Is clinical cognition binary or continuous?
A dominant theory of clinical reasoning is the so-called "dual processing theory," in which the diagnostic process may proceed through a rapid, unconscious, intuitive process (System 1) or a slow, conceptual, analytical process (System 2). Diagnostic errors are thought to arise primarily from cognitive biases originating in System 1. In this issue, Custers points out that this model is unnecessarily restrictive and that it is more likely that diagnostic tasks may proceed through a variety of mental strategies ranging from "analytical" to "intuitive."The authors of this commentary agree that the notion that System 1 and System 2 processes are somehow in competition and will necessarily lead to different conclusions is unnecessarily restrictive. On the other hand, they argue that there is substantial evidence in support of a dual processing model, and that most objections to dual processing theory can be easily accommodated by simply presuming that both processes operate in concertand that solving any task may rely to varying degrees on both processes.


TrueAllele(®) Genotype Identification on DNA Mixtures Containing up to Five Unknown Contributors.
Computer methods have been developed for mathematically interpreting mixed and low-template DNA. The genotype modeling approach computationally separates out the contributors to a mixture, with uncertainty represented through probability. Comparison of inferred genotypes calculates a likelihood ratio (LR), which measures identification information. This study statistically examined the genotype modeling performance of Cybergenetics TrueAllele(®) computer system. High- and low-template DNA mixtures of known randomized composition containing 2, 3, 4, and 5 contributors were tested. Sensitivity, specificity, and reproducibility were established through LR quantification in each of these eight groups. Covariance analysis found LR behavior to be relatively invariant to DNA amount or contributor number. Analysis of variance found that consistent solutions were produced, once a sufficient number of contributors were considered. This study demonstrates the reliability of TrueAllele interpretation on complex DNA mixtures of representative casework composition. The results can help predict an information outcome for a DNA mixture analysis.


Diagnosis and treatment of intracranial hemorrhage in children with hemophilia.
Intracranial hemorrhage (ICH) is a significant complication for children with hemophilia. Identifying risk factors may allow us to establish clinically relevant guidelines for the diagnosis and management of ICH. The purpose of this review is to nucleate evidence from the available literature on the incidence, risk factors, presentation, treatment, and outcomes of ICH that can be utilized to develop a clinically useful framework for the diagnosis and management of hemophiliac patients with the condition. An electronic MEDLINE and EMBASE literature search was undertaken using the key words 'intracranial hemorrhage and hemophilia' and setting limits as: Last 10 years and Review or Randomized Controlled Trial (RCT) or Clinical Trial, or Practice Guidelines. Following review of all articles using predetermined search words and criteria, 31 were retrieved with sufficient data to address our objectives. An algorithm is presented for the management of children (≥3 years-18 years) with hemophilia and suspected ICH. A standardized approach to ICH may reduce unnecessary exposure to radiation via computed tomography scan in a select group of children. Currently there is limited scientific evidence to recommend a diagnostic and therapeutic algorithm for neonates with hemophilia.


The structured core domain of αB-crystallin can prevent amyloid fibrillation and associated toxicity.
Mammalian small heat-shock proteins (sHSPs) are molecular chaperones that form polydisperse and dynamic complexes with target proteins, serving as a first line of defense in preventing their aggregation into either amorphous deposits or amyloid fibrils. Their apparently broad target specificity makes sHSPs attractive for investigating ways to tackle disorders of protein aggregation. The two most abundant sHSPs in human tissue are αB-crystallin (ABC) and HSP27; here we present high-resolution structures of their core domains (cABC, cHSP27), each in complex with a segment of their respective C-terminal regions. We find that both truncated proteins dimerize, and although this interface is labile in the case of cABC, in cHSP27 the dimer can be cross-linked by an intermonomer disulfide linkage. Using cHSP27 as a template, we have designed an equivalently locked cABC to enable us to investigate the functional role played by oligomerization, disordered N and C termini, subunit exchange, and variable dimer interfaces in ABC. We have assayed the ability of the different forms of ABC to prevent protein aggregation in vitro. Remarkably, we find that cABC has chaperone activity comparable to that of the full-length protein, even when monomer dissociation is restricted through disulfide linkage. Furthermore, cABC is a potent inhibitor of amyloid fibril formation and, by slowing the rate of its aggregation, effectively reduces the toxicity of amyloid-β peptide to cells. Overall we present a small chaperone unit together with its atomic coordinates that potentially enables the rational design of more effective chaperones and amyloid inhibitors.


