierarchy of controls, including administrative or work practice, environmental controls, and respiratory protection. Further research is needed to define the most efficient interventions. The importance of preventing transmission of M. tuberculosis in the era of expanding HIV care and treatment in resource-limited settings must be recognized and addressed. PMID- 17624820 TI - Implementation issues in tuberculosis/HIV program collaboration and integration: 3 case studies. AB - The many interactions between tuberculosis (TB) and human immunodeficiency virus (HIV) infection influence the design and implementation of programs to address the needs of patients living with or at risk for both diseases. Collaboration between national TB and HIV programs and some degree of integration of services at a local level have been advocated by the World Health Organization and other international bodies and are recognized as essential in areas where the 2 diseases are prevalent. However, in most settings, strategies to accomplish this are only beginning to reach the field where their impact will be made and the expectation of improving the outcome of both diseases realized. In this article, 3 such strategies, offering varying degrees of collaboration and integration, are described, 1 at a national level in Malawi and 2 at local sites in South Africa. These geographically and programmatically distinct experiences in TB/HIV service integration are instructive, illustrate common themes, and show that the strategy can be successful, but they also show that programmatic, medical, staffing, resource, and scale-up challenges remain. In addition, they indicate that, although broad program principles of TB/HIV service integration are essential, program designs and components may vary by country and even within countries, as a result of differing TB and HIV disease prevalences, resources, levels of expertise, and differences in program settings (urban vs. rural and/or primary vs. district vs. specialty site). Large national programs can successfully provide rapid, uniform and widespread change and implementation but also must negotiate the subtleties of intricacies of TB/HIV interactions, which confound a uniform "one size fits all" public health approach. Conversely, smaller demonstration projects, even with successful outcomes, must grapple with issues related to generalization of findings, wider implementation, and scale up, to benefit larger populations of those in need. PMID- 17624821 TI - Tuberculosis and HIV infection: partners in human tragedy. PMID- 17624822 TI - Facing the crisis: improving the diagnosis of tuberculosis in the HIV era. AB - Although the human immunodeficiency virus (HIV) infection pandemic has had a catastrophic impact on tuberculosis (TB) control efforts, especially in sub Saharan Africa, most of the fundamental concepts reflected in the directly observed treatment, short course (DOTS) strategy still hold true in the HIV era. What has changed, and dramatically, is the importance of speedy and accurate TB diagnosis and the difficulty of achieving this. The disproportionate amount of smear-negative disease in sub-Saharan Africa, which shoulders two-thirds of the global burden of HIV infection and acquired immunodeficiency syndrome, has greatly complicated TB case detection and disease control. Now, 15 years after TB rates began to soar in countries where HIV infection is prevalent, we have learned that the conventional approach -- passively waiting for patients with advanced symptomatic disease to make their way to microscopy centers for diagnosis -- has disastrous consequences. Without better diagnostic tools for TB and effective strategies for their implementation, transmission will not be interrupted, mortality will not be checked, and TB will not be controlled in areas where HIV infection is prevalent. Fortunately, a number of technical opportunities exist for the creation of improved diagnostic tests. Developing and exploiting such tests to support TB control in HIV-infected populations is an urgent priority. A substantial public sector effort is under way to work in partnership with the biotechnology industry to accelerate progress toward that goal. In this article, we will define the need for better TB tests and describe technologies being developed to meet that need. PMID- 17624823 TI - New tuberculosis therapeutics: a growing pipeline. AB - Novel chemotherapeutic drugs are needed to improve tuberculosis (TB) control, especially in the developing world. Given the magnitude of the problem and the resources available in countries that have the highest burden of disease, the present standards of care for the treatment of drug-susceptible TB, drug resistant TB, TB/human immunodeficiency virus (HIV) coinfection, and latent TB infection are all unsatisfactory. Because no truly novel compounds for the treatment of TB have been discovered in the past 40 years, the recent enhanced activity in the research and development of new TB drugs is extremely encouraging. Seven compounds are presently in clinical development specifically for the treatment of TB. Other known antibiotic compound families are being investigated preclinically, in an attempt to identify new antimicrobial drugs with specific antituberculous activity. In addition, novel targets have been identified and are the subject of efforts to validate their potential usefulness in the treatment of TB. PMID- 17624824 TI - Tuberculosis and HIV coinfection: genesis of the supplement and sponsors' contribution. PMID- 17624825 TI - Treatment strategies for HIV-infected patients with tuberculosis: ongoing and planned clinical trials. AB - Currently, there are limited data to guide the management of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infected patients with active tuberculosis (TB), the leading cause of death among individuals with acquired immunodeficiency syndrome (AIDS) in resource-limited areas. Four trials to take place in Southeast Asian, African, and South American countries will address the unresolved question of the optimal timing for initiation of HAART in patients with AIDS and TB: (1) Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA [ANRS 1295/NIH-CIPRA KH001]), (2) Adult AIDS Clinical Trials Group A5221, (3) START, and (4) a trial sponsored by the World Health Organization/Special Programme for Research and Training in Tropical Diseases. Two other clinical questions regarding patients with TB and HIV-1 coinfection are also undergoing evaluation: (1) the benefits of short-term HAART when CD4 cell counts are >350 cells/mm(3) (PART [NIH 1 R01 AI051219-01A2]) and (2) the efficacy of a once-daily HAART regimen in treatment-naive patients (BKVIR [ANRS 129]). Here, we present an overview of these ongoing or planned clinical studies, which are supported by international agencies. PMID- 17624826 TI - Tuberculosis and HIV infection: the global setting. AB - Tuberculosis (TB) and human immunodeficiency virus (HIV) infection make each other's control significantly more difficult. Coordination in addressing this "cursed duet" is insufficient at both global and national levels. However, global policy for TB/HIV coordination has been set, and there is consensus around this policy from both the TB and HIV control communities. The policy aims to provide all necessary care for the prevention and management of HIV-associated TB, but its implementation is hindered by real technical difficulties and shortages of resources. All major global-level institutions involved in HIV care and prevention must include TB control as part of their corporate policy. Country level decision makers need to work together to expand both TB and HIV services, and civil society and community representatives need to hold those responsible accountable for their delivery. The TB and HIV communities should join forces to address the health-sector weaknesses that confront them both. PMID- 17624827 TI - Tuberculosis preventive therapy in the era of HIV infection: overview and research priorities. AB - The recognition of tuberculosis (TB) as a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons has led to renewed interest in TB preventive therapy and its incorporation into the essential package of health care for these individuals. Despite convincing data regarding its efficacy, TB preventive therapy has not been widely implemented. Further work is needed to determine how to overcome the barriers to the implementation of such therapy, including how best to exclude the presence of active TB before providing preventive therapy. Such issues as the optimal duration of preventive therapy for and the role of TB preventive therapy in the treatment of individuals receiving antiretroviral therapy remain to be defined. Ongoing research will help to determine how best to use this intervention in the care of HIV-infected persons and in the control of TB on a wider basis. PMID- 17624828 TI - Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. AB - Access to antiretroviral therapy is rapidly expanding in resource-limited settings, where tuberculosis is the most common opportunistic infection. Coadministration of antitubercular and antiretroviral agents is, therefore, occurring commonly, and it is associated with 3 major complications. First, induction of cytochrome P-450 enzymes and P-glycoprotein by rifampin results in reduced concentrations of nonnucleoside reverse-transcriptase inhibitors and, particularly, protease inhibitors. This potentially results in the loss of antiviral efficacy and the development of viral resistance. Replacing rifampin with rifabutin, which does not significantly affect the concentrations of antiretroviral agents, is advocated but is currently unaffordable in resource limited settings. Second, overlapping toxicities of antitubercular and antiretroviral agents occur frequently, necessitating discontinuation of therapy and increasing the risk of nonadherence. Third, immunopathological reactions, termed "the immune reconstitution inflammatory syndrome," occur frequently when antiretroviral therapy is initiated in patients with tuberculosis. These complexities of coadministration of antitubercular and antiretroviral agents are reviewed, and research priorities are highlighted. PMID- 17624829 TI - Diagnostic and management challenges for childhood tuberculosis in the era of HIV. AB - The diagnosis and management of childhood tuberculosis (TB) pose substantial challenges in the era of the human immunodeficiency virus (HIV) epidemic. The highest TB incidences and HIV infection prevalences are recorded in sub-Saharan Africa, and, as a consequence, children in this region bear the greatest burden of TB/HIV infection. The tuberculin skin test (TST), which is the standard marker of Mycobacterium tuberculosis infection in immunocompetent children, has poor sensitivity when used in HIV-infected children. Novel T cell assays may offer higher sensitivity and specificity than the TST, but these tests still fail to make the crucial distinction between latent M. tuberculosis infection and active disease and are limited by cost considerations. Symptom-based diagnostic approaches are less helpful in HIV-infected children, because of the difficulty of differentiating TB-related symptoms from those caused by other HIV-associated conditions. Knowing the HIV infection status of all children with suspected TB is helpful because it improves clinical management. HIV-infected children are at increased risk of developing active disease after TB exposure/infection, which justifies the use of isoniazid preventive therapy once active TB has been excluded. The higher mortality and relapse rates noted among HIV-infected children with active TB who are receiving standard TB treatment highlight the need for further research to define optimal treatment regimens. HIV-infected children should also receive appropriate supportive care, including cotrimoxazole prophylaxis, and antiretroviral therapy, if indicated. Despite the difficulties experienced in resource-limited countries, the management of children with TB/HIV infection could be vastly improved by better implementation of readily available interventions. PMID- 17624830 TI - HIV infection and multidrug-resistant tuberculosis: the perfect storm. AB - BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) has emerged as a global epidemic, with ~425,000 new cases estimated to occur annually. The global human immunodeficiency virus (HIV) infection epidemic has caused explosive increases in TB incidence and may be contributing to increases in MDR-TB prevalence. METHODS: We reviewed published studies and available surveillance data evaluating links between HIV infection and MDR-TB to quantify convergence of these 2 epidemics, evaluate the consequences, and determine essential steps to address these epidemics. RESULTS: Institutional outbreaks of MDR-TB have primarily affected HIV infected persons. Delayed diagnosis, inadequate initial treatment, and prolonged infectiousness led to extraordinary attack rates and case-fatality rates among HIV-infected persons. Whether this sequence occurs in communities is less clear. MDR-TB appears not to cause infection or disease more readily than drug susceptible TB in HIV-infected persons. HIV infection may lead to malabsorption of anti-TB drugs and acquired rifamycin resistance. HIV-infected patients with MDR-TB have unacceptably high mortality; both antiretroviral and antimycobacterial treatment are necessary. Simultaneous treatment requires 6-10 different drugs. In HIV-prevalent countries, TB programs struggle with increased caseloads, which increase the risk of acquired MDR-TB. Surveillance data suggest that HIV infection and MDR-TB may converge in several countries. CONCLUSIONS: Institutional outbreaks, overwhelmed public health programs, and complex clinical management issues may contribute to the convergence of the MDR-TB and HIV infection epidemics. To forestall disastrous consequences, infection control, rapid case detection, effective treatment, and expanded program capacity are needed urgently. PMID- 17624831 TI - Tolls: you pay them on the way in and on the way out! PMID- 17624832 TI - Microbial genomes to write our history. PMID- 17624833 TI - The effects of maternal malaria and HIV-1 infection on the effort to eliminate neonatal tetanus. PMID- 17624834 TI - Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection. AB - Clinical and virologic manifestations of genital herpes simplex virus type 2 (HSV 2) infection vary widely. We examined frequencies of single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) 2, 3, 4, and 9 in a prospective cohort of 128 HSV-2-infected persons whose viral shedding and lesion frequency was measured by daily sampling from genital secretions. Two TLR2 haplotypes (2 and 4) were associated with increased lesional (P=.008 and P=.03) and shedding (P=.02 and P=.001) rates. An SNP in haplotype 2 (-15607A/G) was also associated with shedding (P=.01) and lesional (P=.008) rates. Polymorphisms in TLR2 may be in part responsible for differences in the severity of HSV-2 infection. PMID- 17624835 TI - Human T lymphotropic virus type 1 subtype C melanesian genetic variants of the Vanuatu Archipelago and Solomon Islands share a common ancestor. AB - BACKGROUND: Melanesia is endemic for human T lymphotropic virus type 1 (HTLV-1) subtype C. In 2005, we identified 4 infected women from Ambae Island, Vanuatu. Subsequently, 4247 Ni-Vanuatu originating from 18 islands were enrolled to define HTLV-1 epidemiological determinants and to characterize the viral strains molecularly. METHODS: Plasma from 1074 males and 3173 females were screened for HTLV-1/2 antibodies by particle agglutination (PA) and an immunofluorescence assay (IFA). Positive and/or borderline samples were then tested by a Western blot (WB) confirmatory assay. DNAs were amplified to obtain a 522-bp env gene fragment. Phylogenetic and molecular-clock analyses were performed. RESULTS: Of 4247 samples, 762 were positive and/or borderline by IFA/PA, and 26 of them were confirmed to be HTLV-1 positive by WB. The overall HTLV-1 seroprevalence was 0.62%. Viral transmission was found within families of infected index case patients. A geographic heterogeneity of HTLV-1 seroprevalence was observed among the islands. All 41 of the new env sequences belonged to HTLV-1 subtype C. Phylogenetic and molecular-clock analyses suggested that Ni-Vanuatu and Solomon Islander strains emerged from a common ancestor ~10,000 years ago. CONCLUSION: The Vanuatu archipelago is endemic for HTLV-1 with a diversity of subtype C variants. These strains were probably introduced into Vanuatu during ancient migration of the original settlers a few thousand years ago. PMID- 17624836 TI - Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005-June 2006. AB - BACKGROUND: Highly pathogenic avian influenza A (H5N1) virus was detected in domestic poultry in Indonesia beginning in 2003 and is now widespread among backyard poultry flocks in many provinces. The first human case of H5N1 virus infection in Indonesia was identified in July 2005. METHODS: Respiratory specimens were collected from persons with suspected H5N1 virus infection and were tested by reverse-transcriptase polymerase chain reaction and viral culture. Serum samples were tested by a modified hemagglutinin inhibition antibody and/or microneutralization assay. Epidemiological, laboratory, and clinical data were collected through interviews and medical records review. Close contacts of persons with confirmed H5N1 virus infection were investigated. RESULTS: From July 2005 through June 2006, 54 cases of H5N1 virus infection were identified, with a case-fatality proportion of 76%. The median age was 18.5 years, and 57.4% of patients were male. More than one-third of cases occurred in 7 clusters of blood related family members. Seventy-six percent of cases were associated with poultry contact, and the source of H5N1 virus infection was not identified in 24% of cases. CONCLUSIONS: Sporadic and family clusters of cases of H5N1 virus infection, with a high case-fatality proportion, occurred throughout Indonesia during 2005-2006. Extensive efforts are needed to reduce human contact with sick and dead poultry to prevent additional cases of H5N1 virus infection. PMID- 17624837 TI - Early evolution of hepatitis C virus (HCV) quasispecies after liver transplant for HCV-related disease. AB - BACKGROUND: End-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period. METHODS: For 17 patients who received an LT for HCV disease, plasma viral quasispecies evolution was determined by sequence analysis of hypervariable region 1 of the E2 envelope gene before transplant (BT), after 7 days (D7), and after 1 month (M1). T helper (Th)1/Th2 cytokine levels were determined concomitantly. RESULTS: HCV quasispecies showed a significant decrease in amino acid diversity at D7 and M1, compared with BT (P<.05). A correlation was observed between low plasma tumor necrosis factor-alpha levels at D7 and decreased quasispecies amino acid complexity at the same date. Nucleic acid diversity was lower for genotype 1 than for genotype 3 infection (P<.05). The complexity and diversity of amino acids were lower in patients with hepatocellular carcinoma (HCC) BT than in those without HCC (P<.05). Conserved amino acid residues within quasispecies were shared by the whole cohort before and after LT. CONCLUSION: Viral structural and/or host immunological features could favor the emergence of fitter HCV strains after LT. PMID- 17624838 TI - Efficacy of the human rotavirus vaccine RIX4414 in malnourished children. AB - The effect of nutritional status on protective efficacy of a live attenuated human rotavirus vaccine (RIX4414) was studied. Vaccine protection was evaluated through a secondary analysis of data from an efficacy study conducted in Brazil, Mexico, and Venezuela. Vaccine efficacy against rotavirus gastroenteritis (RVGE) was similar in well-nourished and malnourished infants: 74.1% (95% confidence interval [CI], 52.2%-86.2%) and 73% (95% CI, 11.2%-92.3%) for severe RVGE and 60.9% (95% CI, 37.4%-75.4%) and 61.2% (95% CI, 10.4%-83.1%) for RVGE of any severity, respectively. RIX4414 significantly decreased the rate of RVGE regardless of nutritional status, which suggests that this patient group can also benefit from rotavirus vaccination. CLINICAL TRIALS REGISTRY: e-Track 444563-006, NCT00385320 (http://www.clinicaltrials.gov). PMID- 17624839 TI - Measles virus vaccine attenuation: suboptimal infection of lymphatic tissue and tropism alteration. AB - The mechanisms of measles virus (MV) vaccine attenuation are insufficiently characterized. Because the Edmonston vaccine strain can enter cells through CD46 in addition to the primary MV receptor signaling lymphocyte activation molecule (SLAM or CD150), we asked whether and how its tropism is altered. In human tonsillar tissue, this vaccine strain infects naive (CD45RA(+)CD62L(+)) T lymphocytes, which express SLAM very infrequently, with much higher efficiency than do wild-type strains. By contrast, it infects B lymphocytes, macrophages, and NK cells with significantly lower efficiencies than those of wild-type strains. Infection levels by wild-type strains correlate with the frequency of SLAM expression and are highest in B cells, which are 40%-55% infected. SLAM expressing T cells are more readily infected by all MV strains than are SLAM expressing B cells. Thus, vaccine attenuation may be caused by tropism alteration in combination with suboptimal replication. PMID- 17624840 TI - Maternal HIV infection and placental malaria reduce transplacental antibody transfer and tetanus antibody levels in newborns in Kenya. AB - BACKGROUND: In clinical trials, maternal tetanus toxoid (TT) vaccination is effective in protecting newborns against tetanus infection, but inadequate placental transfer of tetanus antibodies may contribute to lower-than-expected rates of protection in routine practice. We studied the effect of placental malaria and maternal human immunodeficiency virus (HIV) infection on placental transfer of antibodies to tetanus. METHODS: A total of 704 maternal-cord paired serum samples were tested by ELISA for antibodies to tetanus. The HIV status of all women was determined by an immunoglobulin G antibody-capture particle adherence test, and placental malaria was determined by placental biopsy. Maternal history of TT vaccination was recorded. RESULTS: Tetanus antibody levels were reduced by 52% (95% confidence interval [CI], 30%-67%) in newborns of HIV infected women and by 48% (95% CI, 26%-62%) in newborns whose mothers had active chronic or past placental malaria. Thirty-seven mothers (5.3%) and 55 newborns (7.8%) had tetanus antibody levels <0.1 IU/mL (i.e., were seronegative). Mothers' self-reported history of lack of tetanus immunization was the strongest predictor of seronegativity and of tetanus antibody levels in maternal and cord serum. CONCLUSION: Malarial and HIV infections may hinder efforts to eliminate maternal and neonatal tetanus, making implementation of the current policy for mass vaccination of women of childbearing age an urgent priority. PMID- 17624841 TI - Increased rates of preterm delivery are associated with the initiation of highly active antiretrovial therapy during pregnancy: a single-center cohort study. AB - It remains controversial whether in human