Rapid multicontrast brain imaging on a 0.35T MR-linac.
Magnetic resonance-guided radiation therapy (MRgRT) has shown great promise for localization and real-time tumor monitoring. However, to date, quantitative imaging has been limited for low field MRgRT. This work benchmarks quantitative T1, R2*, and Proton Density (PD)mapping in a phantom on a 0.35 T MR-linac and implements a novel acquisition method, STrategically Acquired Gradient Echo (STAGE). To further validate STAGE in a clinical setting, a pilot study was undertaken in a cohort of brain tumor patients to elucidate opportunities for longitudinal functional imaging with an MR-linac in the brain. STAGE (two triple-echo gradient echo (GRE) acquisitions) was optimized for a 0.35T low-field MR-linac. Simulations were performed to choose two flip angles to optimize signal-to-noise ratio (SNR) and T1-mapping precision. Tradeoffs between SNR, scan time, and spatial resolution for whole-brain coverage were evaluated in healthy volunteers. Data were inputted into a STAGE processing pipeline to yield four qualitative images (T1-weighted, enhanced T1-weighted, proton-density (PD) weighted, and simulated FLuid-Attenuated Inversion Recovery (sFLAIR)), and three quantitative datasets (T1, PD, and R2*). A benchmarking ISMRM/NIST phantom consisting of vials with variable NiCl2 and MnCl2 concentrations was scanned using variable flip angles (VFA) (2-60 degrees) and inversion recovery (IR) methods at 0.35 T. STAGE and VFA T1 values of vials were compared to IR T1 values. As measures of agreement with reference values and repeatability, relative error (RE) and coefficient of variability (CV) were calculated, respectively, for quantitative MR values within the phantom vials (spheres). To demonstrate feasibility, longitudinal STAGE data (pretreatment, weekly, and ~ 2 months post-treatment) were acquired in an IRB-approved pilot study of brain tumor cases via the generation of temporal and differential quantitative MRI maps. In the phantom, RE of measured VFA T1 and STAGE relative to IR reference values were 7.0 ± 2.5% and 9.5 ± 2.2% respectively. RE for the PD vials was 8.1 ± 6.8% and CV for phantom R2* measurements was 10.1 ± 9.9%. Simulations and volunteer experiments yielded final STAGE parameters of FA = 50°/10°, 1 × 1 × 3 mm3 resolution, TR = 40 ms, TE = 5/20/34 ms in 10 min (64 slices). In the pilot study of brain tumor patients, differential maps for R2* and T1 maps were sensitive to local tumor changes and appeared similar to 3 T follow-up MRI datasets. Quantitative T1, R2*, and PD mapping are promising at 0.35 T agreeing well with reference data. STAGE phantom data offer quantitative representations comparable to traditional methods in a fraction of the acquisition time. Initial feasibility of implementing STAGE at 0.35 T in a patient brain tumor cohort suggests that detectable changes can be observed over time. With confirmation in a larger cohort, results may be implemented to identify areas of recurrence and facilitate adaptive radiation therapy.


A phosphate transporter gene from the extra-radical mycelium of an arbuscular mycorrhizal fungus Glomus intraradices is regulated in response to phosphate in the environment.
The majority of vascular flowering plants are able to form symbiotic associations with arbuscular mycorrhizal fungi. These symbioses, termed arbuscular mycorrhizas, are mutually beneficial, and the fungus delivers phosphate to the plant while receiving carbon. In these symbioses, phosphate uptake by the arbuscular mycorrhizal fungus is the first step in the process of phosphate transport to the plant. Previously, we cloned a phosphate transporter gene involved in this process. Here, we analyze the expression and regulation of a phosphate transporter gene (GiPT) in the extra-radical mycelium of the arbuscular mycorrhizal fungus Glomus intraradices during mycorrhizal association with carrot or Medicago truncatula roots. These analyses reveal that GiPT expression is regulated in response to phosphate concentrations in the environment surrounding the extra-radical hyphae and modulated by the overall phosphate status of the mycorrhiza. Phosphate concentrations, typical of those found in the soil solution, result in expression of GiPT. These data imply that G. intraradices can perceive phosphate levels in the external environment but also suggest the presence of an internal phosphate sensing mechanism.


Mayo Clinic employees responded to new requirements for cost sharing by reducing possibly unneeded health services use.
Some health plans have experimented with increasing consumer cost sharing, on the theory that consumers will use less unnecessary health care if they are expected to bear some of the financial responsibility for it. However, it is unclear whether the resulting decrease in use is sustained beyond one or two years. In 2004 Mayo Clinic's self-funded health plan increased cost sharing for its employees and their dependents for specialty care visits (adding a $25 copayment to the high-premium option) and other services such as imaging, testing, and outpatient procedures (adding 10 or 20 percent coinsurance, depending on the option). The plan also removed all cost sharing for visits to primary care providers and for preventive services such as colorectal screening and mammography. The result was large decreases in the use of diagnostic testing and outpatient procedures that were sustained for four years, and an immediate decrease in the use of imaging that later rebounded (possibly to levels below the expected trend). Beneficiaries decreased visits to specialists but did not make greater use of primary care services. These results suggest that implementing relatively low levels of cost sharing can lead to a long-term decrease in utilization.


Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1.
Intraperitoneal administration of human recombinant interleukin-1 (IL-1) to rats can increase blood levels of corticosterone and adrenocorticotropic hormone (ACTH). The route by which IL-1 affects pituitary-adrenal activity is unknown. That the IL-1-induced pituitary-adrenal activation involves an increased secretion of corticotropin-releasing factor (CRF) is indicated by three lines of evidence. First, immunoneutralization of CRF markedly attenuated the IL-1-induced increase of ACTH blood levels. Second, after blockade of fast axonal transport in hypothalamic neurons by colchicine, IL-1 administration decreased the CRF immunostaining in the median eminence, indicating an enhanced release of CRF in response to IL-1. Third, IL-1 did not stimulate ACTH release from primary cultures of anterior pituitary cells. These data further support the notion of the existence of an immunoregulatory feedback circuit between the immune system and the brain.


Measuring AT Usability with the Modified System Usability Scale (SUS).
The modified System Usability Scale (SUS) is a widely used generic measure of product usability. This study concerns the usability of mobile shower commodes using correlations between the SUS and AT device-specific measures. Results suggest the modified SUS, and corresponding adjective-anchored rating scale, are appropriate for measuring MSC usability, and have potential for use with other AT devices.


Dephytinization of a complementary food based on wheat and soy increases zinc, but not copper, apparent absorption in adults.
Complementary foods based on cereals may contain high amounts of phytic acid, which binds strongly to minerals and trace elements. The objective of the study was to evaluate the effect of dephytinization of a cereal-based complementary food on zinc and copper apparent absorption in adults. A dephytinized complementary food (<0.03 mg phytic acid/g) and one containing the native phytic acid concentration (4 mg/g) were labeled extrinsically with stable isotopes ((70)Zn and (65)Cu). Apparent zinc and copper absorption was based on fecal excretion of nonabsorbed labels in 9 adults, using a crossover design. Stable isotopes were quantified by thermal ionization MS. Apparent fractional zinc absorption was significantly higher (P = 0.005; Student's paired t test) from the dephytinized complementary food (34.6 +/- 8.0%; mean +/- SD) than from the complementary food with native phytic acid concentration (22.8 +/- 8.8%). Apparent fractional copper absorption did not differ (P = 0.167; 19.7 +/- 5.1% dephytinized vs. 23.7 +/- 8.1% native phytic acid). These results clearly demonstrate the beneficial effect of dephytinization of a complementary food on fractional absorption of zinc but not of copper in adults. The long-term nutritional benefits of dephytinization of complementary foods should be evaluated in young children.


Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome.
Most cases of DiGeorge syndrome (DGS) and related abnormalities are associated with deletions within 22q11. Shortest region of deletion overlap (SRO) mapping previously identified a critical region (the DGCR) of 500 kb, which was presumed to contain a gene or genes of major effect in the haploinsufficiency syndromes. The DGCR also contains sequences disrupted by a balanced translocation that is associated with DGS--the ADU breakpoint. We have cloned sequences at the breakpoint and screened for novel genes in its vicinity. A series of alternatively spliced transcripts expressed during human and murine embryogenesis, but with no obvious protein encoding potential, were identified. The gene encoding these RNAs has been named DGCR5 and it is disrupted by the patient ADU breakpoint. DGCR5 is distinct from the DGCR3 open reading frame (ORF) previously shown to be interrupted by the ADU translocation, although DGCR3 is embedded within a DGCR5 intron and in the same (predicted) transcriptional orientation. No mutations of DGCR5 have yet been detected. By analogy to other loci encoding conserved, nontranslated RNAs, it is possible that DGCR5 originates from a cis-acting transcriptional control element in the vicinity of the ADU/VDU breakpoint. Disruption of such an element would result in altered transcription of neighboring genes secondary to a position effect, a hypothesis in keeping with recent refinement of the SRO placing the ADU breakpoint outside the DGCR.


A species barrier limits transmission of chronic wasting disease to mink (Mustela vison).
Transmissible mink encephalopathy (TME) occurs as sporadic outbreaks associated with ingestion of feed presumably contaminated with some type of prion disease. Mink lack a species barrier to primary oral challenge with bovine spongiform encephalopathy, whereas they have a barrier to such challenge with scrapie. We investigated whether mink have a species barrier to chronic wasting disease (CWD) by performing primary intracerebral (IC) and primary oral challenge with CWD-positive elk brain. Primary IC challenge resulted in clinical disease in two of eight mink at 31-33 months incubation. Affected mink had spongiform vacuolation and astrocytosis within the central nervous system and immunoreactivity to disease-associated prion protein (PrP(d)) in brain, retina and lymph node. CWD IC recipients had significantly lower brain vacuolation and PrP(d) deposition scores, significantly lower cerebrocortical astrocyte counts and significantly higher hippocampal astrocyte counts than TME IC recipients. Primary oral challenge with CWD-positive elk brain (n=22) or with CWD-negative elk brain given IC (n=7) or orally (n=23) did not result in clinical or microscopic abnormalities during 42 months observation. Novel prion gene polymorphisms were identified at codon 27 (arginine/tryptophan) and codon 232 (arginine/lysine). This study shows that, whilst CWD can cause disease when given IC to mink, the lesions are not characteristic of TME, transmission is inefficient compared with TME and oral challenge does not result in disease. The demonstration of a species barrier in cervid-to-mustelid prion transmission indicates that mink are unlikely to be involved in natural CWD transmission.