The complete coding sequence of hepatitis C virus genotype 5a, the predominant genotype in South Africa.
Hepatitis C virus (HCV) genotype 5a is the predominant genotype in southern Africa with a high prevalence amongst infected blood donors from areas in South Africa. We have determined the nucleotide sequence corresponding to the complete coding region of an HCV isolate, EUH1480, previously classified as genotype 5a, from an Edinburgh haemophiliac. The sequence contained a single open reading frame (ORF) coding for a polyprotein of 3014 amino acids. Comparison with the polyprotein sequences from other HCV genotypes, where the ORF varies from 3008 to 3037 amino acids, showed the observed variation in size was due to differences in lengths of the envelope 2 and the nonstructural 5A proteins. The sequence divergence of HCV genotype 5 ranged from 29.4% nucleotide differences (24.91% amino acid differences) compared with genotype 1c to 32.5% nucleotide differences (30.3% amino acid differences) compared with 2a. Phylogenetic analysis of the available full length nucleotide sequences showed EUH1480 to form a branch distinct from the other HCV types, confirming the classification of type 5a as a separate genotype.


Frequency of fragmented QRS on ECG is increased in patients with rheumatoid arthritis without cardiovascular disease: a pilot study.
Myocardial fibrosis causes the fragmentation of QRS complexes (fQRS) on ECGs. We hypothesized that the frequency of fQRS could be more common in patients with rheumatoid arthritis (RA) than in control subjects. A total of 56 patients with RA were compared with 35 age- and gender-matched fibromyalgia subjects for fQRS. The fQRS was defined as the presence of an additional R wave, or notching of the R or S wave, or the presence of fragmentation in 2 contiguous leads corresponding to the territory of a major coronary artery. Patients with bundle block on ECG and cardiovascular disease were excluded. Twenty-one patients (37.5%) in the RA group had fQRS, while two patients in the control group (5.7%) had fQRS (p = 0.001). No differences were found between the groups in terms of age, gender, or drug use. Duration of disease--years (interquartile range [IQR])--was 10 (8) in the fQRS (+) group, while it was 5 (2) in the fQRS (-) group (p < 0.001). Multivariate logistic regression analysis revealed that duration of disease was associated with the presence of fQRS (B = 1.5, odds ratio = 4.5, p = 0.004, 95% confidence interval = 1.6-12.7). We found that fQRS on ECG was more common in patients with RA without cardiovascular disease than in age- and gender-matched control subjects.


Autonomic regulation across phases of the menstrual cycle and sleep stages in women with premenstrual syndrome and healthy controls.
To investigate the influence of menstrual cycle phase and the presence of severe premenstrual symptoms on cardiac autonomic control during sleep, we performed heart rate variability (HRV) analysis during stable non-rapid eye movement (NREM) and REM sleep in 12 women with severe premenstrual syndrome and 14 controls in the mid-follicular, mid-luteal, and late-luteal phases of the menstrual cycle. Heart rate was higher, along with lower high frequency (HF) power, reflecting reduced vagal activity, and a higher ratio of low frequency (LF) to high frequency power, reflecting a shift to sympathetic dominance, in REM sleep compared with NREM sleep in both groups of women. Both groups of women had higher heart rate during NREM and REM sleep in the luteal phase recordings compared with the mid-follicular phase. HF power in REM sleep was lowest in the mid-luteal phase, when progesterone was highest, in both groups of women. The mid-luteal phase reduction in HF power was also evident in NREM sleep in control women but not in women with PMS, suggesting some impact of premenstrual syndrome on autonomic responses to the hormone environment of the mid-luteal phase. In addition, mid-luteal phase progesterone levels correlated positively with HF power and negatively with LF/HF ratio in control women in NREM sleep and with the LF/HF ratio during REM sleep in both groups of women. Our findings suggest the involvement of female reproductive steroids in cardiac autonomic control during sleep in women with and without premenstrual syndrome.


Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression.
Low folate is associated with poorer response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). Folate supplementation in MDD has been studied in other settings with promising results. The objective of this study was to assess the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI. Twenty-two adults (59% female; mean age 45.2 +/- 11.0 years) with DSM-IV MDD, partial or nonresponse to an SSRI after at least 4 weeks of treatment, and a 17-item Hamilton Depression Rating Scale (HAM-D-17) score > or = 12 were enrolled in this 8-week prospective open trial. Exclusion criteria included current use of anticonvulsants or psychotropics other than an SSRI, or B12 deficiency. Leucovorin (folinic acid), which is metabolized to methylfolate, was added to SSRIs at 15-30 mg/day. Folate levels rose from 28 +/- 19 ng/mL to 301 +/- 203 ng/mL (p < 0.001). HAM-D-17 scores among the 16 completers decreased from 19.1 +/- 3.9 to 12.8 +/- 7.0 (p < 0.01). However only 31% of completers and 27% of the intent-to-treat (ITT) sample achieved response (> or = 50% reduction in HAM-D-17 scores), and only 19% of completers and 18% of the ITT sample achieved remission (HAM-D-17 < or = 7). Leucovorin appears to be modestly effective as an adjunct among SSRI-refractory depressed individuals with normal folate levels. The application of leucovorin as an adjunct in the setting of refractory depression deserves further study.