immunodeficiency virus (HIV)-positive pregnant women an increased rate of preterm delivery is associated with highly active antiretroviral therapy (HAART). Since 1995 the management and outcome of all HIV-infected pregnant women delivering at St. Mary's Hospital London have been prospectively documented. The prevalence of preterm delivery and the correlation between gestational age and type of antiretroviral therapy were sought: preterm delivery occurred in 14.2% of the 211 deliveries. Initiation of HAART during pregnancy was associated with an increased risk of preterm delivery. This was independent of maternal health and class of antiretroviral therapy. PMID- 17624842 TI - Infant morbidity, mortality, and breast milk immunologic profiles among breast feeding HIV-infected and HIV-uninfected women in Botswana. AB - BACKGROUND: Infants of human immunodeficiency virus (HIV)-infected women have high mortality, but the immunologic integrity and protection afforded by the breast milk of HIV-infected women is unknown. METHODS: We determined morbidity and mortality by 24 months among breast-fed infants of 588 HIV-infected and 137 HIV-uninfected women followed-up in a clinical trial in Botswana. A matched case control study compared clinical, behavioral, and breast milk immunologic parameters among 120 HIV-infected women by infant outcome. Breast milk factors were also compared between HIV-infected and HIV-uninfected women. RESULTS: Twenty four-month mortality was 29.5% among HIV-infected infants, 6.7% among HIV-exposed uninfected infants, and 1.6% among HIV-unexposed infants. No differences were detected in breast milk immunologic profiles of HIV-infected women whose infants were either ill or well. Discontinuation of breast-feeding was the strongest predictor of illness (P<.001). Levels in breast milk of pathogen-specific immunoglobulin (Ig) G and IgA to Haemophilus influenzae, Campylobacter jejuni, Helicobacter pylori, Streptococcus pneumoniae, and innate immune factors were not lower among HIV-infected women than among HIV-uninfected women. CONCLUSIONS: Mortality was higher among HIV-infected and HIV-exposed infants than among HIV unexposed infants. However, the immunologic profiles of breast milk among HIV infected women were intact, and discontinuation of breast-feeding was the primary risk for infant morbidity. Thus, the breast milk of HIV-infected women may confer protection against common infant pathogens. TRIAL REGISTRATION: (ClinicalTrials.Gov) identifiers: NCT00197691 and NCT00197652. PMID- 17624843 TI - Laboratory indicators of mastitis are not associated with elevated HIV-1 DNA loads or predictive of HIV-1 RNA loads in breast milk. AB - BACKGROUND: Mother-to-child transmission (MTCT) of HIV-1 has been associated with symptomatic and asymptomatic mastitis and with the quantity of HIV-1 RNA and DNA in maternal milk. An improved understanding of the relationship between indicators of inflammation and HIV-1 loads in breast milk could improve MTCT prevention strategies. METHODS: In a cross-sectional study, laboratory indicators of mastitis (breast milk sodium [Na(+)] concentration, sodium : potassium ratio [Na(+) : K(+)], and leukocyte count) were related to breast milk HIV-1 RNA and DNA loads and were evaluated for predicting viral loads in milk. RESULTS: Mastitis was present in 63 (15%) of 407, 60 (15%) of 407, and 76 (18%) of 412 milk specimens, as defined by Na(+) concentration >12 mmol/L, Na(+) : K(+) >1, and total leukocyte counts > or =10(6) cells/mL, respectively. Each indicator was associated with an increased milk HIV-1 RNA load (P<.05) but not with HIV-1 DNA load. Neutrophils correlated better with milk HIV-1 RNA load than total leukocytes. However, neither neutrophil count, Na(+) concentration, nor Na(+) : K(+) displayed a threshold that was both sensitive and specific for the detection of HIV-1 RNA in milk at thresholds of > or =50 or > or =10(4) copies/mL. CONCLUSIONS: HIV-1 DNA loads in breast milk were not increased during mastitis. Neither milk cell counts nor electrolyte concentrations were useful predictors of milk HIV-1 RNA or DNA loads for individual women. PMID- 17624844 TI - Preservation of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses despite global loss of CD4+ T cells in HCV/HIV coinfection. AB - BACKGROUND: Human immunodeficiency virus (HIV) coinfection and low peripheral blood CD4(+) T cell counts are associated with increased hepatitis C liver disease. METHODS: Hepatitis C virus (HCV)-specific CD4(+) T cell responses were assessed using interferon (IFN)- gamma enzyme-linked immunospot assays on peripheral blood mononuclear cells and expanded liver lymphocytes from HCV monoinfected and HCV/HIV-coinfected subjects. Cell frequencies were determined using flow cytometry. RESULTS: HIV coinfection was associated with decreased CD4(+) T cell percentages in both peripheral blood (21% vs. 48%; P<.0001) and liver (15% vs. 36%; P<.0001) and with reduced responsiveness of peripheral CD4(+) T cells to HCV antigens compared with HCV monoinfection (22% vs. 45%; P=.021). However, intrahepatic HCV-specific responses were maintained in HCV/HIV coinfection, compared with HCV monoinfection (38% vs. 32%; P=.7). Notably, the presence of HCV-specific responses was not related to the frequency of liver CD4(+) T cells (P=.4). Circulating and liver CD4(+) T cell percentages were correlated (r=0.58; P<.0001). Circulating percentages were also inversely associated with liver fibrosis stage among HCV/HIV-coinfected subjects (P=.029). Neither hepatic CD4(+) T cell percentages nor HCV-specific IFN- gamma responses in the liver or periphery predicted stage. CONCLUSIONS: Despite decreases in peripheral blood HCV-specific CD4(+) T cell responses and intrahepatic CD4(+) T cell percentages, intrahepatic HCV-specific CD4(+) IFN- gamma responses were preserved in HCV/HIV coinfection. PMID- 17624845 TI - Absence of erythrocyte-associated HIV-1 in vivo. AB - A recent study found high levels of human immunodeficiency virus type 1 (HIV-1) bound to erythrocytes in HIV-1-infected patients with long-term undetectable plasma HIV-1 loads, potentially representing a novel and important reservoir of HIV-1 infection. To attempt to confirm this finding, we purified erythrocytes from 13 HIV-1-infected patients with long-term undetectable plasma viral load and depleted contaminating CD3(+)CD4(+) lymphocytes using magnetic beads. HIV-1 load of the purified erythrocyte fraction was <20 copies/mL in 11 of 13 patients and 42 and 52 copies/mL in 2 patients. Contrary to the prior report, therefore, erythrocytes do not represent a novel reservoir of HIV-1 infection in these patients. PMID- 17624846 TI - Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis (VL) is a major public health problem in Bihar, accounting for 90% of all cases in India. Development of high levels of resistance to various existing drugs necessitated the search for alternative orally administered drugs. Hospital-based studies have shown that oral miltefosine is a highly effective treatment for VL both in adults and in children. METHODS: An open, single-arm trial was designed to investigate the feasibility of treatment of VL patients with miltefosine in field conditions in 13 centers in Bihar. RESULTS: The phase 4 study was conducted among 1132 adult and pediatric VL patients. Compliance was good, with 1084 (95.5%) patients completing the full 28-day treatment course. Nine hundred and seventy-one (85.8%) patients returned for the final cure assessment at 6 months after treatment. The final cure rate was 82% by intention to treat analysis and 95% by per protocol analysis (similar to the 94% cure rate in hospitalized patients). Treatment related adverse events of common toxicity criteria grade 3 occurred in ~3% of patients, including gastrointestinal toxicity and rise in aspertate amino transferase, alanine amino transferase, or serum creatinine levels, similar to previous clinical experience. CONCLUSION: This study supports the use of miltefosine in an outpatient setting in an area where VL is endemic. PMID- 17624847 TI - Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells. AB - At present, radiation-attenuated plasmodia sporozoites ( gamma -spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma -spz are not without risks. For example, the heterogeneity of the gamma -spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8(+) T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8(+) T cells, given that mice deficient in beta (2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon- gamma . On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate. PMID- 17624848 TI - Protracted sterile protection with Plasmodium yoelii pre-erythrocytic genetically attenuated parasite malaria vaccines is independent of significant liver-stage persistence and is mediated by CD8+ T cells. AB - Irradiation-attenuated sporozoite vaccinations confer sterile protection against malaria infection in animal models and humans. Persistent, nonreplicating parasite forms in the liver are presumably necessary for the maintenance of sterile immunity. A novel vaccine approach uses genetically attenuated parasites (GAPs) that undergo arrested development during liver infection. The fate of GAPs after immunization, their persistence in vaccinated animals, and the immune mechanisms that mediate protection are unknown. To examine the developmental defects of genetically attenuated liver stages in vivo, we created deletions of the UIS3 and UIS4 loci in the Plasmodium yoelii rodent malaria model (Pyuis3[-] and Pyuis4[-]). The low 50% infectious dose of P. yoelii in BALB/c mice provides the most sensitive infectivity model. We show that P. yoelii GAPs reach the liver, invade hepatocytes, and develop a parasitophorous vacuole but do not significantly persist 40 h after infection. A single dose of Pyuis4(-) sporozoites conferred complete protection, but full protection by Pyuis3(-) sporozoites required at least 2 immunizations. CD8(+) T cells were essential for protection, but CD4(+) T cells were not. Our results show that genetically distinct GAPs confer different degrees of protective efficacy and that live vaccine persistence in the liver is not necessary to sustain long-lasting protection. These findings have important implications for the development of a P. falciparum GAP malaria vaccine. PMID- 17624849 TI - Members of the low-molecular-mass rhoptry protein complex of Plasmodium falciparum bind to the surface of normal erythrocytes. AB - The destruction of erythrocytes is one of the most frequently observed causes of severe malarial anemia. Recently, we showed that tagging normal erythrocytes and cells of erythroid precursors with rhoptry-derived proteins can trigger their destruction. In the present study, we used rhoptry-associated protein (RAP)-1 and RAP-3 gene-disruption mutant Plasmodium falciparum parasites and showed that 2 members of a rhoptry protein complex, RAP-1 and RAP-2, bind to the surface of normal erythrocytes. Surface iodination experiments showed that RAP-1 but not RAP 3 mutant parasites lose their capacity to tag erythrocytes. This work opens new doors into the investigation of the molecular mechanism of anemia in patients with malaria. PMID- 17624850 TI - Thrombocytopenia and release of activated von Willebrand Factor during early Plasmodium falciparum malaria. AB - BACKGROUND: Thrombocytopenia occurs early during malarial infection, but its underlying mechanism is unclear. Secretion of von Willebrand factor (vWF) occurs on endothelial cell activation, and it plays an important role in platelet agglutination. METHODS: In 14 healthy human volunteers who were experimentally infected with Plasmodium falciparum, we studied vWF secretion and proteolysis as well as the relationship between changes in circulating platelet numbers and plasma levels of vWF and activated vWF. RESULTS: Platelet numbers started to decrease between days 7 and 9 after infection, which corresponded to the earliest phase of blood-stage infection. With the decrease in platelet numbers, levels of vWF, vWF propeptide (markers of chronic and acute endothelial cell activation, respectively), and activated vWF (exposing the glycoprotein Ib alpha platelet binding domain) increased proportionally. A strong, reciprocal relationship was observed between platelet numbers and levels of both vWF and activated vWF. Activity of the vWF-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) -- a regulator of vWF activity -- remained unchanged. CONCLUSIONS: P. falciparum induces systemic acute endothelial cell activation and release of activated vWF immediately after the onset of blood-stage infection. The resulting platelet agglutination may result in early thrombocytopenia and may play a role in the pathogenesis of malaria. PMID- 17624851 TI - Rickettsiae-stimulated dendritic cells mediate protection against lethal rickettsial challenge in an animal model of spotted fever rickettsiosis. AB - The role played by dendritic cells (DCs), initiators and orchestrators of the immune response, remains unclear in rickettsial infections. To investigate their importance in rickettsioses, we analyzed the responses of murine bone marrow derived DCs (BMDCs) after rickettsial stimulation in vitro and their protective role in vivo. Rickettsia conorii stimulation of BMDCs caused significant maturation and production of proinflammatory cytokines. Transfer of rickettsiae stimulated DCs protected mice from lethal rickettsial challenge by limiting rickettsial proliferation in vivo, whereas partial protection was observed in mice receiving lipopolysaccharide (LPS)-stimulated DCs. Immunity to R. conorii after transfer of DCs was associated with up-regulation of CD40, CD80, CD86, and major histocompatibility complex class II; with production of IL-2, IL-12, and IL 23; and with production of antigen-specific interferon- gamma in T cells. Taken together, our data suggest that a vigorous proinflammatory response in DCs is associated with protective immunity to rickettsiae and that generation of antigen specific immunity is crucial to complete protection. PMID- 17624852 TI - Differential kinetics and molecular recognition mechanisms involved in early versus late growth phase Staphylococcus aureus cell binding to platelet layers under physiological shear conditions. AB - BACKGROUND: Staphylococcus aureus adhesion to platelets via microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) is a critical first step in vascular infection. The molecular mechanisms governing adhesion are influenced by the repertoire of MSCRAMMs expressed on the bacterial surface and the fluid mechanical shear rates present in the vasculature. We compared the predominant adhesion mechanisms between early and late growth phase S. aureus under physiological shear conditions. METHODS: A parallel-plate flow chamber was used to quantify the adhesion of early and late growth phase S. aureus to immobilized platelet layers as a function of wall shear rate. Specifically, we evaluated the influence of clumping factor (Clf) A, ClfB, serine-aspartate repeats, fibronectin-binding proteins (Fnbps), and protein A in supporting S. aureus adhesion to platelets. The ability of the plasma proteins fibrinogen and fibronectin to act as bridging molecules was also investigated. RESULTS: Our results demonstrate a markedly elevated binding efficiency for late growth phase staphylococci to immobilized platelets, compared with that of the early growth phase cells in the high shear regime. During the late growth phase, fibrinogen in concert with von Willebrand factor (vWF) potentiates S. aureus-platelet binding via shear-dependent mechanisms. By contrast, fibrinogen, but not vWF, supports the adhesion of early growth phase S. aureus at the high wall shear rates. During the early growth phase, ClfA is identified as the dominant staphylococcal adhesion receptor, with Fnbps playing a supporting role. CONCLUSION: The results presented here demonstrate a differential mechanism and binding efficiency for the adhesion of early versus late growth phase S. aureus to immobilized platelets. PMID- 17624854 TI - Tumor necrosis factor and increase in alveolar capillary barrier in malaria. PMID- 17624855 TI - Biomarkers and surrogate end points in clinical trials of tuberculosis treatment. PMID- 17624857 TI - Randomized, controlled trial of treatments for second-stage sleeping sickness. PMID- 17624858 TI - Genetic variability in maned wolf based on heterologous short-tandem repeat markers from domestic dog. AB - The maned wolf (Chrysocyon brachyurus) is the largest South American canid. Habitat loss and fragmentation, due to agricultural expansion and predatory hunting, are the main threats to this species. It is included in the official list of threatened wildlife species in Brazil, and is also protected by IUCN and CITES. Highly variable genetic markers such as microsatellites have the potential to resolve genetic relationships at all levels of the population structure (among individuals, demes or metapopulations) and also to identify the evolutionary unit for strategies for the conservation of the species. Tests were carried out to verify whether a class of highly polymorphic tetranucleotide repeats described for the domestic dog effectively amplifies DNA in the maned wolf. All five loci studied were amplified; however, one of these, was shown to be monomorphic in 69 maned wolf samples. The average allele number and estimated heterozygosity per polymorphic locus were 4.3 and 67%, respectively. The genetic variability found for this species, which is considered threatened with extinction, showed similar results when compared to studies of other canids. PMID- 17624859 TI - From geochemistry and biochemistry to prebiotic evolution...we necessarily enter into Ganti's fluid automata. AB - The present study is just an overview of the opening of the geochemical stage for the appearance of life. But that opening would not have been sufficient for the intellectual discovery of the origin of life! The excellent works and many commendable efforts that advance this explanation have not shown the fundamental elements that participate in the theoretical frame of biological evolution. The latter imply the existence of evolutionary transitions and the production of new levels of organization. In this brief analysis we do not intend to introduce the audience to the philosophy of biology. But we do expect to provide a modest overview, in which the geochemical chemolithoautotrophic opening of the stage should be seen, at most, as the initial metabolism that enabled organic compounds to follow the road where a chemical fluid machinery was thus able to undertake the more "sublime" course of organic biological evolution. We think that Tibor Ganti's chemoton is the most significant contribution to theoretical biology, and the only course now available to comprehend the unit of evolution problem without the structuralist and functionalist conflict prevalent in theoretical biology. In our opinion Ganti's chemoton theory travels to the "locus" where evolutionary theory dares to extend itself to entities at many levels of structural organization, beyond the gene or the group above. Therefore, in this and subsequent papers on the prebiotic conditions for the eventual appearance of the genetic code, we explore the formation and the presence of metal sulfide minerals, from the assembly of metal sulfide clusters through the precipitation of nanocrystals and the further reactions resulting in bulk metal sulfide phases. We endeavor to characterize pristine reactions and the modern surfaces, utilizing traditional surface science techniques and computational methods. Moreover, mechanistic details of the overall oxidation of metal sulfide minerals are set forth. We hope that this paper will lead our audience to accept that in a chemically oscillating system the chemoton is a model fluid state automaton capable of growth and self-reproduction. This is not simply a matter of transmitting a pattern, as in inorganic crystals; such self-reproduction must be more complex than crystal growth. Indeed that is what Ganti's theoretical and abstract model offers to us all: we finally have a philosophy of evolutionary units in theoretical biology. PMID- 17624860 TI - Selection and estimation of the heritability of sunflower (Helianthus annuus) pollen collection behavior in Apis mellifera colonies. AB - We selected honey bee colonies (Apis mellifera L.) with a high tendency to collect sunflower pollen and estimated the heritability of this trait. The percentage of sunflower pollen collected by 74 colonies was evaluated. Five colonies that collected the highest percentages of sunflower pollen were selected. Nineteen colonies headed by daughters of these selected queens were evaluated for this characteristic in comparison with 20 control (unselected) colonies. The variation for the proportion of sunflower pollen was greater among colonies of the control group than among these selected daughter colonies. The estimated heritability was 0.26 +/- 0.23, demonstrating that selection to increase sunflower pollen collection is feasible. Such selected colonies could be used to improve sunflower pollination in commercial fields. PMID- 17624861 TI - Genetic diversity of microsatellite loci in Leopardus pardalis, Leopardus wiedii and Leopardus tigrinus. AB - The microsatellite loci FCA045, FCA077, FCA008, and FCA096 are highly variable molecular markers which were used to determine the genetic diversity in 148 captive Leopardus sp. The PCR-amplified products of microsatellite loci were characterized in ABI Prism 310 Genetic Analyzer. Allele numbers, heterozygosity, polymorphism information content, exclusive allele number, and shared alleles were calculated. Sixty-five alleles were found and their sizes ranged from 116 to 216 bp in four microsatellite loci. The heterozygosity ranged from 0.36 to 0.81 in Leopardus pardalis, 0.57 to 0.67 in L. tigrinus and 0.80 to 0.92 in L. wiedii. The polymorphism information content was from 0.80 to 0.88 in L. pardalis, 0.76 to 0.88 in L. tigrinus and 0.77 to 0.90 in L. wiedii. The margay (L. wiedii) showed the highest index of polymorphism among the three species in this study. These results imply that microsatellite DNA markers can help in the study of the genetic diversity of Leopardus specimens. PMID- 17624862 TI - Colony membership is reflected by variations in cuticular hydrocarbon profile in a Neotropical paper wasp, Polistes satan (Hymenoptera, Vespidae). AB - Nestmate recognition is one the most important features in social insect colonies. Although epicuticular lipids or cuticular hydrocarbons have both structural and defensive functions in insects, they also seem to be involved in several aspects of communication in wasps, bees and ants. We analyzed and described for the first time the cuticular hydrocarbons of a Neotropical paper wasp, Polistes satan, and found that variation in hydrocarbon profile was sufficiently strong to discriminate individuals according to their colony membership. Therefore, it seems that small differences in the proportion of these compounds can be detected and used as a chemical-based cue by nestmates to detect invaders and avoid usurpation. PMID- 17624863 TI - Minimization of transcriptional temporal noise and scale invariance in the yeast genome. AB - The analysis of transcriptional temporal noise could