Patients rank toxicity against progression free survival in second-line treatment of advanced renal cell carcinoma.
The aims of this study were to quantify and contrast patient preferences between second-line advanced renal cell carcinoma (RCC) medication profiles and their associated benefits and toxicities, and to help frame the doctor-patient discussion about selecting appropriate RCC therapies. Adult residents of the US with a diagnosis of RCC completed a Web-enabled choice-format conjoint survey consisting of a series of 10 treatment-choice questions, each of which included a pair of hypothetical RCC medication profiles. Each profile was described by various medication attributes (features or outcomes) with varying levels. The attributes included efficacy (progression-free survival [PFS]), tolerability (fatigue, stomach problems, mucositis or stomatitis, hand-foot syndrome [HFS]), serious but rare adverse events (pneumonitis, hepatic impairment), and mode of administration. Treatment-choice questions were based on an experimental design with known statistical properties. Random-parameters logit regression was used to estimate relative preference weights for each attribute level. Benefit equivalent measures (additional months of PFS in exchange for toxicities) were also calculated. Of the 272 patients who completed the survey, the majority were female (53%), white (92%), and had at least a college degree (66%). The mean age was 57 years (standard deviation: 10 years). Over the range of attributes and attribute levels included in the survey, PFS was the most important attribute, followed by fatigue, stomach problems, hepatic impairment, mucositis or stomatitis, HFS, pneumonitis, and mode of administration. To reduce severe fatigue to mild-to-moderate fatigue, patients on average would be willing to forego 4.4 months of PFS. To reduce hepatic impairment risk from 0.5% to 0.0%, patients on average would be willing to forego 1.0 month of PFS. The main study limitation was that patients answered hypothetical treatment-choice questions. This study provides information to physicians about patient priorities when reviewing and selecting RCC therapies with patients.


Generally detected proteins in comparative proteomics--a matter of cellular stress response?
The specificity of proteins identified by proteomics as biomarkers for defined conditions or as components of biological processes and pathways is crucial. We critically reviewed differentially expressed proteins from comparative proteomic studies identified by 2-DE followed by MS, especially with MALDI technique. Based on 66 of those studies, a list of 44 proteins is presented as generally detected proteins regardless of species, in vivo or in vitro conditions, tissues and organs, and experimental objective. Similarly, a list of 28 generally detected protein families is presented. The enriched functions linked to these generally detected proteins reveal that there are some common biological features beyond the technical limitations. Cellular stress response can be the universal reason as to why these proteins are generally expressed differentially. Using those proteins as biomarkers for cellular processes other than stress response should be done with caution. In future proteomic studies more profound approaches should be applied to look beyond these proteins to find specific biomarkers. Our results are discussed in relation to a recent viewpoint publication by Petrak et al. [Proteomics 2008, 8, 1744-1749].


[Dynamic transrectal ultrasound (dTRUS): a new method to diagnose anastomotic insufficiency after radical retropubic prostatectomy].
To prove extravasation after radical retropubic prostatectomy (RRP) nowadays a cystoradiogram is essential. In the present study the diagnostic value of dynamic transrectal ultrasound and cystoradiogram to find an extravasation was compared. For detection of an extravasation Cystoradiogram and dTRUS were performed in 250 patients who had undergone RRP. TRUS was performed dynamically, that means that the urinary bladder was filled up with common salt solution backwards by using the transurethral catheter. Anastomosis was inspected by transrectal ultrasound. Detectable extravasation was measured and documented. To verify the results a cystoradiogram was carried out afterwards. In cases of detectable extravasation the results of measurement were compared to the results of dTRUS. The mean age was 65 years. An extravasation could be detected in 46% within the first 7 days and in 18% after 14 days. At day 21 an extravasation could not be seen in any patient. Seven days postoperative the mean volume of extravasation was 11 ml (3-50 ml) and after 14 days 9 ml (3-25 ml) for dTRUS. For cystoradiogram 12 ml (3-45 ml) and 9 ml (4-23 ml), respectively. The average time until catheter removal was 8 days (5-35 days). 60% of the patients were continent immediately after removing the catheter, 40% were incontinent for not more than 3 months after removal of the catheter (35% ICS I and 5% ICS II). A prolonged urinary incontinence and serious postoperative complications were not observed. Dynamic transrectal ultrasound is a reliable and reasonable method to identify extravasation after RRP. Furthermore radiation exposure (on average 60 cGy/cm(2)/cystoradiogram) can be avoided by replacing the cystoradiogram with dTRUS slips with the dTRUS.


Grip strength and its determinants among older people in different healthcare settings.
low muscle strength is central to geriatric syndromes including sarcopenia and frailty. It is well described in community-dwelling older people, but the epidemiology of grip strength of older people in rehabilitation or long-term care has been little explored. to describe grip strength of older people in rehabilitation and nursing home settings. cross-sectional epidemiological study. three healthcare settings in one town. hundred and one inpatients on a rehabilitation ward, 47 community rehabilitation referrals and 100 nursing home residents. grip strength, age, height, weight, body mass index, number of co-morbidities and medications, Barthel score, Mini-Mental State Examination (MMSE), nutritional status and number of falls in the last year were recorded. grip strength differed substantially between healthcare settings for both men and women (P < 0.0001). Nursing home residents had the lowest age-adjusted mean grip strength and community rehabilitation referrals the highest. Broadly higher grip strength was associated in univariate analyses with younger age, greater height and weight, fewer comorbidities, higher Barthel score, higher MMSE score, better nutritional status and fewer falls. However, after mutual adjustment for these factors, the difference in grip strength between settings remained significant. The Barthel score was the characteristic most strongly associated with grip strength. older people in rehabilitation and care home settings had lower grip strength than reported for those living at home. Furthermore grip strength varied widely between healthcare settings independent of known major influences. Further research is required to ascertain whether grip strength may help identify people at risk of adverse health outcomes within these settings.


GREAT improves functional interpretation of cis-regulatory regions.
We developed the Genomic Regions Enrichment of Annotations Tool (GREAT) to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across an entire genome. Whereas previous methods took into account only binding proximal to genes, GREAT is able to properly incorporate distal binding sites and control for false positives using a binomial test over the input genomic regions. GREAT incorporates annotations from 20 ontologies and is available as a web application. Applying GREAT to data sets from chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3 and p300 in different developmental contexts, we recover many functions of these factors that are missed by existing gene-based tools, and we generate testable hypotheses. The utility of GREAT is not limited to ChIP-seq, as it could also be applied to open chromatin, localized epigenomic markers and similar functional data sets, as well as comparative genomics sets.


Ectopic adrenal gland in an adult inguinal hernial sac: A case report.
A 37-year-old male patient operated for inguinal hernia repair was found to have ectopic adrenocortical tissue in the hernial sac. A 37-year-old man was admitted for bilateral inguinal hernia. An uneventful open repair was done, and the resected hernial sacs were sent to pathology. Histopathology reported the presence of adrenocortical tissue in the right inguinal hernial sac. Ectopic adrenocortical tissue (EACT) in the groin region is not an unusual finding in children, however, it's rarely reported in adult patients. Only 9 cases have been reported in English describing EACT in an adult's inguinal hernia. The finding can be attributed to the close proximity of the developing gonads and adrenal cortex during embryogenesis, and subsequent mechanical translocation of adrenocortical tissue during testicular descent. Some theoretical clinical implications exist for this condition, including secondary hyperplasia after adrenalectomy, adrenal insufficiency in certain situations, and possible neoplastic transformation. Generally, it is recommended that surgeons resect ectopic adrenal glands when identified intra-operatively. However, actively searching for these glands has no known benefit and carries some surgical risks, and is hence not recommended. It is reasonable as well, that clinicians keep the clinical implications of this finding in mind during future follow-ups with such patients. The presence of ectopic adrenocortical tissue in inguinal hernia sacs is a rare encounter in adults. The condition can have several theoretical clinical implications that need to be considered by surgeons while assessing patients in whom this phenomenon is observed.


Mutations in the ubiquitin binding UBZ motif of DNA polymerase eta do not impair its function in translesion synthesis during replication.
Treatment of Saccharomyces cerevisiae cells with DNA-damaging agents elicits lysine 164-linked PCNA monoubiquitination by Rad6-Rad18. Recently, a number of ubiquitin (Ub) binding domains (UBDs) have been identified in translesion synthesis (TLS) DNA polymerases and it has been proposed that the UBD in a TLS polymerase affects its binding to Ub on PCNA and that this binding mode is indispensable for a TLS polymerase to access PCNA at the site of a stalled replication fork. To evaluate the contribution of the binding of UBDs to the Ub moiety on PCNA in TLS, we have examined the effects of mutations in the C2H2 zinc binding motif and in the conserved D570 residue that lies in the alpha-helix portion of the UBZ domain of yeast Poleta. We find that mutations in the C2H2 motif have no perceptible effect on UV sensitivity or UV mutagenesis, whereas a mutation of the D570 residue adversely affects Poleta function. The stimulation of DNA synthesis by Poleta with PCNA or Ub-PCNA was not affected by mutations in the C2H2 motif or the D570 residue. These observations lead us to suggest that the binding of Ub on PCNA via its UBZ domain is not a necessary requirement for the ability of polymerase eta to function in TLS during replication.


An evaluation of rectal artesunate for the pre-hospital management of severe malaria.
Severe falciparum malaria stills accounts for around half a million childhood deaths per year in sub-Saharan Africa. Prompt treatment of sick children close to home starting with artesunate given rectally by appropriately trained people can be lifesaving. Rectal artesunate (RAS) has been developed for use in the WHO approved strategy of pre-referral intervention. This review covers the formulation, pharmacokinetics, safety, efficacy, and implementation of this drug. There is little RCT evidence and the only RCT has been controversial. It is unlikely that there will be further randomized studies in the field. There is a concern that the administration of a single dose of artesunate without adequate follow up therapy may encourage the emergence of artemisinin resistance. Artesunate is an essential drug and RAS is a very useful, potentially lifesaving formulation designed to be quickly administered in remote areas to severely unwell children by non-medical personnel. However, its use needs to be monitored and onward referral for definitive antimalarial treatment ensured.