Aging, depot origin, and preadipocyte gene expression.
Fat distribution changes with aging. Inherent changes in fat cell progenitors may contribute because fat cells turn over throughout life. To define mechanisms, gene expression was profiled in preadipocytes cultured from epididymal and perirenal depots of young and old rats. 8.4% of probe sets differed significantly between depots, particularly developmental genes. Only 0.02% differed with aging, despite using less stringent criteria than for comparing depots. Twenty-five genes selected based on fold change with aging were analyzed in preadipocytes from additional young, middle-aged, and old animals by polymerase chain reaction. Thirteen changed significantly with aging, 13 among depots, and 9 with both. Genes involved in inflammation, stress, and differentiation changed with aging, as occurs in fat tissue. Age-related changes were greater in perirenal than epididymal preadipocytes, consistent with larger declines in replication and adipogenesis in perirenal preadipocytes. Thus, age-related changes in preadipocyte gene expression differ among depots, potentially contributing to fat redistribution and dysfunction.


Discovery of adult T-cell leukemia.
Adult T-cell leukemia (ATL) was first reported as a distinct clinical entity in 1977 in Japan. The predominant physical findings are skin lesions, lymphadenopathy and hepatosplenomegaly. The ATL cells are of mature T-helper phenotype and have a characteristic appearance with indented nuclei. There is striking frequent hypercalcemia with increased numbers of osteoclasts. Central to the identification of the disease is a striking geographic clustering in southwestern Japan and the isolation of human T-cell lymphotropic virus type-1 (HTLV-1) from the cell lines of patients. Worldwide epidemiological studies have been made through international collaborations. Several diseases were found to be related to HTLV-1 infection. Moreover, it was noted that an immunodeficiency state may be induced by HTLV-1 infection. In Japan, HTLV-1 carriers have been estimated to be 1.2 million, and more than 700 cases of ATL have been diagnosed each year.


Comparing DADA2 and OTU clustering approaches in studying the bacterial communities of atopic dermatitis.
Introduction. The pathogenesis of atopic dermatitis (AD) is not yet fully understood, but the bacterial composition of AD patients' skin has been shown to have an increased abundance of Staphylococcus aureus. More recently, coagulase-negative Staphylococcus (CoNS) species were shown to be able to inhibit S. aureus, but further studies are required to determine the effects of Staphylococcus community variation in AD.Aim. Here we investigated whether analysing metabarcoding data with the more recently developed DADA2 approach improves metabarcoding analyses compared to the previously used operational taxonomic unit (OTU) clustering, and can be used to study Staphylococcus community dynamics.Methods. The bacterial 16S rRNA region from tape strip samples of the stratum corneum of AD patients (non-lesional skin) and non-AD controls was metabarcoded. We processed metabarcoding data with two different bioinformatic pipelines (an OTU clustering method and DADA2), which were analysed with and without technical replication (sampling strategy).Results. We found that OTU clustering and DADA2 performed well for community-level studies, as demonstrated by the identification of significant differences in the skin bacterial communities associated with AD. However, the OTU clustering approach inflated bacterial richness, which was worsened by not having technical replication. Data processed with DADA2 likely handled sequencing errors more effectively and thereby did not inflate molecular richness.Conclusion. We believe that DADA2 represents an improvement over an OTU clustering approach, and that biological replication rather than technical replication is a more effective use of resources. However, neither OTU clustering nor DADA2 gave insights into Staphylococcus community dynamics, and caution should remain in not overinterpreting the taxonomic assignments at lower taxonomic ranks.


A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia.
RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.


Temperature dependent refractive index and absorption coefficient of congruent lithium niobate crystals in the terahertz range.
Optical rectification with tilted pulse fronts in lithium niobate crystals is one of the most promising methods to generate terahertz (THz) radiation. In order to achieve higher optical-to-THz energy efficiency, it is necessary to cryogenically cool the crystal not only to decrease the linear phonon absorption for the generated THz wave but also to lengthen the effective interaction length between infrared pump pulses and THz waves. However, the refractive index of lithium niobate crystal at lower temperature is not the same as that at room temperature, resulting in the necessity to re-optimize or even re-build the tilted pulse front setup. Here, we performed a temperature dependent measurement of refractive index and absorption coefficient on a 6.0 mol% MgO-doped congruent lithium niobate wafer by using a THz time-domain spectrometer (THz-TDS). When the crystal temperature was decreased from 300 K to 50 K, the refractive index of the crystal in the extraordinary polarization decreased from 5.05 to 4.88 at 0.4 THz, resulting in ~1° change for the tilt angle inside the lithium niobate crystal. The angle of incidence on the grating for the tilted pulse front setup at 1030 nm with demagnification factor of -0.5 needs to be changed by 3°. The absorption coefficient decreased by 60% at 0.4 THz. These results are crucial for designing an optimum tilted pulse front setup based on lithium niobate crystals.