be an interesting means to study gene expression dynamics and stochasticity in eukaryotes. To study the statistical distributions of temporal noise in the eukaryotic model system Saccharomyces cerevisiae, we analyzed microarray data corresponding to one cell cycle for 6200 genes. We found that the temporal noise follows a lognormal distribution with scale invariance at the genome, chromosomal and sub-chromosomal levels. Correlation of temporal noise with the codon adaptation index suggests that at least 70% of all protein-coding genes are a noise minimization core of the genome. Accordingly, a mathematical model of individual gene expression dynamics was proposed, using an operator theoretical approach, which reveals strict conditions for noise variability and a possible global noise minimization/optimization strategy at the genome level. Our model and data show that minimal noise does not correspond to genes obeying a strictly deterministic dynamics. The natural strategy of minimization consists in equating the mean of the absolute value of the relative variation of the expression level (alpha) with noise (eta). We hypothesize that the temporal noise pattern is an emergent property of the genome and shows how the dynamics of gene expression could be related to chromosomal organization. PMID- 17624864 TI - Determination of serum glucose by horseradish peroxidase-catalysed imidazole chemiluminescence coupled to a micro-flow-injection system. AB - The reactivity of flow-injection (FI)-horseradish peroxidase (HRP)-catalysed imidazole chemiluminescence (CL) was studied for continuous determination of hydrogen peroxide (H(2)O(2)) and serum glucose with immobilized glucose oxidase. Light emission by the HRP-catalysed imidazole CL was obtained when immobilized HRP, alkaline imidazole (in Tricine solution, pH 9.3) and H(2)O(2) were reacted at room temperature. The optimal pH for the CL reaction was 9.3 and the optimal concentration of imidazole was 100 micromol/L. When no imidazole was added, the light intensity of the same H(2)O(2) specimen decreased to a level that could not be quantitatively determined. The spectrum of the light emitted by imidazole CL was in the range 400-600 nm with a peak at 500 nm. The calibration equation for determination of H(2)O(2) was y = 9860x(2) + 3830x + 11,700, where y = light intensity (RLU) and x = concentration of H(2)O(2) (micromol/L). The detection limit of H(2)O(2) was 5 pmol, and the reproducibility of the H(2)O(2) assay was 2.3% of the coefficient of variation (H(2)O(2) 48 micromol/L, n = 13). The CL method was successfully applied to assay glucose after on-line generation of H(2)O(2) with the immobilized glucose oxidase column, resulting in good reproducibility (CV = 3.3% and 1.0% for the standard glucose and the control serum, respectively). PMID- 17624865 TI - Zeolite-based cataluminescence sensor for the selective detection of acetaldehyde. AB - The reactions of acetaldehyde with O atoms in the cages of large-pore zeolites have been discovered to result in light emission. The luminescence characteristics of acetaldehyde vapours passing through the surface of chosen zeolites were studied using a cataluminescence-based detection system. To demonstrate the feasibility of the method, the detection of acetaldehyde using catalysts was studied systematically and a linear response of 0.06-31.2 microg/mL acetaldehyde vapour was obtained. Methanol, ethanol, isopropanol, methylbenzene, chloroform, dichlormethane and acetonitrile did not interfere with the determination of acetaldehyde. Acetaldehyde vapour could also be distinguished from some homologous series such as formaldehyde, cinnamaldehyde, glutaraldehyde and benzaldehyde on this catalyst, possibly due to the stereoselectivity of the zeolite and its specific reaction mechanism. Moreover, acetaldehyde was quantified without detectable interference from formaldehyde in four artificial samples. Thus, this kind of cataluminescence-based sensor could be potentially extended to the analysis of volatile organic compounds in air, and the simple and portable properties of cataluminescence-based sensors could also make them beneficial in many areas of analytical science. PMID- 17624866 TI - Youden Index and the optimal threshold for markers with mass at zero. AB - The Youden Index is often used as a summary measure of the receiver operating characteristic curve. It measures the effectiveness of a diagnostic marker and permits the selection of an optimal threshold value or cutoff point for the biomarker of interest. Some markers, while basically continuous and positive, have a spike or positive mass of probability at the value zero. We provide a flexible modeling approach for estimating the Youden Index and its associated cutoff point for such spiked data and compare it with the standard empirical approach. We show how this modeling approach can be adjusted to take covariate information into account. This approach is applied to data on the Coronary Calcium Score, a marker for atherosclerosis. PMID- 17624867 TI - Analysis of hospital costs as a basis for pricing services in Mali. AB - In a move to achieve a better equity in the funding of access to health care, particularly for the poor, a better efficiency of hospital functioning and a better financial balance, the analysis of hospital costs in Mali brings several key elements to improve the pricing of medical services. The method utilized is the classical step-down process which takes into consideration the entire set of direct and indirect costs borne by the hospital. Although this approach does not allow to estimate the economic cost of consultations, it is a useful contribution to assess the financial activity of the hospital and improve its performance, financially speaking, through a more relevant user fees policy. The study shows that there are possibilities of cross-subsidies within the hospital or within services which improve the recovery of some of the current costs. It also leads to several proposals of pricing care while taking into account the constraints, the level of the hospital its specific conditions and equity. PMID- 17624868 TI - Focusing on the software of managing health workers: what can we learn from high commitment management practices? AB - Knowledge of what constitutes best practice in human resource management (HRM) in public-oriented services is limited and the operational aspects of managing health workers at provision level have been poorly studied. The magnet hospital concept offers some insights into HRM practices that are leading to high commitment. These have been shown to lead to superior performance in not only industrial business firms, but also service industries and the public service. The mechanisms that drive these practices include positive psychological links between managers and staff, organizational commitment and trust. Conditions for successful high commitment management (HiCoM) include health service managers with a strong vision and able to transmit this vision to their staff, appropriate decision spaces for healthcare managers and a pool of reasonable well-trained health workers. For this, adequate remuneration is the first condition. Equally important are the issues of cultural fit and of 'commitment'. What would staff expect from management in return for their commitment to the organization? Salary buys indeed time of employees, but other practices ensure their commitment. Only if these drivers are understood will managers be able to make their HRM practices more responsive to the needs and expectations of the health workers. PMID- 17624869 TI - A sustainability assessment of a health equity fund initiative in Cambodia. AB - All but one of the health equity funds (HEFs) currently operating in Cambodia, introduced to address the adverse effects of low user fee exemption rates, rely heavily on external funding and have high administrative overheads. This article reports on a study of one type of HEF, based in Kirivong Operational Health District (KOD) and operated through local pagoda structures, which demonstrates minimal reliance on external funding and low administrative overheads. We utilize an adapted sustainability assessment framework to assess the ability of pagoda structures to enable financial access for the poorest to public sector health services. We further analyse the strengths and limitations of the pagoda-managed equity fund initiative, with a view to assessing not only its sustainability but its potential for replication in other settings.Our study shows that, against key sustainability indicators (health service utilization and health outcomes; management capacity and financial viability; community mobilization and government support), the pagoda-managed equity fund initiative scores well. However, it is evident that some external financial support is needed to allow the HEFs to function effectively. We conclude with recommendations for replicating the initiative, which include working innovatively with indigenous grassroots organizations to enhance community HEF ownership and to keep administrative overheads low. PMID- 17624870 TI - Movement behaviour in patients with chronic neck pain. AB - BACKGROUND AND PURPOSE: The present study evaluated whether patients with chronic neck pain demonstrate characteristic angular movement deviations during repeated cervical spine movements. METHOD: Sixteen patients with chronic neck pain and a group of 18 aged-matched healthy control subjects performed 10 repetitive maximal cervical movement cycles (flexion/extension, rotation, lateral flexion) at a self determined velocity. To collect the kinematic data of the cervical spine, a three dimensional ultrasonic movement analysis system (Zebris CMS70, Germany) was used. To describe the movement variability in the maximum oscillation amplitudies the intra-subject coefficients of variation (CV %) was calculated. The maximum difference was characterized by the absolute differences between the minimum and maximum oscillation amplitudes of iterated movement cycles. Pain intensity was obtained by visual analogue scales (VAS). RESULTS: The average pain rating of the patients with chronic neck pain indicated moderate neck pain intensity (3.7 (+/ 0.8)). Independent Student's t-tests revealed a significantly decreased range of movement (ROM) in the chronic neck pain group for all anatomic values (p < 0.05), except for the lateral flexion to the right. The maximum differences and variability parameters showed significantly increased values in the chronic neck pain group in all directions (p < 0.001). CONCLUSION: Maximal cervical ROM was significantly lower, and movement variability was significantly higher, in patients compared with healthy control subjects. The differences of cervical motion variability point towards increased movement irregularities in patients with chronic neck pain. The present study shows evidence to support the hypothesis that additional information may be gained from the analysis of movement variability. PMID- 17624871 TI - Efficacy of electrical stimulation to increase muscle strength in people with neurological conditions: a systematic review. AB - BACKGROUND AND PURPOSE: Weakness in partially paralysed muscles is a disabling impairment for people with neurological conditions. Strength training programmes are widely administered to address this impairment. There is a common belief that the effectiveness of strength training programmes can be enhanced by the addition of electrical stimulation. The purpose of this systematic review was to assess the efficacy of electrical stimulation for increasing voluntary strength in people with neurological conditions. METHOD: Eligible randomized trials of electrical stimulation were identified by searches of computerized databases. The search yielded 11,267 abstracts, of which 60 were retrieved. Two assessors independently reviewed full text versions of these articles. RESULTS: Eighteen studies satisfied the inclusion criteria. These studies involved participants with spina bifida (n = 1), cerebral palsy (n = 1), peripheral nerve lesion (n = 1), multiple sclerosis (n = 1), spinal cord injury (n = 3) and stroke (n = 11). The mean (SD) PEDro score for trial quality was 4.9 (1.0) out of 10. Meta analyses of studies involving similar patients were not done because of insufficient data or lack of homogeneity. The results of all studies were analysed individually. CONCLUSION: Several studies suggest a modest beneficial effect of electrical stimulation in patients with stroke. It is not clear whether patients with other types of neurological disabilities benefit from electrical stimulation in the same way. PMID- 17624872 TI - User satisfaction, community participation and quality of life among Chinese wheelchair users with spinal cord injury: a preliminary study. AB - The purpose of the present study was to investigate the relationships between spinal cord injury (SCI), wheelchair users' satisfaction, perceptions of their community participation and quality of life (QoL).Thirty-one community wheelchair users with SCI were administered the Chinese version of the Quebec User Evaluation of Satisfaction with assistive Technology (C-QUEST), the abbreviated Hong Kong version of the World Health Organization Quality of Life Questionnaire (WHO QoL-BREF (HK)) and selected items of 'Participation Restrictions' and 'Environmental Factors' of the International Classification of Functioning Disability and Health (ICF). Only a weak correlation was found between the C QUEST services sub-scores and one ICF environmental factor, that is, health related professionals (Spearman's r = 0.453; p < 0.05). The C-QUEST device sub scores were also weakly correlated with four domain scores of the WHO QoL-BREF (HK) (Spearman's r = 0.412-0.567; p < 0.05). Social relationship, participation in leisure and driving activities had a moderate association with scores of the WHO QoL-BREF (HK) (-0.405 > Spearman's r > -0.583; p < 0.05). It is concluded that community participation (e.g. use of transportation) and human environment (e.g. friends and peers) were more related to QoL, than to users' satisfaction with a wheelchair. Further research with a larger sample is recommended to examine the variables related to SCI and QoL. PMID- 17624873 TI - Usability of playgrounds for children with different abilities. AB - The aim of the present study was to better understand how children with different abilities use playgrounds to engage in creative play and interact socially with their peers. Twenty children aged between 7 and 12 years, with different abilities, participated in interviews. The findings showed that playgrounds served as a reference point for all the children, they challenged a child's physical abilities and provided opportunities for role-playing and social interactions. However, for children with disabilities, playgrounds had limited accessibility, usability and did not support interaction with peers. A methodological limitation of the study was that the interviewer only met the children once. Further research should be carried out to investigate if creating playgrounds according to universal design principles and adapting them to the needs of children with disabilities would improve social interactions and provide more opportunities for play. PMID- 17624874 TI - Quality of life in Swedish workers exposed to hand-arm vibration. AB - The objective of the present study was to analyse whether differences existed among workers exposed to hand-arm vibration (HAV) with regard to quality of life (QoL) issues. One hundred and eight male workers from a heavy manufacturing plant, with and without HAV symptoms, and workers referred to a hand surgery department with severe HAV symptoms participated in the study. The participants attended a clinical interview, were given a physical examination of the hands and administered the Goteborg Quality of Life instrument and the Evaluation of Daily Activity Questionnaire (EDAQ). Results indicated that workers referred to a hand surgery department with more severe HAV symptoms described a lower quality of life, defined here as lower subjective well-being, more symptoms of ill-health and difficulties with activities of daily living (ADL), than workers with no HAV symptoms. Workers from a heavy manufacturing plant with HAV symptoms experienced more difficulties with ADL, especially while working outdoors in cold weather, than workers with no HAV symptoms. Limitations of the present study include the use of a subjective scale to describe HAV symptoms. Further research is recommended on a larger sample of workers at risk for HAV symptoms to develop preventative ergonomic strategies. PMID- 17624875 TI - Effectiveness of health management departments of universities that train health managers in Turkey. AB - This research has [corrected] aimed to examine the effectiveness of the health management departments of universities which [corrected] train health managers in Turkey. The study compares - for lecturers and students - nine variables of organisational effectiveness [corrected] These nine dimensions are derived from Cameron (1978; 1981; 1986) [corrected] Factor analysis was used to validate [corrected] the scale developed by the researcher. For internal consistency and reliability, the [corrected] Cronbach Alpha reliability coefficient and item total correlation were applied. A questionnaire was administered to a [corrected] total of [corrected] 207 people [corrected] in health management departments in [corrected]Turkey. In analysis of the data, [corrected] descriptive statistics and the [corrected] t-test were [corrected]used. According to our [corrected] research findings, at individual [corrected] university level, lecturers found their departments more effective than did [corrected] their students. The highest effectiveness was perceived at Baskent University, a private university [corrected] The best outcome was achieved for 'organisational health', and 'the [corrected] ability to acquire resources' achieved [corrected] the lowest outcome [corrected] Effectiveness overall [corrected] was found to be moderate [corrected] PMID- 17624876 TI - Explaining turnover intention in Korean public community hospitals: occupational differences. AB - OBJECTIVES: Personnel in public hospitals had relatively low job satisfaction despite of tenure employment. High turnover rates degrade hospital image and incur additional costs related to recruitment and training. The purposes of this study were to describe the occupational differences and to identify factors affecting turnover intention among public hospital personnel. METHOD: A questionnaire survey was conducted as part of Administrative Services Quality Evaluation Program by Seoul metropolitan municipality from 1 November to 1 December in 2003. The subjects were 1251 entire hospital personnel in four hospitals. The questionnaire was designed to measure job satisfaction, organizational commitment, turnover intention, and demographic characteristics. Logistic regression analysis was performed to determine factors influencing turnover intention. RESULTS: There were significant differences in job satisfaction, organizational commitment, and turnover intention according to the occupations. The turnover intention rates were highest among physicians, followed by paramedicals and nursing staffs and then administrators. The significant factors affecting turnover intention were involvement and loyalty among physicians, hospital type, satisfaction with systems and loyalty among nursing staffs, satisfaction with relationship and loyalty among administrators, and loyalty among paramedicals. CONCLUSION: There were different moderators that influence turnover intentions of hospital personnel. Loyalty had the most important effect upon turnover intention in all occupations. PMID- 17624877 TI - Assessing uncertainty in outsourcing clinical services at tertiary health centers. AB - When tertiary health centers face capacity constraint, one feasible strategy to meet service demand is outsourcing clinical services to qualified community providers. Clinical outsourcing enables tertiary health centers to meet the expectations of service timeliness and provides good opportunities to collaborate with other health care providers. However, outsourcing may result in dependence and loss of control for the tertiary health centers. Other parties involved in clinical outsourcing such as local partners, patients, and payers may also encounter potential risks as well as enjoy benefits in an outsourcing arrangement. Recommendations on selecting potential outsourcing partners are given to minimize the risks associated with an outsourcing contract. PMID- 17624878 TI - Addressing the phenomenon of bypassing in Albania: the impact of a primary health care strengthening intervention. AB - The purpose of this study is to assess the impact of a primary health care strengthening intervention on bypassing behavior in Albania, a middle-income country that has experienced substantial structural changes that affect PHC and where bypassing among health care clients is common. The intervention aimed to improve the quality of health care in low-level facilities through improved availability and use of health information, the adoption of clinical practice guidelines, and provider training. The study employs a quasi-experimental research design to evaluate the impact of the intervention on health care utilization. The survey findings suggest that the pilot areas outperformed the control areas with respect to a number of key population-based indicators of health care utilization. For example, in the 2-year period between December 2002 and December 2004, bypassing for treatment of simple acute health problems during the month prior to the survey decreased by 47%, and the percentage of chronically ill health care clients who utilized PHC facilities for treatment in the month prior to the survey increased by 29%. These differences, which are statistically significant at the 10% level or better, suggest that the improved performance in the pilot areas is attributable to the intervention. PMID- 17624879 TI - Measuring the shortage of medical practitioners in rural and urban areas in developing countries: a simple framework and simulation exercises with data from India. AB - This paper suggests a simple framework to estimate the shortage of medical practitioners in rural and urban areas in developing countries. Shortages are defined with respect to four main considerations. The overall numbers and also the different categories of practitioners in the rural and urban areas, the relatively greater difficulties of access in the rural areas (which reduce the number of accessible practitioners) and the greater health hazards in those areas (which lead to greater need for medical treatment). The quantitative effect of these factors is examined by undertaking simulation exercises with data for the Ujjain district in Madhya Pradesh state, India and also data for that state. The simulations turned up the following results. The un-weighted total number of practitioners, per head of population, is relatively greater in the rural areas; this is because of the relatively large numbers of the unqualified doctors in those areas. On the other hand, a 'quality adjusted' total, with lower weights for the unqualified doctors, found