Complex Population Structure and Virulence Differences among Serotype 2 Streptococcus suis Strains Belonging to Sequence Type 28.
Streptococcus suis is a major swine pathogen and a zoonotic agent. Serotype 2 strains are the most frequently associated with disease. However, not all serotype 2 lineages are considered virulent. Indeed, sequence type (ST) 28 serotype 2 S. suis strains have been described as a homogeneous group of low virulence. However, ST28 strains are often isolated from diseased swine in some countries, and at least four human ST28 cases have been reported. Here, we used whole-genome sequencing and animal infection models to test the hypothesis that the ST28 lineage comprises strains of different genetic backgrounds and different virulence. We used 50 S. suis ST28 strains isolated in Canada, the United States and Japan from diseased pigs, and one ST28 strain from a human case isolated in Thailand. We report a complex population structure among the 51 ST28 strains. Diversity resulted from variable gene content, recombination events and numerous genome-wide polymorphisms not attributable to recombination. Phylogenetic analysis using core genome single-nucleotide polymorphisms revealed four discrete clades with strong geographic structure, and a fifth clade formed by US, Thai and Japanese strains. When tested in experimental animal models, strains from this latter clade were significantly more virulent than a Canadian ST28 reference strain, and a closely related Canadian strain. Our results highlight the limitations of MLST for both phylogenetic analysis and virulence prediction and raise concerns about the possible emergence of ST28 strains in human clinical cases.


The Role of Diet in Multiple Sclerosis: Mechanistic Connections and Current Evidence.
This review seeks to examine current research related to the role of diet in multiple sclerosis (MS). Recent research in preclinical models, epidemiologic studies, and limited prospectively followed cohorts provide preliminary evidence that dietary factors influence MS incidence, disease course, and symptomatology. Current evidence for the effects of fatty acids, fruits and vegetables, whole grains, dairy, and salt are reviewed. Dietary patterns including overall diet quality, caloric restriction, McDougall diet, Paleolithic diet, and Mediterranean diet are discussed. Hypotheses regarding potential mechanistic connections underlying observed effects are also presented. Several individual dietary components and patterns demonstrate potential for significant impact in MS. Definitive answers regarding the ability of diet to act as a disease modifier in MS will ultimately require large-scale clinical trials. Continued prospective studies and clinical trials to further advance this line of research are warranted.


Identification of adipocyte adhesion molecule (ACAM), a novel CTX gene family, implicated in adipocyte maturation and development of obesity.
Few cell adhesion molecules have been reported to be expressed in mature adipocytes, and the significance of cell adhesion process in adipocyte biology is also unknown. In the present study, we identified ACAM (adipocyte adhesion molecule), a novel homologue of the CTX (cortical thymocyte marker in Xenopus) gene family. ACAM cDNA was isolated during PCR-based cDNA subtraction, and its mRNA was shown to be up-regulated in WATs (white adipose tissues) of OLETF (Otsuka Long-Evans Tokushima fatty) rats, an animal model for Type II diabetes and obesity. ACAM, 372 amino acids in total, has a signal peptide, V-type (variable) and C2-type (constant) Ig domains, a single transmembrane segment and a cytoplasmic tail. The amino acid sequence in rat is highly homologous to mouse (94%) and human (87%). ACAM mRNA was predominantly expressed in WATs in OLETF rats, and increased with the development of obesity until 30 weeks of age, which is when the peak of body mass is reached. Western blot analysis revealed that ACAM protein, approx. 45 kDa, was associated with plasma membrane fractions of mature adipocytes isolated from mesenteric and subdermal adipose deposits of OLETF rats. Up-regulation of ACAM mRNAs in obesity was also shown in WATs of genetically obese db/db mice, diet-induced obese ICR mice and human obese subjects. In primary cultured mouse and human adipocytes, ACAM mRNA expression was progressively up-regulated during differentiation. Several stably transfected Chinese-hamster ovary K1 cell lines were established, and the quantification of ACAM mRNA and cell aggregation assay revealed that the degree of homophilic aggregation correlated well with ACAM mRNA expression. In summary, ACAM may be the critical adhesion molecule in adipocyte differentiation and development of obesity.


Availability of transplantable organs from brain stem dead donors in intensive care units.
By audit from January to June 1989 to quantify, separately for hearts, kidneys, liver, lungs and corneas, the possible increases in transplantable organs from brain stem dead potential donors in intensive care units and to compare them with the increases achieved in October-November 1989, during intense, national publicity about transplantation. Prospective audit of all deaths in intensive care units in England from 1 January to 30 June 1989 and subsequent case study of the impact of publicity on offers and donations during October-November 1989. 15 regional and special health authorities in England. 5803 patients dying in intensive care units, of whom 497 were confirmed as brain stem dead and had no general medical contraindication to organ donation. Organ specific suitability for transplantation (as reported by intensive care units); consent for donation of specific suitable organs; and procurement of specific organs reported as suitable for transplantation and offered. In the 497 (8.6%) brain stem dead potential donors were estimated the organ specific suitability for heart as 63%, kidneys 95%, liver 70%, lungs 29%, and corneas 91%. Refusal of relatives (30%) accounted for major losses of suitable organs of all types. For kidneys the loss was equivalent to 44% of brain stem dead actual kidney donors. No discussion of organ donation was the second most important reason for missed kidney donors, the loss being equivalent to 10% of brain stem dead actual donors. Non-procurement or difficulties with allocating organs was the second most notable cause of missed suitable liver and lung donors; 29% (55) of the offered total of 189 liver donors and 27% (21) of 78 offered suitable lung donors in six months. Non-procurement of suitable, offered organs was rare for kidneys and modest, of the order of 13% and 10% respectively, for heart and corneas. Corneal donation from brain stem dead potential donors might be improved nearly as much (that is, a 78% increase in brain stem dead actual corneal donors) by specific measures to promote corneal donation when other organs are offered as by reducing the overall refusal rate. Restricted offers, non-procurement, and no discussion of donation accounted for nearly equal numbers of lost donations of hearts (each equivalent to 15% of donated hearts). During October-November 1989 when there was intense, positive publicity about transplantation the rates of refusal and non-discussion fell compared with during January-June (22%, 36/163 v 30%, 138/460; 7%, 33/497 v 2%, 4/167 respectively). Offers of suitable donors increased significantly (p less than 0.02) compared with the first six months of 1989, most notably for heart donors (80 v 60.1 expected) and kidney donors (122 v 102.1 expected) but only for kidneys was there a noticeable 17% increase in actual donors (118 actual audited donors v 100.8 expected donors; p = 0.09). Four strategies to increase the supply of transplantable organs from brain stem dead potential donors in intensive care units were identified: (a) reducing refusal of relatives (b) avoiding non-procurement of actually suitable organs (by logistical initiatives) and deterioration of initially suitable organs (by donor care initiatives); (c) converting restricted offers to unrestricted offers; and (d) ensuring discussion with families. Early referral to the transplant team or coordinator gives time for discussion about donor care and agreement on medical suitability for donation of specific organs. Solving some of the logistical problems of non-procurement may be a prerequisite for increased offers to be translated into increased donations. The impact of publicity therefore needs to be measured on offers of suitable donors as well as by actual donations.


Variation in the local population dynamics of the short-lived Opuntia macrorhiza (Cactaceae).
Spatiotemporal variation in demographic rates can have profound effects for population persistence, especially for dispersal-limited species living in fragmented landscapes. Long-term studies of plants in such habitats help with understanding the impacts of fragmentation on population persistence but such studies are rare. In this work, we reanalyzed demographic data from seven years of the short-lived cactus Opuntia macrorhiza var. macrorhiza at five plots in Boulder, Colorado. Previous work combining data from all years and all plots predicted a stable population (deterministic log lamda approximately 0). This approach assumed that all five plots were part of a single population. Since the plots were located in a suburban-agricultural interface separated by highways, grazing lands, and other barriers, and O. macrorhiza is likely dispersal limited, we analyzed the dynamics of each plot separately using stochastic matrix models assuming each plot represented a separate population. We found that the stochastic population growth rate log lamdaS varied widely between populations (log lamdaS = 0.1497, 0.0774, -0.0230, -0.2576, -0.4989). The three populations with the highest growth rates were located close together in space, while the two most isolated populations had the lowest growth rates suggesting that dispersal between populations is critical for the population viability of O. macrorhiza. With one exception, both our prospective (stochastic elasticity) and retrospective (stochastic life table response experiments) analysis suggested that means of stasis and growth, especially of smaller plants, were most important for population growth rate. This is surprising because recruitment is typically the most important vital rate in a short-lived species such as O. macrorhiza. We found that elasticity to the variance was mostly negligible, suggesting that O. macrorhiza populations are buffered against large temporal variation. Finally, single-year elasticities to means of transitions to the smallest stage (mostly due to reproduction) and growth differed considerably from their long-term elasticities. It is important to be aware of this difference when using models to predict the effect of manipulating plant vital rates within the time frame of typical plant demographic studies.


CD133 mRNA may be a suitable prognostic marker for human breast cancer.
Breast cancer is the most commonly malignant cancers in women. CD133 protein is a widely used marker for isolating cancer stem cell (CSC). Its expression is associated with the prognosis of many cancers. However, whether CD133 mRNA could be used as an independent prognostic factor for breast cancer remains inconsistent in previous studies. In this study, I used the Gene Expression-Based Outcome for Breast Cancer Online algorithm (GOBO) software to analysis the prognostic roles of CD133 mRNA in the subtypes of breast cancer. I found that CD133 mRNA is associated with distant metastasis free survival (DMFS) in the patient with all tumors, ER-positive tumors, tamoxifen (TAM) tumors, LN-negative tumors, ER-positive/LN-negative tumors, ER-negative tumors, grade 2 tumors, HER2 enriched tumors, and untreated tumors. These results could provide a molecular target for the subtypes of breast cancer. In this study, I conclude that CD133 mRNA may be a suitable prognostic marker for human breast cancer.