Oral microbiota and implant type membranes.
Candida albicans (Ca), Staphylococcus aureus (Sa), Streptococcus sanguis (Ss), Actinomyces naeslundii (An), Actinomyces odontolyticus (Ao), Porphyromona spp (P spp), Candida glabrata (Cg), Candida krusei (Ck), and Rhodotorula spp (R spp) were tested with equal pieces of biodegradable membranes. Membranes pretreated with saliva or clorhexidine and nontreated control membranes were tested in three different culture media containing 0.1 mL homologous suspension for each strain under study. Incubation was performed at 37 degrees C for 48 hours for aerobiosis and for five days for anaerobiosis. Macroscopy and microscopy were carried out. Membranes were removed, washed, and resuspended. Samples were sonicated, and the supernatant was disseminated on brain heart infusion broth or blood agar. Incubation was repeated, colony-forming unit counts were performed, and statistical analysis was carried out using analysis of variance transforming results to Log10 (x + 1), the highest interaction level was used to calculate standard error. Orthogonal contrast was used to compare the different microorganisms under study. Highest adhesion was found with Ca, Cg, Ck, Sa, and Ss. A sufficient quantity of Actinomyces could not be recovered from the membranes. Results with P spp were poor, confirming lower gram-negative adhesion. Replicate flasks with Ss and Ca were cultivated. Membranes were removed after washing and subjected to scanning electron microscopy, as were untreated control pieces. A cavelike surface was observed. Streptococcus sanguis adhering to the membranes showed extracellular projections. Candida and gram-positive cocci showed great recovery capacity.


Paleopopulation genetics.
Paleopopulation genetics is a new field that focuses on the population genetics of extinct groups and ancestral populations (i.e., populations ancestral to extant groups). With recent advances in DNA sequencing technologies, we now have unprecedented ability to directly assay genetic variation from fossils. This allows us to address issues, such as past population structure, changes in population size, and evolutionary relationships between taxa, at a much greater resolution than can traditional population genetics studies. In this review, we discuss recent developments in this emerging field as well as prospects for the future.


Potential cost savings with terrestrial rabies control.
The cost-benefit of raccoon rabies control strategies such as oral rabies vaccination (ORV) are under evaluation. As an initial quantification of the potential cost savings for a control program, the collection of selected rabies cost data was pilot tested for five counties in New York State (NYS) in a three-year period. Rabies costs reported to NYS from the study counties were computerized and linked to a human rabies exposure database. Consolidated costs by county and year were averaged and compared. Reported rabies-associated costs for all rabies variants totalled $2.1 million, for human rabies postexposure prophylaxes (PEP) (90.9%), animal specimen preparation/shipment to laboratory (4.7%), and pet vaccination clinics (4.4%). The proportion that may be attributed to raccoon rabies control was 37% ($784,529). Average costs associated with the raccoon variant varied across counties from $440 to $1,885 per PEP, $14 to $44 per specimen, and $0.33 to $15 per pet vaccinated. Rabies costs vary widely by county in New York State, and were associated with human population size and methods used by counties to estimate costs. Rabies cost variability must be considered in developing estimates of possible ORV-related cost savings. Costs of PEPs and specimen preparation/shipments, as well as the costs of pet vaccination provided by this study may be valuable for development of more realistic scenarios in economic modelling of ORV costs versus benefits.


Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis.
Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.


Standardised inventories of spiders (Arachnida, Araneae) of Macaronesia II: The native forests and dry habitats of Madeira archipelago (Madeira and Porto Santo islands).
Here we present the data obtained from the samples collected as part of a large research project (MACDIV) which aims at understanding the drivers of spider (Araneae) community assembly in Macaronesian islands. To obtain the data, we applied the sampling protocol COBRA (Conservation Oriented Biodiversity Rapid Assessment), in twelve 50 m x 50 m native forest plots and five dry habitat plots on the island of Madeiraand in 5 dry habitat plots on the island of Porto Santo. Through this publication, we contribute to the knowledge of the arachnofauna of the Madeiran archipelago. From the samples that we collected, we obtained a total of 14,902 specimens, of which 49% were adults (7,263). We identified these specimens to 87 species and 18 morphospecies (undescribed), belonging to 26 families. Species of the family Linyphiidae dominated the samples, with 24 (morpho)species. Out of the 105 recorded (morpho)species, 34 were endemic, 26 native non-endemic, 22 introduced and 23 species of unknown origin. We report seven new records of possibly recently introduced species in the Madeiran archipelago. We also present 21 new records for Madeira island and 32 for Porto Santo (33 for the whole archipelago).