little overall difference between the rural and urban areas. Third, allowance for rural-urban differences in the difficulties of access showed that the number of accessible practitioners is much lower in the rural areas. Fourth, rural-urban differences in the incidence of health hazards and estimates of the need for medical treatment also showed a marked shortage of practitioners in the rural areas. The main implication of the results is that developmental efforts in the rural areas, including improvements in transport facilities and reduction of health hazards, would help to greatly reduce the shortage of practitioners in those areas. Training programmes to improve the quality of practitioners in the rural areas are also required. PMID- 17624880 TI - Rebuilding health systems in post-conflict countries: estimating the costs of basic services. AB - After the fall of the Taliban in 2001, the Afghan transitional government and international donors found the health system near collapse. Afghanistan had some of the worst health indicators ever recorded. To begin activities that would quickly improve the health situation, the Ministry of Health (MOH) needed both a national package of health services and reliable data on the costs of providing those services. This study details the process of determining national health priorities, creating a basic package of services, and estimating per capita and unit costs for providing those services, with an emphasis on the costing exercise. Strategies for obtaining a rapid yet reasonably accurate estimate of health service costs nationwide are discussed. In 2002 this costing exercise indicated that the basic package of services could be provided for US dollars 4.55 per person. In 2006, the findings were validated: the four major donors who contracted with non-governmental organizations (NGOs) to provide basic health services for nearly 80% of the population found per capita costs ranging from dollars 4.30 to dollars 5.12. This study is relevant for other post-conflict countries that are re-establishing health services and seeking to develop cost effective and equitable health systems. PMID- 17624881 TI - The implementation of process orientation at a Swedish hospital. AB - During the last decade, as a response to the need for inter- as well as intra organizational integration, management models initially developed for industry have been spread to health care organizations. Based on 62 in-depth interviews, this qualitative study aims at describing and analyzing the limited success of implementation of process orientation at a Swedish hospital and in doing so, the traditional and the critical approaches are combined. Applying a traditional approach, the limited success of the implementation of process orientation is explained in terms of difficulties to challenge deeply institutionalized organizational routines and the inter-disciplinary boundaries. This might be condensed to the dilemma of how to maintain and develop the specialization of the medical profession while focusing process rather than function and how to enhance inter-organizational integration without hampering intra-organizational collaboration. Applying a critical approach, the limited success is explained in terms of a differentiated translation process and in terms of separation of talk and practice. This means that process orientation, notwithstanding that it might be an efficient tool for the type of integration needed, might be regarded as part of a change discourse, aiming at conveying a picture of an efficient and modern organization. PMID- 17624882 TI - Financial profiling of public hospitals: an application by data mining. AB - This paper presents an application of the data mining method to determine the financial profiles of the public hospitals in Turkey. The study is based on the data compiled in 2004, covering 645 public hospitals run by the Ministry of Health (MoH) as the main provider of primary and secondary health services in Turkey. The public hospitals, currently financed by a mixture of funds allocated from the general budget and individually operated revolving funds, need urgent solutions to their financial problems as a part of an ongoing national reform effort. The analysis adopts the Chi-Square Automatic Interaction Detector (CHAID) decision tree algorithm, as one of the most efficient and up-to-date data mining method used for segmentation. The study has found that the public hospitals could be categorized by the CHAID into 12 different profiles in terms of their financial performance. These profiles have guided us in determining the key financial indicators to be focused upon in the public hospitals and present best practices to improve their respective financial performances. The findings have also allowed policy suggestions as to the financial strategies that may be considered in improving the financial performance of the public hospitals toward a successful health sector reform in Turkey. PMID- 17624883 TI - A methodological and operative framework for the evaluation of an e-health project. AB - Assessing public sector ICT investments represents the premise for successful implementation of an e-health strategy. The recent literature stresses the importance of going beyond the mere financial and/or technical dimensions of the analysis. Consequently, the paper proposes an example of e-health project evaluation aiming to develop measures which get close to the notion of benefits to the different stakeholders involved: top management, patients, local community. The case study refers to an Italian health care organization that implemented a project of digitalization of its clinical reports production few years ago. Based on on-field research, different approaches are used to assess costs and benefits from different stakeholders' perspectives. The results of a multidimensional evaluation are reported to emphasize the need for different measures to assess the sustainability of an e-health project according to the financial convenience, the social role of the organization, and the contingent situation. PMID- 17624884 TI - Ecdysteroids from the medicinal fern Microsorum scolopendria (Burm. f.). AB - Fronds of the fern Microsorum scolopendria are widely used in traditional medicine in the Society Islands. They were investigated for the presence of ecdysteroids, which might be responsible for at least some of their medicinal properties. M. scolopendria represents an excellent source of ecdysone (0.16% of dry weight) and 20-hydroxyecdysone (0.20%), and also contains significant amounts (0.01-0.02%) of makisterones A and C, inokosterone and amarasterone A, together with lower amounts of poststerone and of a compound tentatively identified as 24,28-diepi-cyasterone. During this study, three new minor phytoecdysteroids, namely 20-deoxymakisterone A, a 25(?)-epimer of amarasterone A and 25 deoxyecdysone 22-glucoside were also isolated by a combination of normal- and reversed-phase HPLC and subsequently identified by NMR. PMID- 17624885 TI - Determination of astragalosides in the roots of Astragalus spp. using liquid chromatography tandem atmospheric pressure chemical ionization mass spectrometry. AB - A high-performance liquid chromatography tandem atmospheric pressure chemical ionization mass spectrometry method (HPLC-APCI-MS) has been developed for the characterization of astragalosides in the extracts of the roots of Astragalus spp. The [M - H](-) ions of astragalosides could be clearly observed in selected ion monitoring mode and APCI-MS-MS was used to further identify the structures of the astragalosides. Twelve astragalosides in the extracts of Radix Astragali obtained from Shandong in China were separated and identified. Using this method, astragalosides could be clearly identified and the profiles of these astragalosides could also be used to distinguish Astragalus spp. from different habitat regions. PMID- 17624886 TI - Characterisation of fungal lanostane-type triterpene acids by electrospray ionisation mass spectrometry. AB - Lanostane-triterpene acids obtained from the culture of the fungus Coriolellus malicola were studied by electrospray mass spectrometry in the negative ion mode using quadrupole time-of-flight and quadrupole ion trap analysers. Despite the differences observed in the mass spectra recorded with these instruments, a set of fragment ions was found to be characteristic of the family, depending on the Delta(7,9(11)) or Delta(8) skeleton and the particular functional group at C-3. PMID- 17624887 TI - pH stability of individual folates during critical sample preparation steps in prevision of the analysis of plant folates. AB - The stability and eventual interconversion of nine mono-glutamate folates (5 methyl-tetrahydrofolate, tetrahydrofolate, 5-formyltetrahydrofolate, 5,10 methenyltetrahydrofolate, 5,10-methylenetetrahydrofolate, dihydrofolate, 10 formylfolic acid, 10-formyltetrahydrofolate and folic acid) during the typical sample preparation steps (heat treatment for 10 min at 100 degrees C and incubation for 2 h at 37 degrees C) at different pH values have been investigated by LC-MS/MS. An LC-MS/MS method with isotopically labelled [(13)C(5)]5 methyltetrahydrofolate and [(13)C(5)] folic acid as internal standards has been developed with enhanced sensitivity using a Chromolith RP-18 column. 5 Methyltetrahydrofolate, folic acid and 10-formylfolic acid are relatively stable at different pHs (from 2 to 10) with and without heat treatment. Tetrahydrofolate shows instability at low pH. 5-Formyltetrahydrofolate and 5,10 methenyltetrahydrofolate can interconvert by changes in pH. Tetrahydrofolate and 5,10-methylenetetrahydrofolate can interconvert with formaldehyde or by changes in pH. Incubation at 37 degrees C for 2 h is much less aggressive for most folates as compared with heat treatment at 100 degrees C. At 37 degrees C most folates are stable at pH values between 4 and 8 except tetrahydrofolate and dihydrofolate, which are degraded at low pH. 10-Formyltetrahydrofolate and 5,10 methylenetetrahydrofolate cannot be quantified in the present method because these compounds are converted to 5,10-methenyltetrahydrofolate and tetrahydrofolate, respectively, in the acidic mobile phase. This study provides useful information for the analysis of folates in the future as well as for the interpretation of quantitative results from earlier work. PMID- 17624888 TI - Genetic and alkaloid analysis of Menispermum dauricum DC. by RAPD and HPLC. AB - The aim of the present work was to determine whether dauricine could be used as a taxonomic marker for Menispermum dauricum DC., and to explore the correlation among RAPD, ecological markers and chemical markers. To this end, the chemical and genetic differences of 173 individual samples of M. dauricum from nine different sources were studied based on the relevant ecological factors including longitude, latitude, annual precipitation, mean temperature, annual accumulated temperature and mean sea level. The contents of dauricine in the sample rhizomes were assayed by HPLC with photodiode array detection. The leaves from the same sample were assayed using randomly amplified polymorphism DNA (RAPD). The genetic distances were then compared. Hierarchical cluster analysis and multiple linear stepwise regression analysis were used in the statistical analysis. The results indicated that the contents of dauricine were respectively correlated with the genetic distance (r = 1.000), longitude (r = 0.849), latitude (r = 0.861), annual precipitation (r = 0.903), mean temperature(r = 0.912), annual accumulated temperature (r = 0.919) and mean sea level (r = 0.925). It is concluded that the content of dauricine in M. dauricum is significantly correlated with genetic distance and ecological factors, and may be used as the taxonomic marker. PMID- 17624889 TI - NMR assignment of iso-alpha-acids from isomerised extracts of Humulus lupulus L. cones. AB - Iso-alpha-acids are known to contribute to the characteristic bitter taste of beer. Six iso-alpha-acids were isolated from a carbon dioxide extract of the cones of Humulus lupulus L. by centrifugal partition chromatography followed by separation through beta-cyclodextrin binding. This method overcame the low yield issue of most isolation procedures that results from the low stability of these compounds to light and oxygen. Their full identification was performed using one- and two-dimensional NMR spectrometry, including (1)H- and (13)C-NMR, (1)H-(1)H COSY, HMQC and HMBC and electrospray ionisation mass spectrometry. The results confirmed the structures of the isolated compounds as trans-isocohumulone, cis isocohumulone, trans-isohumulone, cis-isohumulone, trans-isoadhumulone and cis isoadhumulone. Epimers can be easily distinguished by observing the chemical shift differences of the H-5, H-1''', H-2''' and C-5 signals and the different splitting pattern of H-5 and H-2''. PMID- 17624890 TI - Studies on the aroma of mate (Ilex paraguariensis St. Hil.) using headspace solid phase microextraction. AB - Volatile and semi-volatile components of mate (Ilex paraguariensis St. Hil.) were analysed by headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography and mass spectrometry. Five SPME fibres coated separately with 100 microm poly(dimethylsiloxane) (PDMS), 65 microm PDMS-divinylbenzene (DVB), 70 microm carbowax (CW)-DVB, 85 microm carboxen (CAR)-PMDS or 50/30 microm DVB-CAR, were tested. Seventy compounds were identified in the sample headspace, including propanal, (E)-2-pentenal, hexanal, (E)-2-hexenal, 6-methyl-5-hepten-2-one, (E,Z) 2,4-heptadienal, (E,E)-2,4-heptadienal, (E,Z)-3,5-octadien-2-one, beta cyclocitral, 3-ethyl 4-methyl-(1H)-pyrrole-2,5-dione, alpha-ionone, geranylacetone, beta-ionone, dihydroactinidiolide and caffeine. Extraction parameters such as temperature, time and sample mass were studied and optimized. The best conditions for trapping volatile and semi-volatile compounds were obtained using a DVB-CAR fibre at 80 degrees C for 60 min with a sample mass starting from 100 mg in a vial of 4 mL. PMID- 17624891 TI - A capillary zone electrophoresis method for the quantitative determination of hypoxoside in commercial formulations of African potato (Hypoxis hemerocallidea). AB - Hypoxoside is a norlignan diglucoside present in the corms of African potato, Hypoxis hemerocallidea, used as a popular African traditional medicine for its nutritional and immune boosting properties. A specific analytical method employing capillary zone electrophoresis has been developed and validated for the quantitative determination of this analyte. Sulfafurazole was used as internal standard, and electrophoretic separation of both analytes could be achieved within 12 min. Linearity of the method was established within the range 5-60 microg/mL and provided a high degree of accuracy (100 +/- 3%). The recovery of the method was found to be 100 +/- 5% and the RSDs of the intra- and inter-day precision were better than 5.19 and 2.52%, respectively. The limits of detection and quantification were calculated to be 0.5 and 2 microg/mL, respectively. The described method was used for the analysis and quality control of two commercially available products containing African potato. The method can also be used to determine product stability since it could separate the hypoxoside peak from its degraded products obtained from degradation studies. PMID- 17624892 TI - EI/MS fragmentation of abieta-8,11,13-triene diterpenoid derivatives as a tool to identify swartziarboreols in Swartzia extracts. AB - A systematic molecular fragmentation pathway (SMFP) was designed as an identifier to detect swartziarboreols (abieta-8,11,13-triene diterpenoid derivatives) in Swartzia extracts. The SMFP was rationalised through the interpretation of the EI/MS of swartziarboreols isolated from S. arborescens and S. langasdorffii and by analogy with the fragmentations observed for previously isolated compounds. Two pairs of swartziarboreol epimers were identified by GC-MS in an extract of S. langsdorffii using SMFP. Acetylation and methylation of the dichloromethane extract furnished, respectively, 3 and 4, which suggested the occurrence of a new natural orthodiphenolic swartziarboreol. PMID- 17624893 TI - Identification and quantification of C21 steroidal saponins from Radix Cynanchi Atrati by high-performance liquid chromatography with evaporative light scattering detection and electrospray mass spectrometric detection. AB - High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-ESI/MS) and evaporative light scattering detection (HPLC ELSD), respectively, has been performed for the simultaneous identification and quantification of six C(21) steroid saponins, including cynanversicoside A, B, D, G, glaucoside C and glaucogenin C-3-O-beta-d-thevetopyranoside in Radix Cynanchi Atrati. The extraction of the C(21) steroidal saponins was performed using a B 811 Buchi Universal Extraction System in Warm Solvent Mode, and the analyte was concentrated by column chromatography before HPLC analysis. The chromatographic separation was performed on an Agilent Zorbax Extend C(18) analytical column efficiently using gradient elution with acetonitrile and water. The method was validated with acceptable linearities (r > 0.9991) and recoveries (98.2-101.3%). The limits of detection of the C(21) steroid saponins were from 0.2 microg for glaucogenin C-3-O-beta-d-thevetopyranoside to 0.5 microg for cynanversicoside B. The intra- and inter-day precisions of the method were evaluated and were less than 5.0%. The method was successfully used to analyse 20 batches of Radix Cynanchi Atrati. The content of C(21) steroid saponins in the plant material varied significantly from habitat to habitat, confirming the necessity to control the quality of Radix Cynanchi Atrati during its preparation and application in the clinic. PMID- 17624894 TI - Assessment of the importance of glenohumeral peripheral mechanics by practicing physiotherapists. AB - BACKGROUND AND PURPOSE: Physiotherapists develop clinical reasoning theories and applied manual therapy skills through a variety of educational exposures. No studies have assessed the importance of selected theories such as the convex concave rule, capsular pattern and scapulohumeral rhythm during clinical decision making by physiotherapists. The present study investigated which variables physiotherapists considered were associated with the importance of these theories during practice and investigated physiotherapists' perception of translational motion biomechanics of the glenohumeral (GH) joint. METHOD: Six hundred and sixty physiotherapists in the USA volunteered to participate in this study. Using ologit regression analyses, the identifier themes and clinical background characteristics were associated with importance of peripheral biomechanics in manual therapy application and reliability/validity of the scapulohumeral rhythm theory in predicting pathological sequences of the shoulder complex. An intraclass correlation coefficient (ICC) was used to determine agreement regarding necessary translation of the GH joint for normal movement. RESULTS: The majority of physiotherapists indicated that all theories were important or very important during treatment decision-making and reported frequent utilization. Regression models identified that the importance placed on peripheral biomechanics was negatively influenced by academic qualification (bachelors and masters degrees) and gender (men were less likely to report that scapulohumeral rhythm was a reliable/valid predictor of shoulder pathology). ICC values identified excellent agreement among clinicians regarding translational motion. CONCLUSIONS: The importance of biomechanics of the periphery for use, validation and frequency was based heavily on adoption of selected theories of glenohumeral movements despite evidence that suggests the theories lack validity. PMID- 17624895 TI - Perspectives on research evidence and clinical practice: a survey of Australian physiotherapists. AB - BACKGROUND AND PURPOSE: Physiotherapists' use of research evidence with clinical decision-making has interested researchers world-wide since 1980; however, little is known about such practices in Australia. The present survey sought information on Australian physiotherapists' perceptions of the importance of research, and barriers to uptake of evidence in clinical practice, when compared with an international cohort from 2001. METHOD: An Australian-relevant version of an English (UK) National Health Service (NHS) survey instrument was used to canvass 453 physiotherapists, randomly selected from the South Australian Physiotherapy Registration Board 2004-2005 records. The first survey was mailed in August 2005, a reminder was sent two weeks later to non-responders and a follow-up survey was sent in April 2006 to non-responders whose addresses had changed since 2005. RESULTS: There was a 51% response rate. Of the non-responders, 12% were not contactable at their listed address, highlighting the mobility of Australian physiotherapists. Most respondents had undertaken research as students (59.5%) or as students and clinicians (11.5%). Of these, 37.1% were encouraged to embark on more research, and 20.5% were discouraged. The significant predictors of positive perceived importance of research were: previous research experience; being positive about undertaking further research; working in hospitals and holding a postgraduate degree. Clinicians working privately were significantly less likely than managers to be positive about research importance. The only significant predictor for not perceiving barriers to uptake of evidence was being positive about undertaking future research. CONCLUSIONS: The study identified constraints on uptake of evidence into practice that were related to accessing, reading and interpreting published research, and implementing findings. Found consistently across employment categories were barriers relating to lack of time, uncertainty about what the research reported, scepticism about the value of research and being isolated from peer support and literature sources. The responses indicated a positive shift towards evidence uptake since the 2001 NHS survey, suggesting an influence of increased exposure to information on evidence-based practice. A greater focus on research whilst training, the application of educational strategies for empowerment, better knowledge transfer and upskilling within the workplace, and ensuring dedicated time and organizational support for research activities are indicated. PMID- 17624896 TI - Is mechanical deformation of the suboccipital vertebral artery during cervical spine rotation responsible for vertebrobasilar insufficiency? AB - PURPOSE: The atlanto-axial region of the vertebral artery (VA) has traditionally been considered at risk for injury during cervical spine rotation, leading to compromised blood flow to the hindbrain and vertebrobasilar insufficiency or ischaemia (VBI). The anatomical relationships of the suboccipital VA (VA3) and related haemodynamic changes associated with cervical spine movements have been neglected, however. The present review aims to provide a new perspective on possible causes of reduced blood flow to the hindbrain, with particular reference to the functional anatomy of VA3 and related biomechanics of cervical spine rotation, to inform