Disposition in humans of racemic picenadol, an opioid analgesic.
Racemic picenadol is being tested clinically as an analgesic. The (+)-enantiomer of picenadol is an opioid agonist and the (-)-enantiomer is a weak agonist/antagonist. The disposition of racemic [14C] picenadol was studied in healthy men after a single dose was administered im (N = 3) and orally (N = 5). After the dose, virtually none of the radioactivity that appeared in blood was associated with the red cells. In plasma, approximately 4% of the radioactivity was attributable to the parent drug, the remainder being picenadol glucuronide (approximately 35%) and other metabolites. The t1/2 for total radioactivity was 6 hr, that for the unchanged drug was 3.5 hr. Picenadol was present in plasma almost exclusively as the (+)-enantiomer. However, after incubation with glucuronidase and sulfatase, plasma contained 2 to 4 times more (-)- than (+)-picenadol, indicating that more conjugated (-)-picenadol than conjugated (+)-picenadol was in the plasma. After im and oral administration of [14C]picenadol, plasma levels of radioactivity were generally 10 and 70 times higher than those in saliva, respectively. More than 90% of the administered radioactivity was excreted in the urine, mostly as picendol glucuronide, and lesser amounts of picenadol sulfate and N-desmethylpicenadol sulfate. Only about 1% of the administered dose of picenadol appeared unchanged in urine. The disposition of racemic picenadol in humans was stereoselective, the (-)-picenadol apparently being metabolized preferentially over the (+)-enantiomer. This finding was of particular interest in view of the dissimilar pharmacologic activities of the enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)


Primary culture of mouse adipose and fibrous synovial fibroblasts under normoxic and hypoxic conditions.
Synovial fibroblasts have attracted considerable attention in studies of joint diseases. Although mice are useful and powerful in in vitro and in vivo experiments, primary cultures of mouse synovial fibroblasts are notoriously difficult because the mouse synovial tissues are much smaller and cell cycle arrests can be induced more easily in murine cells than in human cells. Here, we report a precise protocol for the isolation and culture of fibroblasts from mouse adipose and fibrous knee joint synovia. In both adipose and fibrous synovial fibroblasts, proliferation was decreased in addition to a higher rate of cellular senescence under normoxic conditions (20% O2); however, it was maintained over 20 days with low cellular senescence under hypoxic conditions (3% O2). The marker gene expression in adipose and fibrous synovial fibroblasts was not markedly altered after a 3-week culture. Both cells displayed similar potencies for chondrogenic, osteogenic, and adipogenic differentiation, and responses to a proinflammatory cytokine. The present method provides a sufficient amount of mouse synovial fibroblasts for in vitro and in vivo experiments in joint biology and the pathophysiology of osteoarthritis and rheumatoid arthritis.


Effects of physical and chemical treatments on the molecular weight and degradation of alginate-hydroxyapatite composites.
Degradation of alginate remains a critical issue to allow predictable biological performance upon implantation of alginate-based materials. Therefore, the objective of the current study is to compare the effects of γ-irradiation (dry state, 20-80 kGy), partial (1 and 4%) periodate oxidation (aqueous solution), and autoclaving (dry state) on the molecular weight of alginate, as well as the degradation behavior of alginate-based composites. The results show that γ-irradiation is by far the most destructive technique characterized by strongly reduced molecular weights and rapid loss of composite integrity upon soaking in simulated body fluid. Partial periodate oxidation is less destructive as characterized by more moderate decreases in molecular weight, but the production of hydrolytically labile bonds compromises the integrity of the resulting composites. Autoclaving is shown to be a powerful tool to reduce the molecular weight of alginate in a controllable and mild manner without compromising the integrity of the resulting alginate-hydroxyapatite composites, simply by increasing the number of repetitive autoclaving cycles.


Measurement and correlates of intimate partner violence among expectant first-time parents.
Research on the implications of varying measurement strategies for estimating levels and correlates of intimate partner violence (IPV) has been limited. This study explored measurement and correlates of IPV using a community sample of 168 couples who were expecting their first child. In line with prior research, couple agreement regarding the presence of violence was low, and maximum reported estimates revealed substantial IPV perpetrated by both expectant mothers and fathers. Different types of IPV scores predicted unique variance in mental health problems and couple relationship distress among both the whole sample and the subsamples who perpetrated any violence. Discussion focuses on the methodological and substantive implications of these findings for the study of IPV during the transition to parenthood.


Spherules on shatter cone surfaces from the vredefort structure, South Africa.
Spherical particles of silicate composition occur on the surface of some shatter cones from the collar rocks around the Vredefort structure, South Africa. They are best developed on shatter cones from a shale horizon but are also found on more arenaceous rocks and banded ironstones. They have not been found on shatter cones from the purer quartzites.


A model of tripeptidyl-peptidase I (CLN2), a ubiquitous and highly conserved member of the sedolisin family of serine-carboxyl peptidases.
Tripeptidyl-peptidase I, also known as CLN2, is a member of the family of sedolisins (serine-carboxyl peptidases). In humans, defects in expression of this enzyme lead to a fatal neurodegenerative disease, classical late-infantile neuronal ceroid lipofuscinosis. Similar enzymes have been found in the genomic sequences of several species, but neither systematic analyses of their distribution nor modeling of their structures have been previously attempted. We have analyzed the presence of orthologs of human CLN2 in the genomic sequences of a number of eukaryotic species. Enzymes with sequences sharing over 80% identity have been found in the genomes of macaque, mouse, rat, dog, and cow. Closely related, although clearly distinct, enzymes are present in fish (fugu and zebra), as well as in frogs (Xenopus tropicalis). A three-dimensional model of human CLN2 was built based mainly on the homology with Pseudomonas sp. 101 sedolisin. CLN2 is very highly conserved and widely distributed among higher organisms and may play an important role in their life cycles. The model presented here indicates a very open and accessible active site that is almost completely conserved among all known CLN2 enzymes. This result is somehow surprising for a tripeptidase where the presence of a more constrained binding pocket was anticipated. This structural model should be useful in the search for the physiological substrates of these enzymes and in the design of more specific inhibitors of CLN2.


MedEx: a medication information extraction system for clinical narratives.
Medication information is one of the most important types of clinical data in electronic medical records. It is critical for healthcare safety and quality, as well as for clinical research that uses electronic medical record data. However, medication data are often recorded in clinical notes as free-text. As such, they are not accessible to other computerized applications that rely on coded data. We describe a new natural language processing system (MedEx), which extracts medication information from clinical notes. MedEx was initially developed using discharge summaries. An evaluation using a data set of 50 discharge summaries showed it performed well on identifying not only drug names (F-measure 93.2%), but also signature information, such as strength, route, and frequency, with F-measures of 94.5%, 93.9%, and 96.0% respectively. We then applied MedEx unchanged to outpatient clinic visit notes. It performed similarly with F-measures over 90% on a set of 25 clinic visit notes.


Transcription Factor E2F3a in Nucleus Accumbens Affects Cocaine Action via Transcription and Alternative Splicing.
Lasting changes in gene expression in brain reward regions, including nucleus accumbens (NAc), contribute to persistent functional changes in the addicted brain. We and others have demonstrated that altered expression of several candidate transcription factors in NAc regulates drug responses. A recent large-scale genome-wide study from our group predicted transcription factor E2F3 (E2F3) as a prominent upstream regulator of cocaine-induced changes in gene expression and alternative splicing. We studied expression of two E2F3 isoforms-E2F3a and E2F3b-in mouse NAc after repeated cocaine administration and assayed the effects of overexpression or depletion of E2f3 isoforms in NAc on cocaine behavioral responses. We then performed RNA sequencing to investigate the effect of E2f3a overexpression in this region on gene expression and alternative splicing and performed quantitative chromatin immunoprecipitation at downstream targets in NAc following E2f3a overexpression or repeated cocaine exposure. Sample sizes varied between experiments and are noted in the text. We showed that E2f3a, but not E2f3b, overexpression or knockdown in mouse NAc regulates cocaine-induced locomotor and place conditioning behavior. Furthermore, we demonstrated that E2f3a overexpression substantially recapitulates genome-wide transcriptional profiles and alternative splicing induced by cocaine. We further validated direct binding of E2F3a at key target genes following cocaine exposure. This study establishes E2F3a as a novel transcriptional regulator of cocaine action in NAc. The findings reveal a crucial role for E2F3a in the regulation of cocaine-elicited behavioral states. Moreover, the importance of this role is bolstered by the extensive recapitulation of cocaine's transcriptional effects in NAc by overexpression of E2f3a.


Lymphocytotoxins in sera from highly sensitized multiparous dialysis patients: antibody class, relationship with the HLA and with paternal antigens.
1. Sera from 11 highly sensitized multiparous dialysis patients were studied in order to define the target antigens, antibody class and relationship with paternal HLA class I antigens of the underlying lymphocytotoxic antibodies. All sera contained lymphocytotoxic antibodies to over 70% of a panel of lymphocytes from 24 donors (panel reactivity greater than 70%). 2. Inhibition of cytotoxic activity against paternal lymphocytes by monoclonal antibodies to HLA framework determinants indicated that all 11 sera contained lymphocytotoxic antibodies to paternal class I antigens. In addition, five sera contained lymphocytotoxic antibodies to paternal class II antigens. 3. In order to determine the extent to which lymphocytotoxic antibodies were directed to paternal antigens, the panel reactivity of sera was compared before and after absorption with paternal peripheral blood lymphocytes. Over 50% of panel reactivity was absorbed from eight out of 11 sera, and in three of these 11 over 80% was absorbed. In the majority of patients this change in panel reactivity could be ascribed to binding of lymphocytotoxic antibodies to specific paternal class I antigens. 4. Digestion of sera with dithiothreitol had no significant effect on panel reactivity, indicating that the lymphocytotoxic antibodies were of immunoglobulin G class. 5. No sera reacted with either autologous lymphocytes or K562 cells, indicating an absence of autoantibodies. 6. These studies imply that panel-reactive lymphocytotoxic antibodies in the sera of highly sensitized multiparous patients are those which mediate hyperacute renal allograft rejection. Their development may be related to secondary humoral responses to antigens in blood transfusions from donors who share paternal class I specificities.