Finding lupus in the ANA haystack.
Diagnosis of SLE in early stages is challenging due to the heterogeneous nature of presenting symptoms and the poor performance metrics of the screening ANA test. Even the more specific double-stranded DNA autoantibody has relatively low predictive value in early disease. A consequence is delayed referral, with the likelihood that some patients have progression of disease prior to specialist evaluation. Tests that might fill this diagnostic gap are therefore needed. The AVISE Connective Tissue Disease Test that uses a multiplex approach to detect autoantibodies and cell-bound complement products has shown utility in distinguishing SLE from other rheumatological conditions. Whether it might be useful in early disease stages to predict progression is addressed in a recent study by Liang and colleagues, who tested clinic patients who had non-specific findings with the objective of determining whether AVISE could predict onset of SLE. While this test provided more useful prognostic information than other available diagnostics, it had relatively low sensitivity, suggesting that significant numbers of patients with preclinical SLE would be missed by this screening. The need remains for development of diagnostics with robust sensitivity and specificity in early disease that would also deliver prognostic information about risk for SLE. Such tests would have great value as a tool for primary providers to more efficiently triage ANA-positive patients for appropriate specialty evaluation.


Injury epidemiology of tennis players at the 2011-2016 Australian Open Grand Slam.
To examine the epidemiology and in-event treatment frequency of injury at the 2011-2016 Australian Open tournaments. Injury incidence was defined as a medical consultation by a tournament physician and in-event treatment frequency as the mean total number of follow-up medical/physiotherapy consultations (2013-2016 tournaments only). Data were collated by sex, injury region and type and reported as frequencies per 10 000 game exposures. Incidence rate s± 95% CI and rate ratios were used to test effects for injury, sex and year. Female players experienced more injuries than male players (201.7 vs 148.6). The shoulder (5.1±1.1 injuries per year), foot (3.2±1.1), wrist (3.1±1.5) and knee (3.1±1.1) were the most commonly injured regions among females. Knee (3.5±1.6), ankle (2.3±1.3) and thigh (2.3±1.5) were the most prevalent male injuries. Upper arm injuries and in-event treatment frequency increased by ≥2.4 times in both sexes over the 5-year period. Muscle injuries were most frequent. There was a greater than twofold increase in men and women with stress fractures over the 5-year period. The torso region, including the neck, thoracic spine, trunk and abdominal, lumbar spine, hip and groin, pelvis/buttock, attracted high in-event treatment frequencies in both sexes. Investigation of injury at the Australian Open suggests that females are more commonly injured than males. Upper and lower extremity injuries affected females while lower limb injuries were more prominent in males. There was an increasing rate of in-event treatments of upper limb and torso injuries as well as stress fractures during the observation period.


White-matter relaxation time and myelin water fraction differences in young adults with autism.
Increasing evidence suggests that autism is associated with abnormal white-matter (WM) anatomy and impaired brain 'connectivity'. While myelin plays a critical role in synchronized brain communication, its aetiological role in autistic symptoms has only been indirectly addressed by WM volumetric, relaxometry and diffusion tensor imaging studies. A potentially more specific measure of myelin content, termed myelin water fraction (MWF), could provide improved sensitivity to myelin alteration in autism. We performed a cross-sectional imaging study that compared 14 individuals with autism and 14 age- and IQ-matched controls. T 1 relaxation times (T 1), T 2 relaxation times (T 2) and MWF values were compared between autistic subjects, diagnosed using the Autism Diagnostic Interview - Revised (ADI-R), with current symptoms assessed using the Autism Diagnostic Observation Schedule (ADOS) and typical healthy controls. Correlations between T 1, T 2 and MWF values with clinical measures [ADI-R, ADOS, and the Autism Quotient (AQ)] were also assessed. Individuals with autism showed widespread WM T 1 and MWF differences compared to typical controls. Within autistic individuals, worse current social interaction skill as measured by the ADOS was related to reduced MWF although not T 1. No significant differences or correlations with symptoms were observed with respect to T 2. Autistic individuals have significantly lower global MWF and higher T 1, suggesting widespread alteration in tissue microstructure and biochemistry. Areas of difference, including thalamic projections, cerebellum and cingulum, have previously been implicated in the disorder; however, this is the first study to specifically indicate myelin alteration in these regions.


GATA2 is associated with familial early-onset coronary artery disease.
The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance.


Parameters of thromboelastography in healthy newborns.
Thromboelastography (TEG) aids in monitoring a patient's global hemostatic system by measuring the rate of clot formation, clot strength, and stability. The usefulness of TEG in pediatric settings, especially with neonates, is limited owing to a lack of neonatal reference values. In this study, neonatal TEG reference intervals were developed and results correlated with other coagulation test parameters. Samples were from women who delivered a neonate after at least 34 weeks of gestation in normal pregnancies. From the recovered placenta, cord blood from the umbilical vein or artery was collected within 30 minutes after delivery and tested. Neonatal TEG reaction time (time clot formation begins), clot firmness (shear elastic modulus strength), and platelet function analysis closure times were significantly lower than those in adult ranges (P< .001). When compared with the values for children, TEG reaction time, angle, coagulation index, clot firmness value, and clot kinetics (time from clot formation to time amplitude reaches 20 mm) were significantly different (P< .001) among neonates. TEG can be used to interpret the data for newborns by using reference values obtained in the present study.