evidence-based practice. METHOD: To support the hypothesis that it is VA3, not the VA in the atlanto-axial region, that is compressed or stretched during cervical spine rotation, current studies of blood flow changes in the VA distal to the region of rotation and possible arterial deformation were retrieved, using AMED, CINAHL, Embase, Pedro and PubMed, and reviewed. RESULTS: Possible sites for VA3 deformation, based on a re-examination of its anatomy and biomechanics, are described. However, no research reports of VA3 blood flow measurements associated with cervical spine rotation have been published to date. Five studies on blood flow changes in the intracranial VA after cervical spine rotation were reviewed. The subjects for four of these reports were young, healthy individuals, and the fifth included older patients and young non patients. The analysis of these studies demonstrated that more rigorous control of variables is necessary before meaningful conclusions can be made. CONCLUSION: The paucity of studies of VA3 emphasises the need for research based on informed understanding of the anatomy and biomechanics of this area. This view on mechanical deformation of VA3 associated with cervical spine rotation as a possible cause of compromised blood flow to the hindbrain and VBI provides further argument for avoiding full-range or sustained cervical spine rotation in clinical practice. PMID- 17624898 TI - Patients' attitudes and beliefs about back pain and its management after physiotherapy for low back pain. AB - BACKGROUND AND PURPOSE: Contemporary guidelines for the management of low back pain often consider patient involvement and responsibility an essential component; however, there has been little exploration of patients' opinions about back pain and its management. METHOD: A qualitative study of patients' perspectives of back pain in the UK; 34 semi-structured interviews were conducted with participants who had recently received physiotherapy for back pain; interviews were transcribed and analysed using framework analysis. A topic guide was used to steer the interview and themes were extracted from the data. RESULTS: Thirteen key themes were revealed; seven of these related to issues of satisfaction with physiotherapy and are described elsewhere. The six themes considered here dealt with the participants' experience of and attitudes to back pain and its management. Themes were: the impact of back pain on their life; perspectives about back pain; its management; their involvement in its management; what strategies they had for self-management; and expectations about the episode of physiotherapy beforehand. CONCLUSIONS: In this group of participants with a history of back pain and physiotherapy treatment a common finding was a degree of acceptance of the back pain problem and the belief that patient involvement in management was essential. These findings would suggest that many patients with back pain may respond positively to the message of self management. However, acceptance of this message was not automatic, but generally occurred gradually in line with patients' experience of back pain and treatment. PMID- 17624899 TI - Preparative isolation and purification of dicaffeoylquinic acids from the Ainsliaea fragrans champ by high-speed counter-current chromatography. AB - Two dicaffeoylquinic acids, namely 3,5-dicaffeoylquinic acid and 4,5 dicaffeoylquinic acid, have been successfully separated by high-speed counter current chromatography (HSCCC) from an extract of Ainsliaea fragrans Champ, followed by an initial clean-up step using AB-8 resin. A two-phase solvent system composed of chloroform:methanol:water (8:8:4) was selected for the isolation with the aqueous-rich phase as the stationary phase and the organic-rich phase as the mobile phase. The developed HSCCC method yielded 34 mg of 3,5-dicaffeoylquinic acid and 17 mg of 4,5-dicaffeoylquinic acid from 150 mg of the crude sample in a one-step separation with purities of 98 and 95%, respectively, as determined by HPLC. The structures of the two compounds were identified from ESI/MS, (1)H- and (13)C-NMR spectroscopic data. PMID- 17624900 TI - Identification of antioxidant phenolic compounds in feverfew (Tanacetum parthenium) by HPLC-ESI-MS/MS and NMR. AB - Antioxidant polyphenolic acids in the medicinal herb feverfew (Tanacetum parthenium) were isolated through in vitro bioassay-orientated antioxidant tests in response to 1,1-diphenyl-2-picrylhydrazyl (DPPH*) free radical scavenging and Fe(2+)-chelating activities. Purification of the active compounds and their structural elucidation involved a variety of techniques including open-column chromatography, HPLC, GC-MS, LC-MS and NMR. Major compounds with potent DPPH* scavenging activities were characterised as 3,5-, 4,5- and 3,4-di-O caffeoylquinic acids (DCQAs). This is the first report of DCQAs found in feverfew. PMID- 17624901 TI - Comparative analysis of the chemical profile of wild and cultivated populations of Corydalis saxicola by high-performance liquid chromatography. AB - Studies on the simultaneous determination and chemical fingerprinting of alkaloids in Corydalis saxicola Bunting. (Yanhuanglian) were performed for authentication purposes. Ninety samples prepared from different parts of C. saxicola, including whole plants, roots, stems, leaves and flowers, from wild and cultivated populations, were submitted to quantitative determination and fingerprint analysis. Five major alkaloids, namely, tetradehydroscoulerine, dehydroapocavidine, dehydroisoapocavidine, coptisine and dehydrocavidine, were quantitatively analysed by reversed-phase HPLC with acceptable recoveries (>98.2%). Chemical fingerprinting of C. saxicola was established and involved 11 markers. The results indicated that there were no obvious differences between the chemical profiles of wild and of cultivated C. saxicola populations, and that the mean alkaloid contents of the five marker compounds in cultivated populations were significantly higher than those of the wild plants. The highest content of total alkaloids (up to 28.8 mg/g) was found in roots of C. saxicola. The total alkaloids of the leaves were approximately 50% of those of roots, suggesting that the leaves may be employed as an alternative source of alkaloids. Chemical fingerprints and quantitative HPLC analysis will have a positive impact on the conservation and cultivation of this medicinal plant. PMID- 17624902 TI - Determination of pseudojujubogenin glycosides from Brahmi based on immunoassay using a monoclonal antibody against bacopaside I. AB - Bacopa monnieri (L.) Wettst. (Brahmi) is an Ayurvedic medicinal plant used for centuries as a memory enhancer. Dammarane-type triterpenoid saponins classified as pseudojujubogenin and jujubogenin glycosides are reported as the active components in this plant. In this study, the monoclonal antibody (MAb) against bacopaside I, a major pseudojujubogenin glycoside found in Brahmi, was produced and characterised. Bacopaside I was conjugated with bovine albumin serum to prepare an immunogen. Hybridomas secreting a monoclonal antibody against bacopaside I was produced by fusing splenocytes from an immunised mouse and SP2/0 Ag14 myeloma cells. The results showed that the antibodies were raised specifically against pseudojujubonin glycosides. An enzyme-linked immunosorbant assay (ELISA) using anti-bacopaside I MAb was performed in the range of 1.95-62.5 ng/mL of bacopaside I, with a limit of detection of 0.5 ng/mL. The method was validated and the practical use of the ELISA for analysing saponin glycosides from Brahmi was demonstrated. PMID- 17624903 TI - Analysis of Rhizoma Polygoni Cuspidati by HPLC and HPLC-ESI/MS. AB - An HPLC method with photodiode array detection (PAD) and ESI/MS detection was developed for the qualitative and quantitative analysis of the major chemical constituents of the dried rhizome of Polygonum cuspidatum Sieb. et Zucc. (Rhizoma Polygoni Cuspidati; Chinese name Hu-Zhang). Based on the chromatographic separation on an Altima C(18) column using 0.5% aqueous acetic acid and acetonitrile as the mobile phase, nine compounds, including stilbenes, stilbene glucosides, anthraquinones and anthraquinone glucosides, were identified by online ESI/MS analysis and seven were quantified by HPLC-PAD. A full validation of the method including sensitivity, linearity, repeatability and recovery was conducted. Linear calibration was achieved over the concentration range 1-200 mg/L with R(2) > 0.999, whilst the limits of detection ranged from 0.51 to 1.57 ng. Repeatability was evaluated by intra- and inter-day assays and the RSD value was within 1.79%. Recoveries of the quantified compounds were within the range 96.0-100.1% with RSD values of less than 2.2%. Five samples of Rhizoma Polygoni Cuspidati from different regions were analysed using the developed method. The major constituents piceid, resveratrol, emodin-8-O-beta-D-glucoside and emodin were selected to provide an index for the quality assessment of the herbal drug. PMID- 17624904 TI - Reversed-phase HPLC-ESI/MS analysis of birch leaf proanthocyanidins after their acidic degradation in the presence of nucleophiles. AB - Mountain birch leaves contain large amounts of structurally variable polymeric proanthocyanidins. Their isolation procedure was enhanced by the addition of liquid-liquid extractions prior to column chromatography over Sephadex LH-20. Isolated polymeric proanthocyanidins were depolymerised by acid-catalysis in the presence of benzyl mercaptan or phloroglucinol in order to study their composition. The resulting degradation products, flavan-3-ols and flavan-3-ol adducts, were analysed with reversed-phase high-performance liquid chromatography using UV photodiode array detection for quantification and electrospray ionisation mass spectrometry for identification. The results showed that polymeric proanthocyanidins contained (epi)gallocatechins and (epi)catechins as the extension units and, mainly, (+)-catechin as the terminal unit. The mean degree of polymerisation was found to be 26 based on thiolysis and 31 based on phloroglucinol degradation. PMID- 17624905 TI - Optimisation of an extraction procedure and chemical characterisation of Croatian propolis tinctures. AB - Three spectrophotometric methods for the quantitative determination of different flavonoid groups and total phenolics in Croatian propolis samples were optimised and validated. The assay based on the formation of aluminium chloride complex (with galangin as a standard) was applied to the quantification of flavones and flavonols, while the 2,4-dinitrophenylhydrazine method (with pinocembrine as a reference) was used for the quantification of flavanones. Total phenolic content was measured by the Folin-Ciocalteau method using reference solution of caffeic acid:galangin:pinocembrine (1:1:1). Through analytical validation, the most suitable extraction conditions (with respect to time, temperature and concentration of extraction solvent) were determined, and final conditions for the extraction were established (80% ethanol, 1 h at the room temperature). The appropriate ratio between the mass of raw propolis and the extraction solvent volume was also established. By the application of the optimised method of extraction, 10 propolis tinctures were prepared and subjected to the analysis of general pharmacopoeial parameters, which are fundamental for the creation of quality specification (relative density, dry residue of extract, content of ethanol, methanol and 2-propanol). Additionally, the content of waxes as the main inactive constituents was determined in order to observe the level of their migration from crude propolis to the prepared tinctures. PMID- 17624906 TI - Phonological or orthographic training for children with phonological or orthographic decoding deficits. AB - In a longitudinal intervention study, Swedish reading disabled children in grades 2-3 received either a phonological (n = 41) or an orthographic (n = 39) training program. Both programs were computerized and interventions took place in ordinary school settings with trained special instruction teachers. Two comparison groups, ordinary special instruction and normal readers, were also included in the study. Results showed strong average training effects on text reading and general word decoding for both phonological and orthographic training, but not significantly higher improvements than for the comparison groups. The main research finding was a double dissociation: children with pronounced phonological problems improved their general word decoding skill more from phonological than from orthographic training, whereas the opposite was observed for children with pronounced orthographic problems. Thus, in this population of children, training should focus on children's relative weakness rather than their relative strength in word decoding. PMID- 17624907 TI - Unimpaired implicit learning in children with developmental dyslexia. AB - Children with dyslexia have consistently been found to have a variety of deficits in motor, cognitive, and sensory processes; however, the few studies that have been reported of the implicit learning ability of these children have produced conflicting results. The present study aimed to investigate the implicit learning abilities of children with developmental dyslexia using a simple cued reaction time task which has not been studied with this group previously. Twenty-three children with developmental dyslexia and 37 normally developing children, between the ages of 8 and 10 years, participated in the task. The results were consistent with the hypothesis in demonstrating that, despite an overall slowing in response times, dyslexic children show the same degree of implicit learning as normal readers, thus, providing evidence for an unimpaired implicit learning mechanism in dyslexic individuals. These results hold implications for the underlying mechanisms of learning, as dyslexic individuals who are impaired on explicit learning tasks, such as reading, spelling and writing, are unimpaired on implicit learning tasks. They suggest the existence of two separate systems of learning, each possessing distinct mechanisms. PMID- 17624908 TI - The dyslexic student and mathematics in higher education. AB - Difficulties that are encountered by dyslexic undergraduates with their learning and understanding of mathematics are explored. Specific consideration is given to issues arising through mathematical content, its delivery, the procedures and processes of 'doing' mathematics, and its assessment. Particular difficulties, which have emerged through exploratory and explanatory multiple-case studies, and witnessed through the provision of one-to-one support to a dyslexic and dyspraxic engineering undergraduate, are detailed. Recommendations for the provision of mathematical support to dyslexic students and proposals for future research are given. PMID- 17624909 TI - Pragmatic abilities in adults with and without dyslexia: a pilot study. AB - This study examines well-compensated adults with dyslexia to see if they experience more problems with pragmatic awareness than the normal population. Social interaction requires an individual to process language at speed by using working memory efficiently, in order to understand the intended, rather than literal, meaning between speaker and hearer. Previous studies have shown evidence amongst the dyslexic population of poor working memory capacity, slower speed of processing and automatization deficit. It is proposed that a dyslexic may not be able to interpret pragmatic content as efficiently as non-dyslexics, due to the need for fast processing in such circumstances, resulting in resource overload and over-intensity of memory. The study compares the score results of 20 dyslexic and 20 non-dyslexic adults on the Dyslexia Adult Screening Test (DAST), the Right Hemisphere Language Battery and the author's own pragmatic competence questionnaire. The results for all three measures indicate a statistically significant difference in pragmatic competence between the two groups and appear to demonstrate a correlation between dyslexia and pragmatic impairment. Consideration of individual subtest items on the DAST lend support to the argument that this may be due to deficits in working memory, processing and automatization. PMID- 17624910 TI - The notion of 'phonology' in dyslexia research: cognitivism--and beyond. AB - Phonology has been a central concept in the scientific study of dyslexia over the past decades. Despite its central position, however, it is a concept with no precise definition or status. The present article investigates the notion of 'phonology' in the tradition of cognitive psychology. An attempt is made to characterize the basic assumptions of the phonological approach to dyslexia and to evaluate these assumptions on the basis of commonly accepted standards of empirical science. First, the core assumptions of phonological awareness are outlined and discussed. Second, the position of Paula Tallal is presented and discussed in order to shed light on an attempt to stretch the cognitive psychological notion of 'phonology' towards auditory and perceptual aspects. Both the core assumptions and Tallal's position are rejected as unfortunate, albeit for different reasons. Third, the outcome of this discussion is a search for what is referred to as a 'vulnerable theory' within this field. The present article claims that phonological descriptions must be based on observable linguistic behaviour, so that hypotheses can be falsified by data. Consequently, definitions of 'dyslexia' must be based on symptoms; causal aspects should not be included. In fact, we claim that causal aspects, such as 'phonological deficit', both exclude other causal hypotheses and lead to circular reasoning. If we are to use terms such as 'phonology' and 'phoneme' in dyslexia research, we must have more precise operationalizations of them. PMID- 17624911 TI - Auditory temporal processing deficits in children with reading disabilities. AB - The role of central auditory processing in reading skill development and reading disorders is unclear. The purpose of this study was to examine whether individuals with specific reading disabilities (SRD) have deficits in processing rapidly presented, serially ordered non-speech auditory signals. To this end, we compared 12 children with SRD and 12 children without SRD on their ability to detect differences and similarities in pure tones of 1000 and 2000 Hz when these signals were presented in pairs (same or different tones, randomly ordered) with short (50 ms) versus long (500 ms) inter-stimulus intervals (ISI). Results showed that the children with SRD had significant difficulty in discriminating between pure tones with short, but not long ISI, whereas the controls performed well with both short and long ISI. The two groups did not differ significantly on measures of attention (d2) and performance IQ, and there were no significant correlations between these measures and ISI performance. There were significant correlations between the short ISI performance and phonologic awareness test results when the two groups were combined. These findings support the specific rapid auditory processing deficit hypothesis of SRD. Examination of intra-subject variability in performance indicated that children from the SRD group showed both decrement in performance with time on task and high overall variability in performance as compared to the controls. These findings underpin the importance of using time series analyses of performance. PMID- 17624912 TI - Bootstrap significance test of synchronous spike events--a case study of oscillatory spike trains. AB - The purpose of this monograph is two folds. Firstly, we introduce challenging spike data to the statistical analysis. The data of two neurons recorded from the cat visual pathway show various non-stationary characteristics not fitted by the Poisson spike train. Spike firings of both neurons are strongly periodic and tightly synchronized. Our second purpose is a case study of applications of various statistical methods for the significance test of the time-varying spike synchrony. We provide various general remarks to the statistical analysis of the synchronous spike activities. At first, we apply the unitary event analysis. The significance limit for the coincident spike events by the Poisson distribution is compared with the limit given by the non-parametric test based on the bootstrap samplings. The bootstrap test performs superior to the Poisson test in two respects: (1) avoids false positives due to the sudden change of spike density; and (2) takes into account the non-stationary change of the spiking pattern at different sampling windows. When the spike trains are highly periodic, the histogram of the number of accidental coincident spike events over the bootstrap samples has a systematically larger variance than the Poisson distribution. We find that a large variance originates from the correlation between the successive coincident spike events in the structured spike trains. The significance of the time-varying synchrony is tested by another statistical method by Ventura et al., which is based on the adaptive smoothing method and the bootstrap significance test. . PMID- 17624913 TI - A novel chiral separation material: polymerized organogel formed by chiral gelators for the separation of D- and L-phenylalanine. AB - N-Stearine-N'-stearyl-L-phenylalanine, a chiral compound, was synthesized and used as a gelator for the gelation of polymerizable solvents, such as ss hydroxyethyl methacrylate (HEMA), styrene, etc. The scanning electron microscope (SEM) images of the gelator aggregates show fibril-like helices, typical chiral aggregates with diameters of 100-200 nm. The solvent molecules were immobilized by capillary forces in the three-dimensional network structures of the organogels. The HEMA organogels containing crosslinker polyethylene glycol dimethacrylates (PEG200DMA) were subsequently polymerized by in situ UV irradiation. A porous polymerized organogels were obtained after removal of gelator aggregates through ethanol extraction. The chiral separation of D- and L phenylalanine was carried out by the adsorption of the polymerized organogels. The adsorption efficiency of L-phenylalanine on the polymerized organogels was found to be dependent on the concentration of the gelator and crosslinker. PMID- 17624914 TI - Fluoxetine vs placebo for depressive symptoms after stroke: failed randomised controlled trial. AB - BACKGROUND: Growth in antidepressant prescribing is a well-recognised phenomenon in developed countries. In stroke care, the evidence of effectiveness from systematic reviews is surprisingly weak. We therefore decided to undertake a randomised controlled trial comparing fluoxetine to placebo. METHODS: Double blind placebo-controlled trial. Cases were high-scorers on the GHQ-28 and we applied minimal exclusion criteria. RESULTS: Despite screening 614 patients we were able to randomise only one into the trial. High rates of refusal to participate and exclusions due to physical ill health were coupled with high rates of prescribing among stroke clinicians, to cause this recruitment problem. CONCLUSIONS: In addition to the predicted practical problems of conducting an RCT in an elderly frail population, it became clear