Reproductive health care for asylum-seeking women - a challenge for health professionals.
Dealing with pregnancy, childbirth and the care of newborn babies is a challenge for female asylum seekers and their health care providers. The aim of our study was to identify reproductive health issues in a population of women seeking asylum in Switzerland, and to examine the care they received. The women were insured through a special Health Maintenance Organisation (HMO) and were attending the Women's Clinic of the University Hospital in Basel. We also investigated how the health professionals involved perceived the experience of providing health care for these patients. A mixed methods approach combined the analysis of quantitative descriptive data and qualitative data obtained from semi-structured interviews with health care providers and from patients' files. We analysed the records of 80 asylum-seeking patients attending the Women's Clinic insured through an HMO. We conducted semi-structured interviews with 10 care providers from different professional groups. Quantitative data were analysed descriptively. Qualitative data analysis was guided by Grounded Theory. The principal health problems among the asylum seekers were a high rate of induced abortions (2.5 times higher than in the local population), due to inadequate contraception, and psychosocial stress due to the experience of forced migration and their current difficult life situation. The language barriers were identified as a major difficulty for health professionals in providing care. Health care providers also faced major emotional challenges when taking care of asylum seekers. Additional problems for physicians were that they were often required to act in an official capacity on behalf of the authorities in charge of the asylum process, and they also had to make decisions about controlling expenditure to fulfil the requirements of the HMO. They felt that these decisions sometimes conflicted with their duty towards the patient. Health policies for asylum seekers need to be designed to assure access to adequate contraception, and to provide psychological care for this vulnerable group of patients. Care for asylum seekers may be emotionally very challenging for health professionals.


Characterization of the microtubule movement produced by sea urchin egg kinesin.
We have used an in vitro assay to characterize some of the motile properties of sea urchin egg kinesin. Egg kinesin is purified via 5'-adenylyl imidodiphosphate-induced binding to taxol-assembled microtubules, extraction from the microtubules in ATP, and gel filtration chromatography (Scholey, J. M., Porter, M. E., Grissom, P. M., and McIntosh, J. R. (1985) Nature 318, 483-486). This partially purified kinesin is then adsorbed to a glass coverslip, mixed with microtubules and ATP, and viewed by video-enhanced differential interference contrast microscopy. The microtubule translocating activity of the purified egg kinesin is qualitatively similar to the analogous activity observed in crude extracts of sea urchin eggs and resembles the activity of neuronal kinesin with respect to both the maximal rate (greater than 0.5 micron/s) and the direction of movement. Axonemes glide on a kinesin-coated coverslip toward their minus ends, and kinesin-coated beads translocate toward the plus ends of centrosome microtubules. Sea urchin egg kinesin is inhibited by high concentrations of SH reagents ([N-ethylmaleimide] greater than 3-5 mM), vanadate greater than 50 microM, and [nonhydrolyzable nucleotides] greater than or equal to [MgATP]. The nucleotide requirement of sea urchin egg kinesin is fairly broad (ATP greater than GTP greater than ITP), and the rate of microtubule movement increases in a saturable fashion with the [ATP]. We conclude that the motile activity of egg kinesin is indistinguishable from that of neuronal kinesin. We propose that egg kinesin may be associated with microtubule-based motility in vivo.


The excitatory amino acid carrier 1 (EAAC1) in the rat nucleus of the solitary tract: subcellular localization suggests no major role in glutamate clearance.
The excitatory amino acid carrier 1 (EAAC1) is a sodium-dependent glutamate transporter widely found in the mammalian brain and mainly localized in the somatodendritic compartment of neurons. The present study was performed to determine whether EAAC1 is present in the rat nucleus of the solitary tract (NST, a sensory brainstem nucleus involved in visceroception) and to document its subcellular localization. Using fluorescent immunolabeling, peroxidase immunostaining and quantitative immunogold labeling, we showed that both intracellular and plasma membrane-associated pools of EAAC1 transporters existed in dendrites of NST neurons. Although plasma membrane-associated transporters were more concentrated in the vicinity of synapses, no labeling was found at the axon-dendrite interface, suggesting that EAAC1 was not (or barely) expressed in this portion of dendritic membrane. Using computer simulation, we next showed that the ability of EAAC1 to efficiently take up synaptically released glutamate was very low outside the axon-dendrite interface. These data suggest that EAAC1 transporters present on NST dendrites may play a minor role if any in glutamate clearance.


Dynamic behavior of Arabidopsis eIF4A-III, putative core protein of exon junction complex: fast relocation to nucleolus and splicing speckles under hypoxia.
Here, we identify the Arabidopsis thaliana ortholog of the mammalian DEAD box helicase, eIF4A-III, the putative anchor protein of exon junction complex (EJC) on mRNA. Arabidopsis eIF4A-III interacts with an ortholog of the core EJC component, ALY/Ref, and colocalizes with other EJC components, such as Mago, Y14, and RNPS1, suggesting a similar function in EJC assembly to animal eIF4A-III. A green fluorescent protein (GFP)-eIF4A-III fusion protein showed localization to several subnuclear domains: to the nucleoplasm during normal growth and to the nucleolus and splicing speckles in response to hypoxia. Treatment with the respiratory inhibitor sodium azide produced an identical response to the hypoxia stress. Treatment with the proteasome inhibitor MG132 led to accumulation of GFP-eIF4A-III mainly in the nucleolus, suggesting that transition of eIF4A-III between subnuclear domains and/or accumulation in nuclear speckles is controlled by proteolysis-labile factors. As revealed by fluorescence recovery after photobleaching analysis, the nucleoplasmic fraction was highly mobile, while the speckles were the least mobile fractions, and the nucleolar fraction had an intermediate mobility. Sequestration of eIF4A-III into nuclear pools with different mobility is likely to reflect the transcriptional and mRNA processing state of the cell.


Autism spectrum disorder prevalence and proximity to industrial facilities releasing arsenic, lead or mercury.
Prenatal and perinatal exposures to air pollutants have been shown to adversely affect birth outcomes in offspring and may contribute to prevalence of autism spectrum disorder (ASD). For this ecologic study, we evaluated the association between ASD prevalence, at the census tract level, and proximity of tract centroids to the closest industrial facilities releasing arsenic, lead or mercury during the 1990s. We used 2000 to 2008 surveillance data from five sites of the Autism and Developmental Disabilities Monitoring (ADDM) network and 2000 census data to estimate prevalence. Multi-level negative binomial regression models were used to test associations between ASD prevalence and proximity to industrial facilities in existence from 1991 to 1999 according to the US Environmental Protection Agency Toxics Release Inventory (USEPA-TRI). Data for 2489 census tracts showed that after adjustment for demographic and socio-economic area-based characteristics, ASD prevalence was higher in census tracts located in the closest 10th percentile compared of distance to those in the furthest 50th percentile (adjusted RR=1.27, 95% CI: (1.00, 1.61), P=0.049). The findings observed in this study are suggestive of the association between urban residential proximity to industrial facilities emitting air pollutants and higher ASD prevalence.


Decreasing antibiotic use, the gut microbiota, and asthma incidence in children: evidence from population-based and prospective cohort studies.
Childhood asthma incidence is decreasing in some parts of Europe and North America. Antibiotic use in infancy has been associated with increased asthma risk. In the present study, we tested the hypothesis that decreases in asthma incidence are linked to reduced antibiotic prescribing and mediated by changes in the gut bacterial community. This study comprised population-based and prospective cohort analyses. At the population level, we used administrative data from British Columbia, Canada (population 4·7 million), on annual rates of antibiotic prescriptions and asthma diagnoses, to assess the association between antibiotic prescribing (at age <1 year) and asthma incidence (at age 1-4 years). At the individual level, 2644 children from the Canadian Healthy Infant Longitudinal Development (CHILD) prospective birth cohort were examined for the association of systemic antibiotic use (at age <1 year) with the diagnosis of asthma (at age 5 years). In the same cohort, we did a mechanistic investigation of 917 children with available 16S rRNA gene sequencing data from faecal samples (at age ≤1 year), to assess how composition of the gut microbiota relates to antibiotic exposure and asthma incidence. At the population level between 2000 and 2014, asthma incidence in children (aged 1-4 years) showed an absolute decrease of 7·1 new diagnoses per 1000 children, from 27·3 (26·8-28·3) per 1000 children to 20·2 (19·5-20·8) per 1000 children (a relative decrease of 26·0%). Reduction in incidence over the study period was associated with decreasing antibiotic use in infancy (age <1 year), from 1253·8 prescriptions (95% CI 1219·3-1288·9) per 1000 infants to 489·1 (467·6-511·2) per 1000 infants (Spearman's r=0·81; p<0·0001). Asthma incidence increased by 24% with each 10% increase in antibiotic prescribing (adjusted incidence rate ratio 1·24 [95% CI 1·20-1·28]; p<0·0001). In the CHILD cohort, after excluding children who received antibiotics for respiratory symptoms, asthma diagnosis in childhood was associated with infant antibiotic use (adjusted odds ratio [aOR] 2·15 [95% CI 1·37-3·39]; p=0·0009), with a significant dose-response; 114 (5·2%) of 2182 children unexposed to antibiotics had asthma by age 5 years, compared with 23 (8·1%) of 284 exposed to one course, five (10·2%) of 49 exposed to two courses, and six (17·6%) of 34 exposed to three or more courses (aOR 1·44 [1·16-1·79]; p=0·0008). Increasing α-diversity of the gut microbiota, defined as an IQR increase (25th to 75th percentile) in the Chao1 index, at age 1 year was associated with a 32% reduced risk of asthma at age 5 years (aOR for IQR increase 0·68 [0·46-0·99]; p=0·046). In a structural equation model, we found the gut microbiota at age 1 year, characterised by α-diversity, β-diversity, and amplicon sequence variants modified by antibiotic exposure, to be a significant mediator between outpatient antibiotic exposure in the first year of life and asthma diagnosis at age 5 years (β=0·08; p=0·027). Our findings suggest that the reduction in the incidence of paediatric asthma observed in recent years might be an unexpected benefit of prudent antibiotic use during infancy, acting via preservation of the gut microbial community. British Columbia Ministry of Health, Pharmaceutical Services Branch; Canadian Institutes of Health Research; Allergy, Genes and Environment (AllerGen) Network of Centres of Excellence; Genome Canada; and Genome British Columbia.