Measuring diabetic neuropathy. Assessment and comparison of clinical examination and quantitative sensory testing.
The need for a standardized and valid means of assessing diabetic neuropathy has been increasingly recognized. To identify potential components of such an assessment, interobserver variation (neurologist and internist) of a standard neurologic examination and the comparability of this examination with vibratory and thermal sensitivity testing was studied. The study population comprised the first 100 participants in a neuropathy substudy of 25- to 34-yr-old subjects with insulin-dependent diabetes mellitus taking part in a cohort follow-up study. Symptoms of dysesthesias, paresthesias, and burning, aching, or stabbing pain revealed good interobserver agreement. Signs of neuropathy, more prevalent in the great toe than index finger, showed poor interobserver agreement for vibration, but fair interobserver agreement for touch and pinprick. Mean quantitative sensory thresholds differed significantly by clinical category of abnormal vibratory and pinprick sensations. Threshold testing showed twice the prevalence of abnormality compared with clinical examination. It is concluded that components of the clinical examination can be identified that, along with quantitative sensory-threshold testing, may provide a satisfactory core assessment for use both in epidemiologic studies and incorporation into more in-depth protocols required for clinical research and practice. The clinical relevance of the greater prevalence of abnormalities on threshold testing will be established by long-term follow-up.


ELISA testing for common food antigens in four dry dog foods used in dietary elimination trials.
This study evaluated four over the counter venison dry dog foods available from one on-line retail vendor for potential contamination with common known food allergens: soy, poultry or beef. An amplified, double sandwich type enzyme linked immunosorbent assay (ELISA) test of soy, poultry and beef proteins were performed by an independent accredited food laboratory. The ELISA test for poultry protein was found to be unreliable when testing in dry dog foods because false negatives occurred. ELISA testing of control diets for both soy and beef proteins performed as expected and could be useful in antigen testing in dry dog foods. Three of the four over the counter (OTC) venison canine dry foods with no soy products named in the ingredient list were ELISA positive for soy; additionally one OTC diet tested positive for beef protein with no beef products listed as an ingredient list. One OTC venison diet was not found to be positive for soy, poultry or beef proteins. However, none of the four OTC venison diets could be considered suitable for a diagnostic elimination trial as they all contained common pet food proteins, some of which were readily identifiable on the label and some that were only detected by ELISA. Therefore, if the four OTC venison products selected in this study are representative of OTC products in general, then the use of OTC venison dry dog foods should not be used during elimination trials in suspected food allergy patients.


Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study.
Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Recurrent GBM patients with < or = 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.


Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.
RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.


Gene expression patterns associated with p53 status in breast cancer.
Breast cancer subtypes identified in genomic studies have different underlying genetic defects. Mutations in the tumor suppressor p53 occur more frequently in estrogen receptor (ER) negative, basal-like and HER2-amplified tumors than in luminal, ER positive tumors. Thus, because p53 mutation status is tightly linked to other characteristics of prognostic importance, it is difficult to identify p53's independent prognostic effects. The relation between p53 status and subtype can be better studied by combining data from primary tumors with data from isogenic cell line pairs (with and without p53 function). The p53-dependent gene expression signatures of four cell lines (MCF-7, ZR-75-1, and two immortalized human mammary epithelial cell lines) were identified by comparing p53-RNAi transduced cell lines to their parent cell lines. Cell lines were treated with vehicle only or doxorubicin to identify p53 responses in both non-induced and induced states. The cell line signatures were compared with p53-mutation associated genes in breast tumors. Each cell line displayed distinct patterns of p53-dependent gene expression, but cell type specific (basal vs. luminal) commonalities were evident. Further, a common gene expression signature associated with p53 loss across all four cell lines was identified. This signature showed overlap with the signature of p53 loss/mutation status in primary breast tumors. Moreover, the common cell-line tumor signature excluded genes that were breast cancer subtype-associated, but not downstream of p53. To validate the biological relevance of the common signature, we demonstrated that this gene set predicted relapse-free, disease-specific, and overall survival in independent test data. In the presence of breast cancer heterogeneity, experimental and biologically-based methods for assessing gene expression in relation to p53 status provide prognostic and biologically-relevant gene lists. Our biologically-based refinements excluded genes that were associated with subtype but not downstream of p53 signaling, and identified a signature for p53 loss that is shared across breast cancer subtypes.