that most clinicians are not in equipoise about the value of antidepressant medication despite the lack of strong evidence for its effectiveness. PMID- 17624915 TI - Agronomic, chemical and genetic profiles of hot peppers (Capsicum annuum ssp.). AB - A study on morphology, productive yield, main quality parameters and genetic variability of eight landraces of hot pepper (Capsicum annuum ssp.) from Southern Italy has been performed. Morphological characters of berries and productivity values were evaluated by agronomic analyses. Chemical and genetic investigations were performed by HPLC and random amplified polymorphic DNA (RAPD)-PCR, respectively. In particular, carotenoid and capsaicinoid (pungency) contents were considered as main quality parameters of hot pepper. For the eight selected samples, genetic similarity values were calculated from the generated RAPD fragments and a dendrogram of genetic similarity was constructed. All the eight landraces exhibited characteristic RAPD patterns that allowed their characterization. Agro-morphological and chemical determinations were found to be adequate for selection, but they resulted useful only for plants grown in the same environmental conditions. RAPD application may provide a more reliable way based on DNA identification. The results of our study led to the identification of three noteworthy populations, suitable for processing, which fitted into different clusters of the dendrogram. PMID- 17624916 TI - Association analyses of GIP and GIPR polymorphisms with traits of the metabolic syndrome. AB - Glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin release via interaction with its pancreatic receptor (GIP receptor (GIPR)). GIP also acts as vasoactive protein. To investigate whether variations in GIP and GIPR genes are associated with risk factors of the metabolic syndrome we sequenced gene regions and identified two coding SNPs (GIP Ser103Gly, GIPR Glu354Gln) and one splice site SNP (GIP rs2291726) in 47 subjects. Interestingly, in silico analyses revealed that splice site SNP rs2291726 results in a truncated protein and classified GIPR variant Glu354Gln as a functional amino acid change. Association analyses were performed in a case-cohort study of incident cardiovascular disease (CVD) nested in the EPIC-Potsdam cohort. No significant associations between incident CVD and GIP Ser103Gly and rs2291726 were found. For GIPR Glu354Gln, we obtained a nominal association of heterozygous minor allele carrier with CVD in a codominant model adjusted for BMI, sex, and age (OR: 0.67, CI: 0.50-0.91, p = 0.01) or additional covariates of CVD (OR: 0.72, CI: 0.52-0.97, p = 0.03). In conclusion, we identified a common splice site mutation (rs2291726) of the GIP gene which results in a truncated protein and provide preliminary evidence for an association of the heterozygous GIPR Glu354Gln genotype with CVD. PMID- 17624917 TI - Geographic-based ecological correlation studies using supplemental case-control data. AB - It is well known that the ecological study design suffers from a variety of biases that render the interpretation of its results difficult. Despite its limitations, however, the ecological study design is still widely used in a range of disciplines. The only solution to the ecological inference problem is to supplement the aggregate data with individual-level data and, to this end, Haneuse and Wakefield (Biometrics 2007; 63:128-136) recently proposed a hybrid study design in which an ecological study is supplemented with a sample of case control data. The latter provides the basis for the control of bias, while the former may provide efficiency gains. Building on that work, we illustrate the use of the hybrid design in the context of a geographical correlation study of lung cancer mortality from the state of Ohio. Focusing on epidemiological applications, we initially provide an overview of the use of ecological studies in scientific research, highlighting the breadth of current application as well as advantages and drawbacks of the design. We consider the interplay between the two sources of information in the design: ecological and case-control, and then provide details on a Bayesian spatial random effects model in the setting of the hybrid design. Issues of specification are addressed, as well as sensitivity to modeling assumptions. Further, an interesting feature of these data is that they provide an example of how the proposed design may be used to resolve the ecological fallacy. PMID- 17624918 TI - Field distribution and DNA transport in solid tumors during electric field mediated gene delivery. AB - Gene therapy has a great potential in cancer treatment. However, the efficacy of cancer gene therapy is currently limited by the lack of a safe and efficient means to deliver therapeutic genes into the nucleus of tumor cells. One method under investigation for improving local gene delivery is based on the use of pulsed electric field. Despite repeated demonstration of its effectiveness in vivo, the underlying mechanisms behind electric field-mediated gene delivery remain largely unknown. Without a thorough understanding of these mechanisms, it will be difficult to further advance the gene delivery. In this review, the electric field-mediated gene delivery in solid tumors will be examined by following individual transport processes that must occur in vivo for a successful gene transfer. The topics of examination include: (i) major barriers for gene delivery in the body, (ii) distribution of electric fields at both cell and tissue levels during the application of external fields, and (iii) electric field induced transport of genes across each of the barriers. Through this approach, the review summarizes what is known about the mechanisms behind electric field mediated gene delivery and what require further investigations in future studies. PMID- 17624919 TI - Studies on neurosteroids XXII. Liquid chromatography-tandem mass spectrometric method for profiling rat brain 3-oxo-4-ene-neuroactive steroids. AB - A sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) method for the simultaneous determination of five 3 oxo-4-ene-neuroactive steroids, i.e. androstenedione, testosterone (T), progesterone (PROG), 20alpha-dihydroprogesterone and 20beta-dihydroprogesterone, in rat brain has been developed and validated. The brain steroids were extracted with methanol-acetic acid, purified using solid-phase extraction cartridges and subjected to LC-ESI-MS/MS. The method does not require derivatization. Deuterium labeled T and PROG were used as the internal standards, and quantification was based on the selected reaction monitoring mode. This method allowed the reproducible and accurate quantification of the brain neuroactive steroids using 100 mg of tissue; the intra- and inter-assay relative standard deviations were below 4.7 and 4.3%, respectively, and the accuracy values were 97.6-103.2% for all the steroids. The limits of quantitation were 0.1 ng/g tissue for all the steroids. The application of this developed method for the analysis of changes in the brain neuroactive steroid levels by immobilization stress is also presented. PMID- 17624920 TI - Prostate cancer survival is dependent on season of diagnosis. AB - BACKGROUND: We have earlier found that the prognosis for several cancers is dependent on season of diagnosis. More recently, both prostate cancer incidence and mortality have been shown to increase with increasing latitude, which probably relates to photosynthesis of vitamin D. METHODS: The 3 year survival of prostate cancer patients has been analyzed with the Cox regression method for two age groups at different latitudes in Norway. RESULTS: Patients diagnosed during the summer and autumn had the best prognosis (Ralative risk (RR) death 0.8; 95% CI 0.75-0.85). Similar results were observed in three regions of the country that differ with respect to annual fluences of solar UV radiation, incidence rates of squamous cell carcinoma (SCC) and intake of fish. Furthermore, similar relationship between the season and survival was seen among patients 65 years old, although the younger group had a slightly larger advantage of summer and autumn diagnosis. CONCLUSIONS: The seasonal effect on prognosis may be related to the seasonal variations of calcidiol (the marker of vitamin D status). The lack of latitude effect and the similarity of prognosis for different age groups may be related to higher consumption of vitamin D in food in the north region and to increase of such consumption with age. PMID- 17624921 TI - Ebselen attenuates cadmium-induced testicular damage in mice. AB - This study was designed to examine if ebselen, an organoselenium compound with antioxidant and glutathione peroxidase-mimetic properties, attenuates testicular injury caused by intraperitoneal administration of CdCl(2). A number of toxicological parameters were evaluated in the testes of mice, such as delta aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, ascorbic acid levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Ebselen attenuated lipid peroxidation levels altered by CdCl(2). delta-ALA-D activity inhibited by the highest dose of CdCl(2) was attenuated by ebselen. A significant negative correlation between lipid peroxidation levels and delta-ALA-D activity was observed. Ebselen restored ascorbic acid levels reduced by CdCl(2). A significant negative correlation between ascorbic acid levels and delta-ALA-D activity reinforces the idea that ebselen attenuated the damage induced by CdCl(2) via its antioxidant property. The significant correlation between ALT and delta-ALA-D activity supports the assumption that ebselen prevented damage caused by CdCl(2). The results show that ebselen attenuated oxidative stress, a process important for CdCl(2) toxicity. PMID- 17624923 TI - The combination of antagonists of LHRH with antagonists of GHRH improves inhibition of androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancers. AB - BACKGROUND: Antagonists of growth hormone-releasing hormone (GHRH) could extend the duration of response of androgen sensitive prostate cancers to androgen deprivation. METHODS: We investigated the effect of new GHRH antagonists MZ-J-7 118 and MZ-J-7-138 and luteinizing hormone-releasing hormone (LHRH) antagonist Cetrorelix or castration on androgen sensitive MDA-PCa-2b and LuCaP-35 prostate cancer models xenografted into nude mice. Animals bearing androgen-independent LuCaP-35V prostatic cancer model were also treated with MZ-J-7-118. RESULTS: Receptors for LHRH and GHRH were present in MDA-PCA-2b, LuCaP-35, and LuCaP-35V tumors. GHRH antagonists increased the inhibitory effect of surgical castration and LHRH antagonists on androgen sensitive MDA-PCa-2b and LuCaP-35 tumors. The time to relapse of androgen-dependent LuCaP-35 tumors was extended by GHRH antagonists. Growth of androgen-independent LuCaP-35V xenografts was also significantly inhibited by MZ-J-7-118. In MDA-PCa-2b tumors treatment with MZ-J-7 118 caused a significant decrease of VEGF and Cetrorelix or its combination with MZ-J-7-118 reduced EGF. The B(max) of EGF receptors was significantly reduced by Cetrorelix, MZ-J-7-118 and their combination. CONCLUSIONS: Our findings suggest that the use of a combination of antagonists of GHRH and LHRH could improve the therapy for androgen sensitive prostate cancer. Antagonists of GHRH could be also considered for treatment of androgen-independent prostate cancers. PMID- 17624922 TI - Evaluation of local tolerance of the antiretroviral spermicide (WHI-07)-loaded gel-microemulsion in the porcine female reproductive tract. AB - The local tolerance of the antiretroviral spermicide, WHI-07 (5-bromo-6-methoxy 5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate) loaded gel-microemulsion was evaluated in a physiologically relevant and sensitive porcine model. Gilts (Duroc) in nonestrus stages of the reproductive cycle received either a single or a daily intravaginal application of 2.0% WHI-07 via a gel-microemulsion for 6 days. Cervicovaginal lavage (CVL) fluid was obtained for up to 72 h after a single exposure and the cellular profile and levels of inflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) were quantitated by flow cytometry and chemiluminescence-based multiplex immunoassay, respectively. The reproductive tract (vagina, cervix, uteri and Fallopian tubes) harvested on day 7 was scored histologically for evidence of mucosal irritation using a new scoring criterion for ten histological endpoints that reflect pathological changes in the epithelial/ subepithelial and vascular/perivascular compartments. When compared with irritant reactions caused by the detergent-type spermicide, benzalkonium chloride (BZK), the scatter profile of CVL immune cells and basal levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF alpha) in CVL fluid were unaffected by intravaginal exposure to 2% WHI-07. Unlike BZK, endpoint histology of the proximal and distal regions of the reproductive tract from gilts treated with 2.0% WHI-07 via gel-microemulsion for 6 days did not result in mucosal irritation or alteration in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues and underlying/surrounding muscles. Based on surrogate markers for inflammation, leukocyte profile and histologic data for local tolerance, repeated intravaginal administration of WHI-07 via gel-microemulsion as a prophylactic contraceptive is unlikely to cause vaginal irritation. PMID- 17624924 TI - Androgen receptor-mediated repression of novel target genes. AB - BACKGROUND: The androgen receptor (AR) plays a pivotal role in prostate cancer (PCa) initiation and progression. To date, studies have focused disproportionately on androgen-stimulated genes such as prostate-specific antigen (PSA), while repressed genes have gained little attention, even though they too may be involved in regulating cell growth, differentiation, and apoptosis. METHODS: ChIP Display was used to identify putative AR target genes in the ablation-resistant human PCa cell line, C4-2B. Quantitative real-time reverse transcription-PCR analysis was used to measure gene expression in cells subjected to dihydrotestosterone (DHT) timecourse and dose-response, as well as AR knock down and bicalutamide-treatments. RESULTS: We report on three genes, KIAA1217, CHRM1, and WBSCR28, which were newly identified in a screen for AR-occupied regions in C4-2B PCa cells, and which were repressed by treatment with DHT. AR knock-down resulted in increased KIAA1217, CHRM1, and WBSCR28 mRNA, indicating that, like PSA stimulation, AR represses these three genes even in the absence of added ligand. DHT decreased KIAA1217 and CHRM1 pre-mRNA levels, suggesting AR mediated transcriptional inhibition. Cycloheximide attenuated DHT-mediated repression of CHRM1, suggesting the requirement of new protein synthesis. Furthermore, bicalutamide treatment did not mimic, but rather antagonized DHT mediated KIAA1217 repression. Unlike the handful of androgen-repressed genes studied thus far, AR occupancy at KIAA1217, CHRM1, and WBSCR28 was mapped outside their respective 5'-promoter regions. CONCLUSIONS: Many more genes likely share AR-mediated gene repression through distal regulatory elements. Further study of such targets and their transcriptional regulation may help explain the receptor's tumorigenicity in PCa. PMID- 17624925 TI - The GPI-anchored CD52 antigen of the sperm surface interacts with semenogelin and participates in clot formation and liquefaction of human semen. AB - CD52 is a human glycosylphosphatidylinositol (GPI)-anchored antigen exclusively expressed in leukocytes and epididymal cells. It is also present in sperm, being inserted in their plasma membrane as they pass through the epididymis. In a previous paper we identified a new CD52 form without GPI anchor by fast performance liquid chromatography (FPLC) fractionation of semen components. The form has a lower negative charge than the GPI-anchored form and occurs as the only CD52 form in prostasome-free seminal plasma. It was also found associated with the ejaculated sperm, but in contrast to the GPI-anchored one, it is lost during the capacitation process. In this paper we indicate that (1) the GPI anchored CD52 of the sperm surface serves as receptor for semenogelin I during clot formation, (2) liquefaction involves cleavage of the GPI anchor from certain CD52 molecules, releasing sperm from the clot and the soluble antigen bound to semenogelin fragments into the seminal plasma and (3) the clot is a sponge-like structure housing sperm. Soluble CD52 was immunopurified from the soluble CD52 containing FPLC fraction using CAMPATH-1G and was found to be complexed with a semenogelin-derived peptide of the carboxyl terminal portion of semenogelin I, having the sequence SQTEKLVAGKQI and starting from amino acid 376. Immunoprecipitation and immunoblot analyses using CAMPATH-1G and anti-semenogelin as immunoprecipitating antibodies and anti-gp20 and anti-semenogelin as immunoblot detectors of the corresponding antigens, confirmed that the soluble CD52 formed a complex with semenogelin. The semenogelin-CD52 soluble form was found to be a direct consequence of the liquefaction process since only the GPI anchored CD52 was recovered in uniquefied semen after recovering sperm and seminal plasma by urea solubilization of the clot. PMID- 17624926 TI - A comparison of bootstrap methods and an adjusted bootstrap approach for estimating the prediction error in microarray classification. AB - This paper first provides a critical review on some existing methods for estimating the prediction error in classifying microarray data where the number of genes greatly exceeds the number of specimens. Special attention is given to the bootstrap-related methods. When the sample size n is small, we find that all the reviewed methods suffer from either substantial bias or variability. We introduce a repeated leave-one-out bootstrap (RLOOB) method that predicts for each specimen in the sample using bootstrap learning sets of size ln. We then propose an adjusted bootstrap (ABS) method that fits a learning curve to the RLOOB estimates calculated with different bootstrap learning set sizes. The ABS method is robust across the situations we investigate and provides a slightly conservative estimate for the prediction error. Even with small samples, it does not suffer from large upward bias as the leave-one-out bootstrap and the 0.632+ bootstrap, and it does not suffer from large variability as the leave-one-out cross-validation in microarray applications. PMID- 17624927 TI - Hypoxia-inducible factor-1alpha (HIF-1alpha) gene polymorphisms, circulating insulin-like growth factor binding protein (IGFBP)-3 levels and prostate cancer. AB - BACKGROUND: The Hypoxia-inducible factor-1 (HIF-1) plays an important role in regulating angiogenesis in response to hypoxia. Two non-synonymous polymorphisms (P582S C-->T and A588T G-->A) in the coding region of the subunit 1alpha (HIF 1alpha) gene have been associated with enhanced stability of the protein and androgen-independent prostate cancer (CaP). Insulin-like growth factor binding protein (IGFBP)-3 mRNA is more abundantly expressed in hypoxia-related inflammatory angiogenesis and recent in vivo data suggest that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis. METHODS: We examined the association of these polymorphisms with CaP among 1,072 incident cases and 1,271 controls, and further explored their joint associations with various prediagnostic plasma vascular endothelial growth factor (VEGF), IGF-I, and IGFBP 3 levels. RESULTS: Neither the P582S nor the A588T polymorphism was associated with risk of overall or metastatic/fatal CaP. However, we found that, among men with the homozygous CC wild-type (but not CT/TT) of the HIF-1alpha P582S, higher IGFBP-3 levels (>/= vs. or=5 cm=51) performed at the time of admission. RESULTS: AFI numeric values were significantly related to the following maternal-neonatal variables: high maternal body temperature (P7 at 5 min (P50th percentile. There was no relationship between blood flow, resistance or maximum venous capacity with BMI in control subjects. BMI was inversely related to plasma AngII concentrations in those POTS patients with decreased peripheral blood flow, consistent with cachectic properties of the octapeptide. Patients with low-flow POTS had decreased body mass, but decreased body mass alone cannot account for findings of peripheral vasoconstriction. In conclusion, the findings suggest that reduced body mass relates to increased plasma AngII. PMID- 17624939 TI - Is the influence of variation in the ACE gene on the prospective risk of Type 2 diabetes in middle-aged men modified by obesity? AB - There is strong evidence for the presence of a functional renin-angiotensin system in diabetogenic tissues, and ACE (angiotensin-converting enzyme) inhibitors may improve glucose metabolism in those individuals at high risk of developing T2DM (Type 2 diabetes). In the present study, we tested the hypothesis that subjects with genetically lower plasma and tissue ACE activity, because of their ACE [I/D (insertion/deletion)] genotype, would have a lower risk of T2DM in 2642 healthy middle-aged Caucasian men (mean age, 56 years) followed-up for 15 years. Obesity was the strongest predictor of T2DM, with an HR (95% CI) [hazard ratio (95% confidence interval)] of 3.74 (2.66-5.26) (P<0.0001). Overall there was no association between ACE genotype (II homozygotes, n=623; and D allele carriers, n=2019) and risk of T2DM, and although in lean men there was no genotype difference in risk in D allele carriers compared with II homozygotes [adjusted HR=0.75 (95% CI, 0.46-1.22)], in obese (body mass index >30 kg/m(2)) men the risk of T2DM was higher [adjusted HR=4.26 (95% CI, 1.30-13.93)] with a genotype-obesity interaction of P=0.01. A similar pattern of risk was seen by re analysis of a previously published case-control study, where D allele carriers had a non-significant 1.30 (0.97-1.74)-fold higher risk of developing T2DM than II homozygotes when non-obese, but a 1.79 (1.17-2.72) (P=0.007)-fold higher risk when obese. Further prospective studies are needed to confirm these findings. The ACE D allele may worsen glucose metabolism, which could raise the prospective T2DM risk in obese men, but not in lean men. In obesity, adipose tissue undergoes inflammatory infiltration and the subsequent higher levels of pro-inflammatory angiotensin II may explain this association. PMID- 17624940 TI - Immunoreceptors and integrins. PMID- 17624941 TI - Compartmentalization of ITAM and integrin signaling by adapter molecules. AB - Adapters are multidomain molecules that recruit effector proteins during signal transduction by immunoreceptors and integrins. The absence of these scaffolding molecules profoundly affects development and function of various hematopoietic lineages, underscoring their importance as regulators of signaling cascades. An emerging aspect of the mechanism by which engaged immunoreceptors and integrins transmit signals within the cell is by differential usage of various adapters that function to nucleate formation of distinct signaling complexes in a specific location within the cell. In this review, we discuss the mechanisms by which adapter proteins coordinate signal transduction with an emphasis on the role of subcellular compartmentalization in adapter