Post-marketing studies of pharmaceutical opioid abuse-deterrent formulations: a framework for research design and reporting.
Opioid formulations with properties to deter abuse (abuse-deterrent formulations; ADFs) have been developed as one response to the prescription opioid 'epidemic'. As for all medicines, ADFs undergo evaluation of safety and efficacy prior to registration for marketing. However, reduced extra-medical use (the primary intended outcome of ADFs and reason for their introduction) can only be established in post-marketing observational studies, comparing them to opioid formulations without abuse-deterrent properties. This has implications for various features of study design and analysis. We discuss proposals for the design, conduct, governance and reporting of post-marketing studies on the effectiveness of pharmaceutical and opioid ADFs. A review of current guidance documents, public work-shops and forums and our own experience with post-marketing studies of ADFs. Research questions for post-marketing studies on ADFs of opioids should reasonably be framed around detecting any probable intended or unintended clinical and/or meaningful changes in specific aspects of extra-medical use (e.g. injection use) and harms. Outcomes reported by prevalence and frequency of occurrence and disaggregated by specific product and route of administration can illustrate the magnitude of ADF impact. We argue that a multi-faceted approach is required, using data from both general population and sentinel high-risk cohorts and from primary and secondary data sources. The comparator (historical non-ADF formulation of that opioid, equivalent current generic or similar opioid product), duration of monitoring and analytical approach require justification and should be sufficient to add weight to conclusions of causality. To maximize transparency, we recommend explicit declarations of funding and conflict of interest, establishment of an advisory committee, publication of study protocol and access to study results.


Wnt Signaling in Cardiac Disease.
Wnt signaling encompasses multiple and complex signaling cascades and is involved in many developmental processes such as tissue patterning, cell fate specification, and control of cell division. Consequently, accurate regulation of signaling activities is essential for proper embryonic development. Wnt signaling is mostly silent in the healthy adult organs but a reactivation of Wnt signaling is generally observed under pathological conditions. This has generated increasing interest in this pathway from a therapeutic point of view. In this review article, the involvement of Wnt signaling in cardiovascular development will be outlined, followed by its implication in myocardial infarct healing, cardiac hypertrophy, heart failure, arrhythmias, and atherosclerosis. The initial experiments not always offer consensus on the effects of activation or inactivation of the pathway, which may be attributed to (i) the type of cardiac disease, (ii) timing of the intervention, and (iii) type of cells that are targeted. Therefore, more research is needed to determine the exact implication of Wnt signaling in the conditions mentioned above to exploit it as a powerful therapeutic target.


Experimental strategies to promote spinal cord regeneration--an integrative perspective.
Detailed pathophysiological findings of secondary damage phenomena after spinal cord injury (SCI) as well as the identification of inhibitory and neurotrophic proteins have yielded a plethora of experimental therapeutic approaches. Main targets are (i) to minimize secondary damage progression (neuroprotection), (ii) to foster axon conduction (neurorestoration) and (iii) to supply a permissive environment to promote axonal sprouting (neuroregenerative therapies). Pre-clinical studies have raised hope in functional recovery through the antagonism of growth inhibitors, application of growth factors, cell transplantation, and vaccination strategies. To date, even though based on successful pre-clinical animal studies, results of clinical trials are characterized by dampened effects attributable to difficulties in the study design (patient heterogeneity) and species differences. A combination of complementary therapeutic strategies might be considered pre-requisite for future synergistic approaches. Here, we line out pre-clinical interventions resulting in improved functional neurological outcome after spinal cord injury and track them on their intended way to bedside.


Proteome analysis of Borrelia burgdorferi response to environmental change.
We examined global changes in protein expression in the B31 strain of Borrelia burgdorferi, in response to two environmental cues (pH and temperature) chosen for their reported similarity to those encountered at different stages of the organism's life cycle. Multidimensional nano-liquid chromatographic separations coupled with tandem mass spectrometry were used to examine the array of proteins (i.e., the proteome) of B. burgdorferi for different pH and temperature culture conditions. Changes in pH and temperature elicited in vitro adaptations of this spirochete known to cause Lyme disease and led to alterations in protein expression that are associated with increased microbial pathogenesis. We identified 1,031 proteins that represent 59% of the annotated genome of B. burgdorferi and elucidated a core proteome of 414 proteins that were present in all environmental conditions investigated. Observed changes in protein abundances indicated varied replicon usage, as well as proteome functional distributions between the in vitro cell culture conditions. Surprisingly, the pH and temperature conditions that mimicked B. burgdorferi residing in the gut of a fed tick showed a marked reduction in protein diversity. Additionally, the results provide us with leading candidates for exploring how B. burgdorferi adapts to and is able to survive in a wide variety of environmental conditions and lay a foundation for planned in situ studies of B. burgdorferi isolated from the tick midgut and infected animals.


Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma.
Recent evidence suggests that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that tumorous tissues have higher 5alpha-reductase (5alphaR) and lower 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO) and 20alpha-HSO activities. The resulting higher levels of 5alpha-reduced progesterone metabolites such as 5alpha-pregnane-3,20-dione (5alphaP) in tumorous tissue promote cell proliferation and detachment, whereas the 4-pregnene metabolites, 4-pregnen-3alpha-ol-20-one (3alphaHP) and 4-pregnen-20alpha-ol-3-one (20alphaDHP), more prominent in normal tissue, have the opposite (anti-cancer-like) effects. The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression. Semi-quantitative RT-PCR was used to compare relative expression (as a ratio of 18S rRNA) of 5alphaR type 1 (SRD5A1), 5alphaR type 2 (SRD5A2), 3alpha-HSO type 2 (AKR1C3), 3alpha-HSO type 3 (AKR1C2) and 20alpha-HSO (AKR1C1) mRNAs in paired (tumorous and nontumorous) breast tissues from 11 patients, and unpaired tumor tissues from 17 patients and normal tissues from 10 reduction mammoplasty samples. Expression of 5alphaR1 and 5alphaR2 in 11/11 patients was higher (mean of 4.9- and 3.5-fold, respectively; p < 0.001) in the tumor as compared to the paired normal tissues. Conversely, expression of 3alpha-HSO2, 3alpha-HSO3 and 20alpha-HSO was higher (2.8-, 3.9- and 4.4-fold, respectively; p < 0.001) in normal than in tumor sample. The mean tumor:normal expression ratios for 5alphaR1 and 5alphaR2 were about 35-85-fold higher than the tumor:normal expression ratios for the HSOs. Similarly, in the unmatched samples, the tumor:normal ratios for 5alphaR were significantly higher than the ratios for the HSOs. The study shows changes in progesterone metabolizing enzyme gene expression in human breast carcinoma. Expression of SRD5A1 (5alphaR1) and SRD5A2 (5alphaR2) is elevated, and expression of AKR1C1 (20alpha-HSO), AKR1C2 (3alpha-HSO3) and AKR1C3 (3alpha-HSO2) is reduced in tumorous as compared to normal breast tissue. The changes in progesterone metabolizing enzyme expression levels help to explain the increases in mitogen/metastasis inducing 5alphaP and decreases in mitogen/metastasis inhibiting 3alphaHP progesterone metabolites found in breast tumor tissues. Understanding what causes these changes in expression could help in designing protocols to prevent or reverse the changes in progesterone metabolism associated with breast cancer.


Deciphering pharmacokinetics and pharmacodynamics of fosfomycin.
Fosfomycin, a low molecular weight and hydrophilic drug with negligible protein binding, is eliminated almost exclusively by glomerular filtration, whose clearance is subject to patient renal function. The volume of distribution approximates to the extracellular body water (about 0.3 L/Kg) in healthy volunteers, but it is increased in critically ill patients with bacterial infections. Fosfomycin presents a high ability to distribute into many tissues, including inflamed tissues and abscess fluids. Based on PK/PD analysis and Monte Carlo simulations, we have evaluated different fosfomycin dosing regimen to optimize the treatment of septic patients due to Enterobacterales and Pseudomonas aeruginosa. As PK/PD targets, we selected %T>MIC > 70% for all pathogens, and AUC24/MIC > 24 and AUC24/MIC > 15 for net stasis of Enterobacterales and P. aeruginosa, respectively. Pharmacokinetic parameters in critically ill patients were obtained from the literature. Several dosing regimens were studied in patients with normal renal function: fosfomycin 2-8 g given every 6-12 hours, infused over 30 minutes- 24 hours. At the susceptibility EUCAST breakpoint for Enterobacterales and Staphylococcus spp. (MIC ≤ 32 mg/L), fosfomycin 4 g/8h or higher infused over 30 minutes achieved a probability of target attainment (PTA) > 90%, based in both %T>MIC and AUC24/MIC. For MIC of 64 mg/L, fosfomycin 6 g/6h in 30-minute infusion and 8 g/ 8h in 30-minute and 6 hours infusions also achieved PTA values higher than 90%. No fosfomycin monotherapy regimen was able to achieve PK/PD targets related to antimicrobial efficacy for P. aeruginosa with MICs of 256-512 mg/L.


Risk factors predictive of poor quality preparation during average risk colonoscopy screening: the importance of health literacy.
Inadequate colonoscopy bowel preparation can lead to increased procedural time, decreased diagnostic yield, and an increased complication rate. Little is known about which patient characteristics may predict poor bowel preparation for routine, average-risk colonoscopy evaluation. 300 consecutive patients who underwent routine, average risk outpatient screening colonoscopy during 01/01/2005 to 12/30/2008 at a primary care internal medicine clinic were retrospectively identified. Patients were between 50-80 years old and used the standard preparation of 2000ml polyethylene glycol solution (MoviPrep)(R). Differences in mean values between each group (inadequate vs. adequate preparation) were compared using the Student t-test. Categorical variables were compared using chi2 test. A multivariate logistical regression analysis was performed to identify characteristics predictive of poor colonoscopy preparation. Of the 300 consecutive patients referred for routine outpatient colonoscopy examination, 15% had inadequate or poor colonoscopy preparation. The majority of patients with poor colonoscopy preparation (86.7%) reported either failure to complete the 2000 ml preparation or failure to follow written instructions. In the multivariate model, the four biggest clinical contributors to poor colonoscopy were an interpreter requirement, Medicaid insurance, single status, and having more than 8 active prescription medications. Among patients who underwent average-risk screening colonoscopy evaluation, the use of an interpreter and having Medicaid insurance were the largest predictors of inadequate colonoscopy preparation. These characteristics may be surrogate markers of lower health care literacy. Interventions to reduce poor colonoscopy preparation should be targeted at these patient populations.