The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study.
Few studies have approached the subject of polypharmacotherapy systematically. This retrospective review of 178 patients with refractory bipolar disorder or unipolar depression (Research Diagnostic Criteria or DSM-III-R criteria) discharged from the National Institute of Mental Health (NIMH) Biological Psychiatry Branch between 1974 and 1996 was conducted to assess the degree and efficacy of "add-on" pharmacotherapy. Following completion of formal structured blinded research protocols, patients entered a treatment phase (often again on a blind basis) in which all agents available in the community could be utilized. Each patient's retrospective life chart and all prospective double-blind nurse- and self-rated NIMH data were reviewed. The overall degree of improvement at discharge was assessed by rating on the Clinical Global Impressions scale (CGI) as modified for bipolar illness (CGI-BP). A 78% improvement rate (moderate or marked on the CGI) was achieved at the time of discharge. There was a significant relationship between number of medications utilized at discharge as a function of discharge date (r = 0.45, p < .0001). The percentages of patients discharged on treatment with 3 or more medications were 3.3% (1974-1979), 9.3% (1980-1984), 34.9% (1985-1989), and 43.8% (1990-1995). No correlation was found between polypharmacy and age (r = -0.03, p = .66). Patients more recently discharged from the NIMH had an earlier age at illness onset, more lifetime weeks depressed, and a higher rate of rapid cycling than patients in the earlier cohorts. Increasing numbers of medications in more recent NIMH cohorts were required to achieve the same degree of improvement at hospital discharge. More systematic approaches to the complex regimens required for treatment of patients with refractory mood disorder are clearly needed.


Environmental asbestos exposure and mesothelioma cases in Bari, Apulia region, southern Italy: a national interest site for land reclamation.
Asbestos is an environmental carcinogen, and asbestos-related diseases are a global-scale public health issue. We report three cases (one male and two females) of pleural malignant mesothelioma (PMM) caused by environmental asbestos exposure reported by the Apulia Regional Operating Centre (COR) to the National Mesothelioma Registry (ReNaM). The patients revealed no history of asbestos exposure even after detailed assessment. The environmental (neighborhood) asbestos exposure for each of the three cases was due to both the residential history of the subjects and their workplace, close to a military barracks, at a distance of between 45 and 100 m. Moreover, in addition to this new source of pollution, an asbestos cement factory was located in the urban area of Bari municipality, in the Apulia region, southern Italy. Environmental-residential/neighborhood asbestos exposure in the city of Bari, a contaminated area classified as a site of national concern for land reclamation, is discussed also with reference to the military barracks.


Hierarchical generative biclustering for microRNA expression analysis.
Clustering methods are a useful and common first step in gene expression studies, but the results may be hard to interpret. We bring in explicitly an indicator of which genes tie each cluster, changing the setup to biclustering. Furthermore, we make the indicators hierarchical, resulting in a hierarchy of progressively more specific biclusters. A non-parametric Bayesian formulation makes the model rigorous yet flexible and computations feasible. The model can additionally be used in information retrieval for relating relevant samples. We show that the model outperforms four other biclustering procedures on a large miRNA data set. We also demonstrate the model's added interpretability and information retrieval capability in a case study. Software is publicly available at http://research.ics.tkk.fi/mi/software/treebic/.


White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study.
Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14-65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p < 0.0033) and reached peak maturation younger in patients (27 years) compared to controls (33 years). Additionally, three distinct patterns of neuropathology emerged when investigating white matter fiber tracts in patients: (1) developmental abnormalities in limbic fibers, (2) accelerated aging and abnormal maturation in long-range association fibers, (3) severe developmental abnormalities and accelerated aging in callosal fibers. Our findings strongly suggest that white matter in schizophrenia is affected across entire stages of the disease. Perhaps most strikingly, we show that white matter changes in schizophrenia involve dynamic interactions between neuropathological processes in a tract-specific manner.


Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients.
Kidney transplantation is the therapy of choice for many patients with end-stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long-term survival. The place of target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006. To evaluate the short and long-term benefits and harms of TOR-I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients. We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. All randomised controlled trials (RCTs) and quasi-RCTs in which drug regimens, containing TOR-I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report. Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. The certainty of the evidence was assessed using GRADE MAIN RESULTS: Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant. Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies. Compared with CNI and antimetabolite, TOR-I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy-proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence). Compared with antimetabolites and CNI, TOR-I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy-proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence). Lower dose TOR-I and standard dose CNI compared with higher dose TOR-I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy-proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence). Lower dose of TOR-I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy-proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence). It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow-up. In studies with follow-up to three years, TOR-I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR-I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR-I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR-I regimens. While further new studies are not required, longer-term follow-up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR-I, are in maintaining kidney transplant function and survival beyond three years.