function. PMID- 17624942 TI - Convergence of immunoreceptor and integrin signaling. AB - A common signaling pathway is known to operate downstream of immunoreceptors, such as the T-cell, B-cell, or Fc receptors, following engagement by their respective ligands. This pathway involves Src family kinase-mediated tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) that recruit and activate spleen tyrosine kinase (Syk) or Zap70 (zeta-associated protein of 70 kDa) kinases, which in turn activate a variety of downstream signals. Evidence has been building from a variety of sources, particularly mouse models, that molecules involved in the immunoreceptor signaling pathway are also required for signals initiated by integrins. Integrins are the major cell surface receptors that mediate adhesion of leukocytes to a variety of extracellular matrix proteins and counter-receptors expressed on endothelial cells. Integrin ligation is a critical step in the activation of leukocyte effector functions (such as neutrophil degranulation or lymphocyte proliferation). Integrin signaling through pathways common to those utilized by immunoreceptors provides a mechanism by which leukocyte adhesion can regulate activation of cellular responses. In animal models, integrin-mediated signal transduction plays a critical role in inflammatory disease. In this review, we discuss the convergence of immunoreceptor and integrin signaling, focusing on how these pathways modulate leukocyte activation. PMID- 17624943 TI - Tec kinases, actin, and cell adhesion. AB - The Tec family non-receptor tyrosine kinases have been recognized for their roles in the regulation of phospholipase C-gamma and Ca(2+) mobilization downstream from antigen receptors on lymphocytes. Recent data, however, show that the Tec family kinase interleukin-2-inducible T-cell kinase (Itk) also participates in pathways regulating the actin cytoskeleton and 'inside-out' signaling to integrins downstream from the T-cell antigen receptor. Data suggest that Itk may function in a kinase-independent fashion to regulate proper recruitment of the Vav1 guanine nucleotide exchange factor. By enhancing actin cytoskeleton reorganization, recruitment of signaling molecules to the immune synapse, and integrin clustering in response to both antigen and chemokine receptors, the Tec kinases serve as modulators or amplifiers that can increase the duration of T cell signaling and regulate T-cell functional responses. PMID- 17624944 TI - T-cell receptor signaling to integrins. AB - Integrin adhesion receptors are critical for antigen recognition by T cells and for regulated recirculation and trafficking into and through various tissues in the body. T-cell receptor (TCR) signaling induces rapid increases in integrin function that facilitate T-cell activation by promoting stable contact with antigen-presenting cells and extracellular proteins in the environment. In this review, we outline the molecular mechanisms by which the TCR signals to integrins and present a model that highlights four key events: (i) initiation of proximal TCR signals nucleated by the linker for activated T cells (LAT) adapter protein and involving Itk, phospholipase C-gamma1, Vav1, and Src homology 2 domain containing leukocyte-specific phosphoprotein of 76 kDa; (ii) transmission of integrin activation signals from the LAT signalosome to integrins by protein kinase (PK) C and the adapter protein, adhesion and degranulation-promoting adapter protein; (iii) assembly of integrin-associated signaling complexes that include PKD, the guanosine triphosphatase Rap1 and its effectors, and talin; and (iv) reorganization of the actin cytoskeleton by WAVE2 and other actin-remodeling proteins. These events coordinate changes in integrin conformation and clustering that result in enhanced integrin functional activity following TCR stimulation. PMID- 17624945 TI - Regulation of T-cell antigen receptor-mediated inside-out signaling by cytosolic adapter proteins and Rap1 effector molecules. AB - Integrins are critical for the migration of T cells to lymphoid organs and to sites of inflammation and are also necessary for productive interactions between T cells and antigen-presenting cells. Integrin activation is enhanced following T cell receptor (TCR) engagement, as signals initiated by the TCR increase affinity and avidity of integrins for their ligands. This process, known as inside-out signaling, has been shown to require several molecular components including the cytosolic adapter proteins adhesion and degranulation-promoting adapter protein and Src homology 2 domain-containing adapter protein of 55 kDa, the low molecular weight guanosine triphosphatase Rap1, and the Rap1 effector proteins Rap1 guanosine triphosphate-interacting adapter molecule, regulator of adhesion and cell polarization enriched in lymphoid tissues, and protein kinase D1. Herein, we review recent findings about how the TCR is linked to integrin activation through inside-out signaling. PMID- 17624946 TI - Signaling by small GTPases in the immune system. AB - The Ras superfamily consists of over 50 low-molecular-weight proteins that cycle between an inactive guanosine diphosphate-bound state and an active guanosine triphosphate (GTP)-bound state. They are involved in a variety of signal transduction pathways that regulate cell growth, intracellular trafficking, cell migration, and apoptosis. Several methods have been devised to measure the activation state of Ras proteins, defined as the percent of Ras molecules in the active GTP-bound state. We have previously developed a quantitative biochemical method that can be applied to animal and human tissues and have used it to measure the activation state of Ras, Rap1, Rheb, and Rho proteins in cultured cells and in animal and human tumors. Ras, Rac, and Rho all play roles in regulating the functions of T and B lymphocytes and dendritic cells, and these proteins are clearly important in maintaining normal immune system function. PMID- 17624947 TI - Guanine nucleotide exchange factors of the cytohesin family and their roles in signal transduction. AB - Members of the cytohesin protein family, a group of guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (ARF) guanosine triphosphatases, have recently emerged as important regulators of signal transduction in vertebrate and invertebrate biology. These proteins share a modular domain structure, comprising carboxy-terminal membrane recruitment elements, a Sec7 homology effector domain, and an amino-terminal coiled-coil domain that serve as a platform for their integration into larger signaling complexes. Although these proteins have a highly similar overall build, their individual biological functions appear to be at least partly specific. Cytohesin 1 had been identified as a regulator of beta2 integrin inside-out regulation in immune cells and was subsequently shown to be involved in mitogen-associated protein kinase signaling in tumor cell proliferation as well as in T-helper cell activation and differentiation. Cytohesin-3, which had been discovered to be strongly associated with T-cell anergy, was very recently described as an essential component of insulin signal transduction in Drosophila and in human and murine liver cells. Future work will aim to dissect the mechanistic details of the modes of action of the cytohesins as well as to define the precise roles of these versatile proteins in vertebrates at the genetic level. PMID- 17624948 TI - Small GTPases and LFA-1 reciprocally modulate adhesion and signaling. AB - Leukocyte-function-associated antigen-1 (LFA-1) is an integrin that is critical for T-cell adhesion and immunologic responses. As a transmembrane receptor and adhesion molecule, LFA-1 signals bidirectionally, whereby information about extracellular ligands is passed outside-in while cellular activation is transmitted inside-out to the adhesive ectodomain. Here, we review the role of small guanosine triphosphatases (GTPases) in LFA-1 signaling. Rap1, a Ras-related GTPase, appears to be central to LFA-1 function. Rap1 is regulated by receptor signaling [e.g. T-cell receptor (TCR), CD28, and cytotoxic T-lymphocyte antigen-4 (CTLA-4)] and by adapter proteins [e.g. adhesion and degranulation-promoting adapter protein (ADAP) and Src kinase-associated phosphoprotein of 55 kDa (SKAP 55)]. Inside-out signaling flows through Rap1 to regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP interacting adapter molecule (RIAM) that act in conjunction with the cytoskeleton on the cytosolic domain of LFA-1 to increase adhesion of the ectodomain. Outside-in signaling also relies on small GTPases such as Rho proteins. Vav-1, a guanine nucleotide exchange factor for Rho proteins, is activated as a consequence of LFA-1 engagement. Jun-activating binding protein-1 (JAB-1) and cytohesin-1 have been implicated as possible outside-in signaling intermediates. We have recently shown that Ras is also downstream of LFA-1 engagement: LFA-1 signaling through phospholipase D (PLD) to RasGRP1 was required for Ras activation on the plasma membrane following stimulation of TCR. PMID- 17624949 TI - Integrin modulation and signaling in leukocyte adhesion and migration. AB - The movement of leukocytes from the blood into peripheral tissues plays a key role in immunity as well as chronic inflammatory and autoimmune diseases. The shear force of blood flow presents special challenges to leukocytes as they establish adhesion on the vascular endothelium and migrate into the underlying tissues. Integrins are a family of cell adhesion and signaling molecules, whose function can be regulated to meet these challenges. The affinity of integrins for their vascular ligands can be stimulated in subseconds by chemoattractant signaling. This aids in inducing leukocyte adhesion under flow conditions. Further, linkage of these integrins to the actin cytoskeleton also helps to establish adhesion to the endothelium under flow conditions. In the case of alpha4beta1 integrins, this linkage of the integrin to the cytoskeleton is mediated in part by the binding of paxillin to the alpha4 integrin subunit and the subsequent binding of paxillin to the cytoskeleton molecule talin. The movement of leukocytes along the vascular endothelium and in between endothelial cells requires the temporal and spatial regulation of small guanosine triphosphatases, such as Rac1. We describe mechanisms through which alpha4beta1 integrin signaling regulates appropriate Rac activation to drive leukocyte migration. PMID- 17624950 TI - The role of the integrin LFA-1 in T-lymphocyte migration. AB - A successful immune response depends on the migration of lymphocytes into lymph nodes or inflamed tissues where they make contact with antigen-presenting cells. We are interested in how one member of the integrin family, leukocyte function associated antigen-1 (LFA-1), controls the function and, in particular, the migration of immune cells. We find that this integrin operates not only as an adhesion receptor for T lymphoblasts (T cells) but also induces their migration in vitro at approximately 15 microm/min. Migration requires active myosin light chain kinase at the leading edge and Rho kinase at the trailing edge of the cell. Two active conformations of LFA-1 are differently distributed on the T-cell membrane and regulate independent aspects of migration. High-affinity LFA-1 is located in a midcell 'focal zone' and influences the speed of migration, whereas intermediate affinity LFA-1 controls leading edge adhesions. Manipulating LFA-1 conformation in vivo can be performed, for example, by creating the active conformation in a transgenic mouse, and this model gives further insight into the role of LFA-1 in migration. In humans, the beneficial effect of functioning CD18 integrins in combating infections in vivo is illustrated by rare patients displaying two forms of leukocyte adhesion deficiency. In summary, we speculate that T cells have evolved a mode of rapid migration that is of paramount importance in achieving the high-speed immune surveillance upon which depends the body's protection against diverse invaders from pathogens to cancer cells. PMID- 17624951 TI - Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions. AB - Cell-cell and cell-matrix interactions are of critical importance in immunobiology. Leukocytes make extensive use of a specialized repertoire of receptors to mediate such processes. Among these receptors, integrins are known to be of crucial importance. This review deals with the central role of integrins and their counterreceptors during the establishment of leukocyte-endothelium contacts, interstitial migration, and final encounter with antigen-presenting cells to develop an appropriate immune response. Particularly, we have addressed the molecular events occurring during these sequential processes, leading to the dynamic subcellular redistribution of adhesion receptors and the reorganization of the actin cytoskeleton, which is reflected in changes in cytoarchitecture, including leukocyte polarization, endothelial docking structure formation, or immune synapse organization. The roles of signaling and structural actin cytoskeleton-associated proteins and organized membrane microdomains in the regulation of receptor adhesiveness are also discussed. PMID- 17624952 TI - The molecular makeup and function of regulatory and effector synapses. AB - Physical interactions between T cells and antigen-presenting cells (APCs) form the basis of any specific immune response. Upon cognate contacts, a multimolecular assembly of receptors and adhesion molecules on both cells is created, termed the immunological synapse (IS). Very diverse structures of ISs have been described, yet the functional importance for T-cell differentiation is largely unclear. Here we discuss the principal structure and function of ISs. We then focus on two characteristic T-cell-APC pairs, namely T cells contacting dendritic cells (DCs) or naive B cells, for which extremely different patterns of the IS have been observed as well as fundamentally different effects on the function of the activated T cells. We provide a model on how differences in signaling and the involvement of adhesion molecules might lead to diverse interaction kinetics and, eventually, diverse T-cell differentiation. We hypothesize that the preferred activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1) and of the negative regulator for T-cell activation, cytotoxic T-lymphocyte antigen-4 (CTLA-4), through contact with naive B cells, lead to prolonged cell-cell contacts and the generation of T cells with regulatory capacity. In contrast, DCs might have evolved mechanisms to avoid LFA 1 overactivation and CTLA-4 triggering, thereby promoting more dynamic contacts that lead to the preferential generation of effector cells. PMID- 17624953 TI - Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. AB - Migration of leukocytes into tissue is a key element of innate and adaptive immunity. While the capturing of leukocytes to the blood vessel wall is well understood, little is known about the mechanisms underlying the actual transmigration of leukocytes through the vessel wall (diapedesis). Even a basic question such as whether leukocytes migrate through openings between adjacent endothelial cells (junctional pathway) or through single endothelial cells (transcellular pathway) is still a matter of intensive debate. It is generally accepted that both pathways exist; however, whether they are of equal physiological significance is unclear. Several endothelial adhesion and signaling molecules have been identified, most of them at endothelial cell contacts, which participate in leukocyte diapedesis. A concept is evolving suggesting that transendothelial migration of leukocytes is a stepwise process. Blocking or eliminating some of the different adhesion and signaling proteins results in very different effects, such as trapping of leukocytes above endothelial cell contacts, in between endothelial cells, or between the endothelium and the underlying basement membrane. Other proteins are involved in the opening of endothelial cell contacts and yet others in their maintenance providing the barrier for extravasating leukocytes. The various molecular players and the functional steps involved in diapedesis are discussed. PMID- 17624954 TI - The role of integrins and coreceptors in refining thresholds for B-cell responses. AB - Despite compelling evidence that a large proportion of antigens encountered in vivo by B cells are membrane bound, the general view is that B cells are mainly activated by soluble antigens. This notion may have been biased somewhat over the years because the high affinity of the B-cell receptor (BCR) for soluble intact ligands allows efficient B-cell stimulation in vitro. In vivo, however, even soluble antigens are likely to be deposited on the surface of antigen-presenting cells, either by complement or Fc receptors in the form of immune complexes, thus becoming more potent stimulators of B-cell activation. In this framework, the BCR works in a complex environment of integrins and coreceptors, as well as the B cell cytoskeleton. Over the last few years, we have focused on B-cell membrane bound antigen recognition. Here, we discuss some of our findings in the context of what is currently known in this exciting new field. PMID- 17624955 TI - Tonic B-cell and viral ITAM signaling: context is everything. AB - The presence of an immunoreceptor tyrosine-based activation motif (ITAM) makes immunoreceptors different from other signaling receptors, like integrins, G coupled protein receptors, chemokine receptors, and growth factor receptors. This unique motif has the canonical sequence D/Ex(0-2)YxxL/Ix(6-8)YxxL/I, where x represents any amino acid and is present at least once in all immunoreceptor complexes. Immunoreceptors can promote survival, activation, and differentiation by transducing signals through these highly conserved motifs. Traditionally, ITAM signaling is thought to occur in response to ligand-induced aggregation, although evidence indicates that ligand-independent tonic signaling also provides functionally relevant signals. The majority of proteins containing ITAMs are transmembrane proteins that exist as part of immunoreceptor complexes. However, oncogenic viruses also have ITAM-containing proteins. In this review, we discuss what is known about tonic signaling by both cellular and viral ITAM-containing proteins and speculate what we might learn from each context. PMID- 17624956 TI - Ca(2+) signaling in antigen receptor-activated B lymphocytes. AB - B cells respond to antigen stimulation with mobilization of the Ca(2+) second messenger in two phases operated by two distinct sets of effector proteins. First, an antigen receptor-specific Ca(2+) initiation complex is assembled, activated, and targeted to the plasma membrane to trigger the transient release of Ca(2+) from intracellular stores of the endoplasmic reticulum. Second, more ubiquitously expressed Ca(2+) channels of the plasma membrane are opened to allow for sustained Ca(2+) influx from the extracellular medium. Depending on the developmental stage of the B cell, the kinetics and profile of the two phases are adjusted at multiple levels of positive and negative regulation. A molecular basis for the Ca(2+) signaling plasticity is provided by cytosolic and transmembrane adapter proteins. They act as signal organizers, which control enzyme/substrate interactions by directing the different signaling modules into specific subcellular compartments. These arrangements orchestrate a graduated activation of Ca(2+)-sensitive downstream pathways, which ultimately determine appropriate cellular responses, namely elimination of autoreactive B cells or proliferation and differentiation of immunocompetent B cells into antibody secreting plasma cells. PMID- 17624957 TI - Platelet integrins and immunoreceptors. AB - Stable platelet adhesion to extracellular matrices and the formation of a hemostatic or pathological thrombus are dependent on integrin alphaIIbbeta3, also known as GPIIb-IIIa. However, maximal platelet responses to vascular injury may involve the participation of other integrins expressed in platelets (alphaVbeta3, alpha2beta1, alpha5beta1, and alpha6beta1). Platelet membrane 'immunoreceptors' contain at least one subunit with an extracellular immunoglobulin superfamily domain and/or an intracellular stimulatory immunoreceptor tyrosine-based activation motif (ITAM) or immunoreceptor tyrosine-based inhibitory motif (ITIM). Platelet ITAM receptors, such as FcgammaRIIA and the GPVI-FcRgamma complex, promote activation of integrins, while ITIM receptors, such as platelet endothelial cell adhesion molecule-1, may promote their inhibition. This review summarizes the structure and function of platelet integrins and immunoreceptors, the emerging functional relationships between these receptor classes, and the consequences of their interaction for platelet function in hemostasis and thrombosis. PMID- 17624958 TI - Use, misuse and extensions of "ideal gas" models of animal encounter. AB - Biologists have repeatedly rediscovered classical models from physics predicting collision rates in an ideal gas. These models, and their two-dimensional analogues, have been used to predict rates and durations of encounters among animals or social groups that move randomly and independently, given population density, velocity, and distance at which an encounter occurs. They have helped to separate cases of mixed-species association based on behavioural attraction from those that simply reflect high population densities, and to detect cases of attraction or avoidance among conspecifics. They have been used to estimate the impact of population density, speeds of movement and size on rates of encounter between members of the opposite sex, between gametes, between predators and prey, and between observers and the individuals that they are counting. One limitation of published models has been that they predict rates of encounter, but give no means of determining whether observations differ significantly from predictions. Another uncertainty is the robustness of the predictions when animal movements deviate from the model's assumptions in specific, biologically relevant ways. Here, we review applications of the ideal gas model, derive extensions of the model to cover some more realistic movement patterns, correct several errors that have arisen in the literature, and show how to generate confidence limits for expected rates of encounter among independently moving individuals. We illustrate these results using data from mangabey monkeys originally used along with the ideal gas model to argue that groups avoid each other. Although agent-based simulations provide a more flexible alternative approach, the ideal gas model remains both a valuable null model and a useful, less onerous, approximation to biological reality. PMID- 17624959 TI - On the electrodetection threshold of aquatic vertebrates with ampullary or mucous gland electroreceptor organs. AB - Reinterpretation of research on the electric sense in aquatic organisms with ampullary organs results in the following conclusions. The detection limit of limnic vertebrates with ampullary organs is 1 microV cm(-1), and of marine fish is 20 nV cm(-1). Angular movements are essential for stimulation of the ampullary