Epidural abscess of the cervical spine: MR findings in five cases.
Cervical epidural abscess is an uncommon infectious process of the spinal epidural space. Although this disorder is often unsuspected clinically, the patient's signs and symptoms may suggest other diagnoses that frequently lead to an MR examination. We retrospectively reviewed the MR examinations of five patients with surgically proved cervical epidural abscess in order to assist in the diagnosis of this clinically elusive disorder. Each epidural abscess was evaluated for MR signal intensity, location, extent, delineation, and enhancement pattern. We assessed the spinal cord for compression and signal intensity and analyzed the vertebrae, intervertebral disks, and paraspinal soft tissue. Compared with the spinal cord, the abscess was isointense or hypointense on T1-weighted spin-echo images and hyperintense on T2-weighted images. The abscess was hyperintense or isointense relative to the cord on T2* gradient-echo images. Enhancement of the abscess occurred in the two patients given an IV injection of gadopentetate dimeglumine. The epidural abscess was located anteriorly in three patients, posteriorly in one, and was circumferential in one. The abscess extended from two to nine vertebral bodies in length. In each case, the abscess caused some degree of spinal cord compression, and one patient had bright signal intensity within the cord on T2-weighted images. Three patients had MR changes of accompanying osteomyelitis and paravertebral abscess. MR imaging is useful in diagnosing cervical epidural abscess and in evaluating associated abnormality of the spinal cord, vertebral bodies, intervertebral disks, and paraspinal soft tissue.


[The inhibition stage of lipid peroxidation during stress].
Stress is shown to induce at first the generalized inhibition of lipid peroxidation (LPO), and then the activation of LPO. In brain and blood serum of rats subjected to continuous footshock as well as to restraint stress LPO products decreased and superoxide scavenging activity increased during the initial period of stress, after 1 hour of footshock LPO indices nearly reached normal values, and after 2 hours of footshock the accumulation of LPO products and decrease of superoxide scavenging activity were seen. LPO inhibition was accompanied by accumulation of easy oxidizable brain phospholipids and by depletion of brain cholesterol, during LPO activation brain cholesterol content and cholesterol-phospholipid ratio increased. The content of LPO products--fluorescent Schiff bases in blood plasma of women suffering from algomenorrhea at first decreased (O-12 h) and then dramatically increased (12-24 h) after a onset of pain at the beginning of menstruation. The data suggest that the stage of LPO inhibition precedes its activation during stress.


Sensitivity of serum markers for pancreatitis in dogs with macroscopic evidence of pancreatitis.
Pancreatitis is recognized as an important and common problem in dogs, but diagnosis can be challenging. Recently, new assays for the measurement of trypsin-a1-proteinase inhibitor complexes and canine pancreatic lipase immunoreactivity (cPLI and Spec cPL) have been developed and analytically validated. This is the first report of a direct comparison of the sensitivity of these and other more traditional serum markers for the diagnosis of canine pancreatitis in a subset of dogs with this disease (i.e., dogs with both macroscopic and microscopic changes characteristic of pancreatitis). Serum cPLI and Spec cPL concentrations showed the highest sensitivity for the diagnosis of pancreatitis in this group of patients. Further studies will be required to compare the specificity of these serum markers and thus determine their overall clinical utility.


Rapidity of response to hypoxic conditions during exercise.
Previous studies have found decreases in arterial oxygen saturation to be temporally linked to reductions in power output (PO) during time-trial (TT) exercise. The purpose of this study was to determine whether preexercise desaturation (estimated from pulse oximetry [SpO2]), via normobaric hypoxia, would change the pattern of PO during a TT. The authors tested the hypothesis that the starting PO of a TT would be reduced in the EARLY trial secondary to a reduced SpO2 but would not be reduced in LATE until ~30 s after the start of the TT. Eight trained cyclists/triathletes (4 male, 4 female) performed 3 randomly ordered 3-km TTs while breathing either room air (CONTROL) or hypoxic air administered 3 min before the start of the TT (EARLY) or at the beginning of the TT (LATE). There was no effect of hypoxia on PO during the first 0.3 km of either the EARLY or the LATE trial compared with CONTROL, although there was a significant decrease in pre-TT SpO2 in EARLY vs CONTROL and LATE. The time for PO to decrease was ~40 s after the start of the TT in both EARLY and LATE. The results support the strong effect of the preexercise template on the pattern of PO during simulated competition and suggest that reductions in SpO2 are not direct signals to decrease PO.


Exploring why residents of socioeconomically deprived neighbourhoods have less favourable perceptions of their neighbourhood environment than residents of wealthy neighbourhoods.
Residents of socioeconomically deprived areas perceive their neighbourhood as less conducive to healthy behaviours than residents of more affluent areas. Whether these unfavourable perceptions are based on objective neighbourhood features or other factors is poorly understood. We examined individual and contextual correlates of socioeconomic inequalities in neighbourhood perceptions across five urban regions in Europe. Data were analysed from 5205 participants of the SPOTLIGHT survey. Participants reported perceptions of their neighbourhood environment with regard to aesthetics, safety, the presence of destinations and functionality of the neighbourhood, which were summed into an overall neighbourhood perceptions score. Multivariable multilevel regression analyses were conducted to investigate whether the following factors were associated with socioeconomic inequalities in neighbourhood perceptions: objectively observed neighbourhood features, neighbourhood social capital, exposure to the neighbourhood, self-rated health and lifestyle behaviours. Objectively observed traffic safety, aesthetics and the presence of destinations in the neighbourhood explained around 15% of differences in neighbourhood perceptions between residents of high and low neighbourhoods; levels of neighbourhood social cohesion explained around 52%. Exposure to the neighbourhood, self-rated health and lifestyle behaviours were significant correlates of neighbourhood perceptions but did not contribute to socioeconomic differences. This cross-European study provided evidence that socioeconomic differences in neighbourhood perceptions are not only associated with objective neighbourhood features but also with social cohesion. Levels of physical activity, sleep duration, self-rated health, happiness and neighbourhood preference were also associated with neighbourhood perceptions.


Green chromatography determination of fatty acid methyl esters in biodiesel.
This work proposes a green, simple and rapid chromatographic methodology for separation and determination of a group of 13 fatty acids methyl esters (FAMEs) by using a capillary gas chromatography with a flame ionization detector. The method was successfully applied for the determination of FAMEs in biodiesel samples from commercial and waste cooking oils, synthesized by homogeneous catalysis. Detection and quantification limits were in the μg L(-1) level. Direct injection of sample solution was compared with solid-phase extraction and solid-phase microextraction procedures, giving similar results. The lower analysis time represent considerable improvement compared with other papers. The described methodology is especially suitable for process control applications. The samples analysed showed total contents of FAMEs higher than 96.5%, which verifies the European regulations.


Heating and pain sensation produced in human skin by millimeter waves: comparison to a simple thermal model.
Cutaneous thresholds for thermal pain were measured in 10 human subjects during 3-s exposures at 94 GHz continuous wave microwave energy at intensities up to approximately 1.8 W cm(-2). During each exposure, the temperature increase at the skin's surface was measured by infrared thermography. The mean (+/- s.e.m.) baseline temperature of the skin was 34.0+/-0.2 degrees C. The threshold for pricking pain was 43.9+/-0.7 degrees C, which corresponded to an increase in surface temperature of approximately 9.9 degrees C (from 34.0 degrees C to 43.9 degrees C). The measured increases in surface temperature were in good agreement with a simple thermal model that accounted for heat conduction and for the penetration depth of the microwave energy into tissue. Taken together, these results support the use of the model for predicting thresholds of thermal pain at other millimeter wave (length) frequencies.


Aberration-reduced holographic spherical gratings for Rowland circle spectrographs.
We used a numerical minimization method to design a Rowland holographic spherical grating that is recorded with two stigmatic laser sources. The method aims at simultaneously reducing all aberrations up to fourth order over a significant spectral range. In the context of a high spectral resolution, far-ultraviolet spectrograph, an original solution is found that implies a nonclassical recording geometry with one virtual source. This solution satisfies the requirement of a resolving power of ~ 30 000 with the unquestionable advantage of manufacturing and testing simplicity. Finally, another example, which is obtained in a different context, shows that the properties of this recording geometry probably have a general applicability.


Learning sobriety together: A randomized clinical trial examining behavioral couples therapy with alcoholic female patients.
Married or cohabiting female alcoholic patients (n = 138) and their non-substance-abusing male partners were randomly assigned to 1 of 3 equally intensive interventions: (a) behavioral couples therapy plus individual-based treatment (BCT; n = 46), (b) individual-based treatment only (IBT; n = 46), or (c) psychoeducational attention control treatment (PACT; n = 46). During treatment, participants in BCT showed significantly greater improvement in dyadic adjustment than those in IBT or PACT; drinking frequency was not significantly different among participants in the different conditions. During the 1-year posttreatment follow-up, compared with participants who received IBT or PACT, participants who received BCT reported (a) fewer days of drinking, (b) fewer drinking-related negative consequences, (c) higher dyadic adjustment, and (d) reduced partner violence.


Investigating response time and accuracy in online classifier learning for multimedia publish-subscribe systems.
The enormous growth of multimedia content in the field of the Internet of Things (IoT) leads to the challenge of processing multimedia streams in real-time. Event-based systems are constructed to process event streams. They cannot natively consume multimedia event types produced by the Internet of Multimedia Things (IoMT) generated data to answer multimedia-based user subscriptions. Machine learning-based techniques have enabled rapid progress in solving real-world problems and need to be optimised for the low response time of the multimedia event processing paradigm. In this paper, we describe a classifier construction approach for the training of online classifiers, that can handle dynamic subscriptions with low response time and provide reasonable accuracy for the multimedia event processing. We find that the current object detection methods can be configured dynamically for the construction of classifiers in real-time, by tuning hyperparameters even when training from scratch. Our experiments demonstrate that deep neural network-based object detection models, with hyperparameter tuning, can improve the performance within less training time for the answering of previously unknown user subscriptions. The results from this study show that the proposed online classifier training based model can achieve accuracy of 79.00% with 15-min of training and 84.28% with 1-hour training from scratch on a single GPU for the processing of multimedia events.


CD73 is involved in lymphocyte binding to the endothelium: characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73.
We have recently described a monoclonal antibody (mAb) 4G4 recognizing a 70-kD molecule constitutively expressed on human endothelial cells and on subpopulations of lymphocytes. We showed that this molecule, which we named lymphocyte-vascular adhesion protein 2 (L-VAP-2), mediates lymphocyte adhesion to cultured endothelial cells. Protein sequencing of tryptic peptides from immunoaffinity-purified L-VAP-2 revealed sequence identity between L-VAP-2 and CD73 (ecto-5'-nucleotidase, E.C.22.214.171.124), and COS cells transfected with a CD73 cDNA were positively stained with the mAb 4G4, which recognizes L-VAP-2. mAb 4G4 was also able to partially inhibit the ecto-5'-nucleotidase activity of peripheral blood lymphocytes. Moreover, cross-precipitation studies performed with mAb 4G4 and a CD73 workshop mAb 1E9 showed that these two antibodies recognize the same molecule. Since the tissue distribution and biochemical characteristics of the two molecules are also similar, we conclude that L-VAP-2 and CD73 are the same glycoprotein. Adhesion experiments showed significantly increased binding of freshly isolated lymphocytes to COS cells transfected with a CD73 cDNA, as compared to mock-transfected COS cells, and binding of lymphocytes to CD73-expressing COS cells was inhibited by the presence of mAb 4G4 in the adhesion assay. CD73 is a glycosyl phosphatidylinositol-linked molecule previously shown to have a cosignalling role in T lymphocyte proliferation. Our data suggest that it also has a function in mediating lymphocyte adhesion to the endothelium.


Characterization of genome-wide transcriptional changes in liver and adipose tissues of ZDF (fa/fa) rats fed R-α-lipoic acid by next-generation sequencing.
We report on the characterization of lipogenic tissue transcriptional networks that support physiological responses of obese rats to a lipid-lowering bioactive food compound, R-α-lipoic acid (LA). Nine-week-old male Zucker diabetic fatty (fa/fa) rats were fed a chow diet supplemented with 3 g LA per kg diet or pair fed for 2 wk. At the end of the trial, high-quality RNA was extracted from the liver and epididymal fat and subjected to transcriptome analysis by RNA-Seq technology. Results showed a substantially higher number of differentially expressed genes [DEG, false discovery rate adjusted P ≤ 0.05 and absolute log2 (fold change) ≥ 1] in the liver (110 genes) vs. epididymal fat (10 genes). Most epididymal fat DEG were also differentially expressed in liver and shared directionality of change. Gene Ontology (GO) analysis of these transcripts revealed significant enrichment of GO categories related to immune response, stress response, lipid metabolism, and carboxylic acid metabolic processes. Of interest, interferon-related genes involved in defense against microorganisms and innate immune response were induced by LA. Lipid metabolism-related transcript changes observed in LA-fed animals included downregulation of lipogenic genes (Pnpla3, Pnpla5, Elovl6, Acly, Gpam, and Aacs) and concomitant upregulation of short-, medium-, and long-chain fatty acid metabolic processes (Acot1, Acot2, Acsf2, and Crat). Transcriptional changes were accompanied by the lowering of abdominal adiposity and blood triacylglycerol levels. We conclude that LA dietary supplementation induces prominent gene expression changes in liver in support of significant improvement of whole-body lipid status.


Common or redundant neural circuits for duration processing across audition and touch.
Certain features of objects or events can be represented by more than a single sensory system, such as roughness of a surface (sight, sound, and touch), the location of a speaker (audition and sight), and the rhythm or duration of an event (by all three major sensory systems). Thus, these properties can be said to be sensory-independent or amodal. A key question is whether common multisensory cortical regions process these amodal features, or does each sensory system contain its own specialized region(s) for processing common features? We tackled this issue by investigating simple duration-detection mechanisms across audition and touch; these systems were chosen because fine duration discriminations are possible in both. The mismatch negativity (MMN) component of the human event-related potential provides a sensitive metric of duration processing and has been elicited independently during both auditory and somatosensory investigations. Employing high-density electroencephalographic recordings in conjunction with intracranial subdural recordings, we asked whether fine duration discriminations, represented by the MMN, were generated in the same cortical regions regardless of the sensory modality being probed. Scalp recordings pointed to statistically distinct MMN topographies across senses, implying differential underlying cortical generator configurations. Intracranial recordings confirmed these noninvasive findings, showing generators of the auditory MMN along the superior temporal gyrus with no evidence of a somatosensory MMN in this region, whereas a robust somatosensory MMN was recorded from postcentral gyrus in the absence of an auditory MMN. The current data clearly argue against a common circuitry account for amodal duration processing.


Constraint around Quarter-Power Allometric Scaling in Wild Tomatoes (Solanum sect. Lycopersicon; Solanaceae).
The West-Brown-Enquist (WBE) metabolic scaling theory posits that many organismal features scale predictably with body size because of selection to minimize transport costs in resource distribution networks. Many scaling exponents are quarter-powers, as predicted by WBE, but there are also biologically significant deviations that could reflect adaptation to different environments. A central but untested prediction of the WBE model is that wide deviation from optimal scaling is penalized, leading to a pattern of constraint on scaling exponents. Here, we demonstrate, using phylogenetic comparative methods, that variation in allometric scaling between mass and leaf area across 17 wild tomato taxa is constrained around a value indistinguishable from that predicted by WBE but significantly greater than 2/3 (geometric-similarity model). The allometric-scaling exponent was highly correlated with fecundity, water use, and drought response, suggesting that it is functionally significant and therefore could be under selective constraints. However, scaling was not strictly log-log linear but rather declined during ontogeny in all species, as has been observed in many plant species. We caution that although our results supported one prediction of the WBE model, it did not strongly test the model in other important respects. Nevertheless, phylogenetic comparative methods such as those used here are powerful but underutilized tools for metabolic ecology that complement existing methods to adjudicate between models.


Effects of therapeutic angiogenesis with plasmid VEGF165 on ventricular function in a canine model of chronic myocardial infarction.
Therapeutic angiogenesis is currently under investigation in ischemic heart disease. We examined the effect on left ventricular function induced by therapeutic angiogenesis by intramyocardial injection of plasmid VEGF(165), in a canine model of chronic myocardial infarction. Left thoracotomy was performed in 10 mongrel dogs, and myocardial infarction induced by ligation of the major diagonal coronary artery. At 7 postoperative (p.o.) day (pre-treatment), left ventricular ejection fraction was assessed by echocardiogram, and a second procedure was done: saline or plasmid VEGF(165) at 200 mg/mL was injected over 10 points of the ischemic areas of control or treated groups, respectively. Fourteen days later (post-treatment, day 21) a control echocardiogram was performed, the animals were sacrificed and histological examination was performed. Ejection fraction was maintained in the treated group: 52.45 +/- 15.1% on day 7 and 48.53 +/-11.74% on day 21 (P=0.59), and tended to decrease in the control group, from 59.3 +/- 4% to 39.37 +/- 19.43% (P=0.04), although absolute values did not differ significantly between groups. Histological examination revealed a non significant increase in capillary vessels number in all areas in treated group. Paradoxically, arterioles were significantly less in number in all areas of treated dogs. Intramyocardial injection of plasmid VEGF(165), in this canine model of chronic myocardial infarction, resulted in preservation of left ventricular ejection fraction, contrary to the control group where left ventricular ejection fraction showed continuous decline during the experiment. Histological examination, however, was unable to explain completely these results.


Concurrent HIV/AIDS diagnosis increases the risk of short-term HIV-related death among persons newly diagnosed with AIDS, 2002-2005.
Despite the overall effectiveness and availability of highly active antiretroviral therapy (HAART), 1500 HIV-related deaths still occur annually in New York City. In considering ways to further reduce deaths, we assessed the contribution of concurrent HIV/AIDS diagnosis to HIV-related mortality in New York City among persons newly diagnosed with AIDS. We used Cox regression to conduct a retrospective cohort analysis of HIV-related mortality among 15,211 residents age 13+ reported with AIDS to the population-based HIV/AIDS registry between January 2002 and June 2005. Concurrent HIV/AIDS diagnosis was defined as a diagnosis of AIDS occurring within 1 month of initial diagnosis of HIV. HIV-related mortality was 20.2% among persons diagnosed concurrently and 12.2% among those diagnosed nonconcurrently (p < 0.0001). Concurrent HIV/AIDS was associated with more than twice the risk of HIV-related death within the 4 months after diagnosis (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.94-2.65) but no increased risk thereafter (HR 1.12, 95% CI 0.77-1.61). Other significant predictors of death included injection drug use and birth in the Caribbean or Latin America. After 4 years 11.9% of all HIV-related deaths were attributable to a concurrent HIV/AIDS diagnosis. Public health initiatives that facilitate early diagnosis of HIV may reduce HIV-related mortality by giving people the opportunity to initiate care and begin treatment with HAART before immunosuppression places them at risk for opportunistic illness and death.


Efficient γ-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL.
One of the most commonly used methods for in vivo MRS detection of γ-aminobutyric acid (GABA) is the MEGA-point-resolved spectroscopy (MEGA-PRESS) technique. However, accurate quantification of GABA using MEGA-PRESS is complicated by spectral co-editing of macromolecular resonances. In this article, a new pulse sequence is presented which enables GABA editing at 3T with the removal of macromolecule contamination. This sequence combines the conventional MEGA editing scheme with the SPECIAL localisation technique, and is therefore named MEGA-SPECIAL. Simulations and phantom experiments indicate that this new approach provides improved GABA editing efficiency relative to MEGA-PRESS, and in vivo results demonstrate effective removal of macromolecule contamination. In a study of the occipital lobe of five healthy volunteers, the macromolecule-corrected GABA/creatine ratio was found to be 0.093 ± 0.007 (mean ± standard deviation), whereas prior to macromolecule correction, the ratio was found to be 0.173 ± 0.013.