system in uniform d.c. fields. Angular movements in the geomagnetic field also generate induction voltages, which exceed the 20 nV cm(-1) limit in marine fish. As a result, marine electrosensitive fish are sensitive to motion in the geomagnetic field, whereas limnic fish are not. Angular swimming movements generate a.c. stimuli, which act like the noise in a stochastic resonance system, and result in a detection threshold in marine organisms as low as 1 nV cm(-1). Fish in the benthic space are exposed to stronger electric stimuli than fish in the pelagic space. Benthic fish scan the orientation plane for the maximum potential difference with their raster of electroreceptor organs, in order to locate bioelectric prey. This behaviour explains why the detection threshold does not depend on fish size. Pelagic marine fish are mainly exposed to electric fields caused by movements in the geomagnetic field. The straight orientation courses found in certain shark species might indicate that the electric sense functions as a simple bisensor system. Symmetrical stimulation of the sensory raster would provide an easy way to keep a straight course with respect to a far field stimulus. The same neural mechanism would be effective in the location of a bioelectric prey generating a near-field stimulus. The response criteria in conditioning experiments and in experiments with spontaneous reactions are discussed. PMID- 17624960 TI - Mammalian evolution and biomedicine: new views from phylogeny. AB - Recent progress resolving the phylogenetic relationships of the major lineages of mammals has had a broad impact in evolutionary biology, comparative genomics and the biomedical sciences. Novel insights into the timing and historical biogeography of early mammalian diversification have resulted from a new molecular tree for placental mammals coupled with dating approaches that relax the assumption of the molecular clock. We highlight the numerous applications to come from a well-resolved phylogeny and genomic prospecting in multiple lineages of mammals, from identifying regulatory elements in mammalian genomes to assessing the functional consequences of mutations in human disease loci and those driving adaptive evolution. PMID- 17624961 TI - Ecology of Australia: the effects of nutrient-poor soils and intense fires. AB - Australia, the flattest, driest, and geologically oldest vegetated continent, has a uniquely high proportion of nutrient-poor soils. We develop a "Nutrient Poverty/Intense-Fire Theory," which postulates that most anomalous features of organisms and ecosystems of Australia are the evolutionary consequences of adaptations to nutrient poverty, compounded by intense fire that tends to occur as a result of nutrient poverty. The fundamental tenet of the theory is that plants growing in environments with plentiful light and periodic adequate moisture, but on soils poor in phosphorus, zinc, and other indispensible nutrients, can synthesize carbohydrates in excess of the amount that can be combined with, or catalyzed by, these nutrients for metabolism and production of nutrient-rich foliage and reproductive tissues. They use this "expendable energy" to produce well-defended foliage, large quantities of lignified tissues, and readily digestible exudates. Rapid accumulation of nutrient-poor biomass, a result of low rates of herbivory, provides fuel for intense fire. Intense fire exacerbates nutrient poverty by volatilizing certain micronutrients critical for animals. Anomalous features of organisms of Australia that can be explained by this theory, rather than by climate or phylogenetic history alone, include the following: most woody plants have long-lived, durable foliage; plants defend their tissues primarily with carbon-rich but nutrient-poor compounds; an unusually high proportion of plants protects seeds from fire and granivores in sturdy, woody capsules or follicles; plants allocate unusually large amounts of expendable energy to production of carbon-based exudates, such as nectar and gums; an unusually high proportion of plant species is pollinated by vertebrates that average larger size than pollinators on other continents; herbivores are small and have slow metabolism; there are no ruminants, mammals that eat mainly subterranean plant matter, or fungus-culturing termites and ants; vegetation dominated by leaf-spinescent plants is more extensive than vegetation dominated by stem-spinescent plants; nitrogen-fixing plants are major components of most vegetation types; there is a higher proportion of myrmecochorous plant species than on any other continent; there are hardly any stem-succulent and few leaf succulent, perennial, non-halophytic plant species; and an unusually high proportion of bird species breeds cooperatively. Although the Nutrient Poverty/Intense-Fire Theory can provide plausible explanations for these anomalous features, some puzzles remain, among them the great success of introduced herbivores, the lack of grazers on extensive grasslands on cracking clays, the apparently low productivity of ants, and the prominence of the parasitic plants of Australia. By examining the ratios of available energy to nutrients, particularly scarce nutrients, ecologists may identify processes not previously recognized as important for life forms or biotic adaptation on other continents. PMID- 17624962 TI - Why are there so many insect species? Perspectives from fossils and phylogenies. AB - Over half of all described species are insects, but until recently our understanding of the reasons for this diversity was based on very little macroevolutionary evidence. Here I summarize the hypotheses that have been posed, tests of these hypotheses and their results, and hence identify gaps in knowledge for future researchers to pursue. I focus on inferences from the following sources: (i) the fossil record, normally at family level, and (ii) insect phylogenies, sometimes combined with: (iii) the species richness of insect higher taxa, and (iv) current extinction risks. There is evidence that the species richness of insects has been enhanced by: (i) their relative age, giving time for diversification to take place; (ii) low extinction rates. There is little evidence that rates of origination have generally been high or that there are limits on numbers of species. However, the evidence on macroevolutionary rates is not yet so extensive or coherent as to present unequivocal messages. As regards morphological, ecological, or behavioural hypotheses, there is evidence that diversity has been enhanced by (iii) flight or properties resulting from it like enhanced dispersal, (iv) wing folding, and (v) complete metamorphosis. However, in all these cases the evidence is somewhat equivocal, either because of statistical issues or because evidence from different sources is conflicting. There is extensive evidence that diversity is affected by (vi) the ecological niche. Comparative studies indicate that phytophagy generally increases net diversification rates, and reduces extinction risk. However, niche specialization is also associated with an increase in extinction risk. Small body size (vii) is often associated with low extinction risk in comparative studies, but as yet there is no solid evidence that it consistently enhances net rates of diversification. Mouthpart diversity (viii) has generally increased over time in the insects, but cannot explain the apparent great increase in diversity seen in the Cretaceous and Tertiary. Sexual selection and sexual conflict (ix) are two processes that are widespread in insects, and there is comparative evidence linking both to increased diversification. Although some comparative evidence links tropical distributions (x) to increased rates of diversification, the extent to which latitudinal richness gradients are unusual in insects is equivocal. There is little to no direct evidence from fossils and phylogenies that insect diversity has generally been affected by (i) sensory- or neuro sophistication, (ii) population size or density, (iii) generation time or fecundity, (iv) the presence of an exoskeleton or cuticle, (v) segmentation or appendage diversity, (vi) adaptability or genetic versatility, though all of these remain plausible hypotheses awaiting further tests. The data suggest that the insect body ground plan itself had no direct effect on insect diversity. Thus, whilst studies to date have given substantial understanding, substantial gaps still remain. Future challenges include: (i) interpreting conflicting messages from different sources of data; (ii) rating the importance of different hypotheses that are statistically supported; (iii) linking specific proximate to specific ultimate explanations and vice versa; and (iv) understanding how different ultimate hypotheses might be dependent on each other. PMID- 17624963 TI - The sense of smell: molecular basis of odorant recognition. AB - Most animal species rely on odorant compounds to locate food, predators, or toxins. The sense of smell is also involved in animal communication, and revealing the underlying mechanisms will therefore facilitate a deeper understanding of animal behaviour. Since the 1940s different theories have speculated on the fundamental basis of olfaction. It was assumed that odorant molecules were recognized by selective protein receptors in the nose, triggering a nervous signal processed by the brain. The discovery of these receptors in the early 1990s allowed great progress in understanding the physiological and biochemical principles of olfaction. An overview of the different mechanisms involved in the coding of odour character as well as odour intensity is presented here, focusing on the biochemical basis of odorant recognition. Despite the enormous progress achieved in recent years, details of odorant-receptor interaction at the molecular level and the mechanisms of olfactory receptor activation are poorly understood. The likely role of metal ions in odorant recognition is discussed, and also the perireceptor events involved in odorant transport and biotransformation, with a view to providing a comprehensive overview of mammalian olfaction to guide future computational structural models and the design of functional experiments. Recent studies have analysed the olfactory genome of several species, providing information about the evolution of olfaction. The role of the olfactory system in animal communication is also described. PMID- 17624964 TI - Leave it all behind: a taxonomic perspective of autotomy in invertebrates. AB - Autotomy is defined herein as the shedding of a body part, where (1) the loss of the body part is defensive (autotomy helps prevent the whole animal from being compromised and is in response to external stimuli); (2) shearing occurs by an intrinsic mechanism along a breakage plane (there has been selection for certain body parts to be pulled off easily); and (3) the loss is controlled - the animal moves away from the trapped limb, the loss is under some form of central control (neural or hormonal), or the body part is detached quickly. Autotomy (under this defensive definition) has evolved independently for a diverse array of body parts in many taxa; we have summarised available information for over 200 invertebrate species. The advantages of autotomy include escape from entrapment, an effective form of attack, expulsion of an infected body part or in limiting wounding. We discuss how the incidence of autotomy may therefore be correlated with various traits such as limb function, sex differences, other defence mechanisms, habitat disturbance, and sociality. There are also costs associated with autotomy. Short term costs include loss of a specialised appendage or organ, reduced speed and stability, or even death. Long-term costs include compromised foraging and feeding (often leading to reduced growth), altered anti-predator, competitive or reproductive behaviour, and even defective development. Regenerating lost appendages may also incur significant costs for the individual. We examine the costs and benefits of autotomy, and discuss the evolutionary selective pressures that contribute to the prevalence and effectiveness of autotomy in invertebrates. PMID- 17624965 TI - Exploring the role of vision in social foraging: what happens to group size, vigilance, spacing, aggression and habitat use in birds and mammals that forage at night? AB - I examined the role of vision in social foraging by contrasting group size, vigilance, spacing, aggression and habitat use between day and night in many species of birds and mammals. The literature review revealed that the rate of predation/disturbance was often reduced at night while food was considered more available. Social foraging at night was prevalent in many species suggesting that low light levels at night are not sufficient to prevent the formation and cohesion of animal groups. Group sizes were similar or larger at night than during the day in more than half the bird populations and in the majority of mammal populations. Factors such as calls, feeding noises or smells may contribute to the formation and cohesion of groups at night. Larger numbers of foragers at night may also facilitate the aggregation of more foragers. Vigilance levels were usually lower at night perhaps as a response to the lower predation risk or to the decreased value of scanning for predators that are difficult to locate. Low light levels may also make visual cues that promote aggression less conspicuous, which may be a factor in the lower levels of aggression documented at night. Spacing varied as a function of time of day in response to changes in foraging mode or food availability. Habitats that are avoided during the day were often used at night. Foraging at night presents birds and mammals with a new set of constraints that influence group size, time budgeting and habitat use. PMID- 17624966 TI - The policing of cannabis in the United Kingdom. PMID- 17624967 TI - Liver cirrhosis in eastern Europe. PMID- 17624968 TI - The art and the science of scaling-up needle and syringe programmes. PMID- 17624969 TI - Life-time cannabis use and late onset mood and anxiety disorders. PMID- 17624970 TI - When is alcohol just another drug? Some thoughts on research and policy. AB - AIM: To reflect on the divergence and overlap between alcohol and illicit drugs with respect to both current policies and policy research. RESULTS: For demand reduction, there is considerable overlap in programs and services for prevention and even more clearly for treatment. For supply controls there is mostly divergence, reflecting the difference in legal status. Research generally follows the same pattern. However, a cross-cutting research agenda on the supply side has merit. CONCLUSION: Even in a prohibition regime, law-enforcement agencies have considerable discretion. A systematic, pragmatic, 'evidence-based' use of that discretion to reduce harm is possible. It can be accomplished only by a continuing program of policy research that measures the harms of drug use and drug enforcement, assesses the effects of current policies on both these sources of social cost and explores alternative strategies. There is a similarly important project for alcohol and tobacco control policy. The goal for research on alcohol and tobacco is to document the extent to which supply controls can be effective in reducing harm; the additional goal for illicit drugs is to document just how much the current ideologically driven approach is costing the public. PMID- 17624971 TI - Alcohol as a 'drug': a moral revolution. PMID- 17624972 TI - Is alcohol foodstuff? PMID- 17624973 TI - A cross-cutting research agenda on alcohol, tobacco and other drugs: where to start? PMID- 17624975 TI - Does cannabis use predict the first incidence of mood and anxiety disorders in the adult population? AB - AIMS: To investigate whether cannabis use predicted the first incidence of mood and anxiety disorders in adults during a 3-year follow-up period. DESIGN AND PARTICIPANTS: Data were derived from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective study in the adult population of 18-64 years. The analysis was carried out on 3881 people who had no life-time mood disorders and on 3854 people who had no life-time anxiety disorders at baseline. MEASUREMENTS: Life-time cannabis use and DSM-III-R mood and anxiety disorders, assessed with the Composite International Diagnostic Interview (CIDI). FINDINGS: After adjustment for strong confounders, any use of cannabis at baseline predicted a modest increase in the risk of a first major depression (odds ratio 1.62; 95% confidence interval 1.06-2.48) and a stronger increase in the risk of a first bipolar disorder (odds ratio 4.98; 95% confidence interval 1.80-13.81). The risk of 'any mood disorder' was elevated for weekly and almost daily users but not for less frequent use patterns. However, dose-response relationships were less clear for major depression and bipolar disorder separately. None of the associations between cannabis use and anxiety disorders remained significant after adjustment for confounders. CONCLUSIONS: The associations between cannabis use and the first incidence of depression and bipolar disorder, which remained significant after adjustment for strong confounders, warrant research into the underlying mechanisms. PMID- 17624976 TI - Prevalence and socio-demographic correlates of drug use among adolescents: results from the Mexican Adolescent Mental Health Survey. AB - AIMS: To estimate the life-time and 12-month prevalence of illicit drug use among Mexican adolescents, the age of onset of first drug use and the socio-demographic correlates. METHOD: A multi-stage probability survey of adolescents aged 12-17 years residing in the Mexico City Metropolitan Area was carried out in 2005. Adolescents were administered the computer-assisted adolescent version of the World Mental Health Composite International Diagnostic Interview by trained lay interviewers in their homes. The response rate was 71% (n = 3005). Descriptive and logistic regression analyses were performed considering the multi-stage and weighted sample design of the survey. FINDINGS: Of the adolescents, 5.2% have ever tried illicit drugs, 2.9% in the last 12 months. The most frequently used drugs are marijuana, followed by tranquilizers/stimulants. The median age of first use is 14 years. Correlates of life-time drug use are older age, having dropped out of school, parental drug problems, low religiosity and low parental monitoring. CONCLUSIONS: While drug use among Mexican adolescents is lower than among adolescents from other developed countries, its increasing prevalence with age and the narrowing male/female ratio calls for firm public health actions, particularly prevention strategies. PMID- 17624977 TI - Who are the new amphetamine users? A 10-year prospective study of young Australians. AB - AIMS: Despite good evidence of increased availability and use of amphetamines world-wide, relatively little is known about the epidemiology of young adult amphetamine use; relationships with social functioning, other drug use and mental health at this age; nor of the adolescent predictors of such use. We examined these issues using a representative cohort of young people followed-up in Victoria, Australia. METHODS: A stratified, random sample of 1943 adolescents was recruited from secondary schools across Victoria at age 14-15 years. This cohort was interviewed on eight occasions until the age of 24-25 years (78% follow-up at that age). Cross-sectional and predictive associations were assessed using logistic regression. RESULTS: At age 24 years, 12% of the sample had used amphetamines in the past year, with 1-2% using at least weekly. Young adult amphetamine use was predicted strongly by adolescent drug use and was associated robustly with other drug use and dependence in young adulthood. Associations were stronger for more frequent users. Among young adults who had not been using amphetamines at age 20 years, the strongest predictor of use at age 24 years was the use of other drugs, particularly cannabis, at 20 years. Psychological distress did not predict independently an increased likelihood of amphetamine use in this cohort. CONCLUSION: Young people in Australia using amphetamine at age 24 years are highly likely to be significant polydrug users. The risks for both initiation of young adult amphetamine use, and maintenance of such use, pertain to the heavy use of other drugs. Interventions for heavy amphetamine users at this age are likely to require attention to multiple drug problems. PMID- 17624978 TI - Do coping skills mediate the relationship between cognitive-behavioral therapy and reductions in gambling in pathological gamblers? AB - AIMS: Cognitive-behavioral therapy (CBT) is useful for treating substance abusers, and recent data suggest it is also efficacious for pathological gamblers. CBT is purported to exert its beneficial effects by altering coping skills, but data supporting coping changes as the mechanism of action are mixed. This study examined whether coping skills acquisition mediated the effects of CBT on decreasing gambling in pathological gamblers. DESIGN: Participants were assigned randomly to CBT plus referral to Gamblers Anonymous (GA) or to GA referral alone. Setting Out-patient clinic. PARTICIPANTS: A total of 127 pathological gamblers. MEASUREMENTS: Participants completed the Coping Strategies Scale (CSS) before treatment and 2 months later; indices of gambling behavior and problems were administered pretreatment and at months 2 and 12. FINDINGS: Overall, CSS scores increased for participants in both conditions, but those receiving CBT evidenced larger increases than those in the GA condition (P < 0.05), and they also reduced gambling more substantially between pretreatment and month 2. Changes in CSS scores mediated the relationship between treatment assignment and gambling outcomes from pretreatment to month 2, but little evidence of mediation occurred for the long-term follow-ups. CONCLUSIONS: CBT's beneficial effects in decreasing gambling may be related partly to changes in coping responses, and improvements in coping are associated with long-term changes in gambling. However, relationships between coping skills and gambling behavior are fairly strong, regardless of treatment received. PMID- 17624979 TI - A randomized trial of bupropion and/or nicotine gum as maintenance treatment for preventing smoking relapse. AB - AIM: To investigate the efficacy of maintenance treatment with bupropion and/or nicotine gum for reducing smoking relapse. DESIGN, SETTING AND PARTICIPANTS: A 48 week study was conducted at a university-based smoking cessation clinic between February 2001 and October 2005. A total of 588 smokers received bupropion and nicotine patch in 8 weeks of open-label treatment (OLT); 289 abstainers during the last 4 weeks of OLT were randomized in double-blind placebo-controlled fashion to one of four arms for 16 weeks of maintenance treatment (MT) followed by 24 weeks of non-treatment follow-up (NTFU). INTERVENTION: Bupropion (300 mg/day) and 2 mg nicotine gum, used alone or combined, and comparable placebo pill and placebo gum. Behavioral counseling at all visits. OUTCOME: Time to relapse (TTR) from randomization. Relapse is defined as the first 7 consecutive days of smoking. Abstinence verified by carbon monoxide