Fibronectin mediates Treponema pallidum cytadherence through recognition of fibronectin cell-binding domain.
The specificity of the interaction between Treponema pallidum and fibronectin was demonstrated. Treatment of host cells with only antifibronectin sera and not anticollagen or antilaminin sera, inhibited treponemal cytadsorption. Incubation of fibronectin-coated coverslips with monoclonal antibody to the cell-binding domain of fibronectin reduced treponemal attachment to the same extent as antifibronectin serum. Both iodinated fibronectin and iodinated cell-binding domain bound to T. pallidum in a saturable manner. Specificity of the T. pallidum association with the cell-binding domain was the most effective inhibitor of the binding of either radioiodinated cell-binding domain or fibronectin to T. pallidum. Scatchard analysis gave Kd on the order of 10(-7) M for both cell-binding domain and fibronectin binding to T. pallidum, consistent with the high affinity interaction of these organisms with host cell surfaces. Finally, the same level of attachment of treponemes was achieved on coverslips coated with cell-binding domain as that observed for organisms incubated with fibronectin, indicating that the cell-binding domain polypeptide is functionally identical to fibronectin in mediating T. pallidum adherence.


A Mathematician's Odyssey.
In this overview of my research, I have aimed to give the background as to how I came to be involved in my various areas of interest, with an emphasis on the early phases of my career, which largely determined my future directions. I had the enormous good fortune to have worked under two of the most outstanding scientists of the twentieth century, R.A. Fisher and Joshua Lederberg. From mathematics and statistics, I went to population genetics and the early use of computers for modeling and simulation. Molecular biology took me into the laboratory and eventually to somatic cell genetics and human gene mapping. One chance encounter led me into the HLA field and another led me into research on cancer, especially colorectal cancer. On the way, I became a champion of the Human Genome Project and of the need for scientists to help promote the public understanding of science.


Patients of an interdisciplinary cancer treatment center: use of, knowledge about, and demand for CAM treatment options.
to assess the use of, knowledge about, and the demand for information concerning complementary and alternative medicine (CAM) in cancer patients. A cross-sectional survey was performed on consecutive patients visiting the outpatient tumor treatment center of a university hospital at Munich, Germany. The authors used a questionnaire with questions on sociodemographics, tumor diagnosis and treatment, current symptoms, previous use of CAM, and expectations and attitudes with respect to CAM. 52% used at least 1 CAM method, 24% did not use CAM but asked for consultation, and 24% neither used CAM nor were interested; 59% rated CAM treatment as personally important; 76% and 34% described themselves as well informed about conventional treatment and CAM, respectively. Current CAM use was associated with higher degrees of information and subjective importance, and not suffering from lymphatic cancer and metastases. CAM is a relevant topic for the care of cancer patients.


Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a french area with very high whole-cell vaccine coverage.
Although France has had a vaccination program for 40 years, since 1990, an increase in whooping cough cases with parent-infant transmission has been observed. This study prospectively assessed the frequency of Bordetella pertussis infection in adults who consulted general practitioners for a persistent cough without an evident diagnosis. Among 217 patients, 70 (32%) confirmed whooping cough cases were identified. One case was culture positive, 36 were polymerase chain reaction positive, and 40 had increases or decreases of > or =2-fold in anti-pertussis toxin IgG titer between serum samples collected during the acute and convalescent phases. The median duration of cough in confirmed cases was 49 days (range, 13-123 days). Of the patients, 60% reported vaccination, and 33% reported whooping cough in infancy. Pertussis should be considered for diagnosis of acute and chronic cough in adults. Future studies should evaluate the public health interest of booster doses of pertussis vaccine in adults.


All-cause mortality among breast cancer patients in a screening trial: support for breast cancer mortality as an end point.
It has recently been suggested that all-cause mortality is a more appropriate end point than disease specific mortality in cancer screening trials, and that disease specific mortality is biased in favour of screening. This suggestion is based partly on supposed inconsistencies between all-cause mortality results and disease specific results in cancer screening trials, and alleged increases in deaths from causes other than breast cancer among breast cancer cases diagnosed among women invited to screening. We used data from the Swedish Two-County Trial of mammographic screening for breast cancer, in which 77 080 women were randomised to an invitation to screening and 55 985 to no invitation. We estimated relative risks (RRs) (invited v control) of death from breast cancer, death from other causes within the breast cancer cases, and death from all causes within the breast cancer cases. RRs were adjusted for age and took account of the longer follow up of breast cancer cases in the invited group due to lead time. There was a significant 31% reduction in breast cancer mortality in the invited group (RR 0.69, 95% confidence interval (CI) 0.58-0.80; p<0.001). There was no significant increase in deaths from other causes among breast cancer cases in the invited group (RR 1.12, 95% CI 0.96-1.31; p=0.14). A significant 19% reduction in deaths from all causes was observed among breast cancer cases in the group invited to screening (RR 0.81, 95% CI 0.72-0.90; p<0.001). A more conservative estimation gave a significant 13% reduction (RR 0.87, 95% CI 0.78-0.97; p=0.01). These findings are consistent with the magnitude of the reduction in breast cancer mortality. Invitation to screening was associated with a reduction in deaths from all causes among breast cancer cases, consistent with high participation rates in screening. There is no significant evidence of bias in cause of death classification in the Two-County Trial, and as breast cancer mortality is the targeted clinical outcome in breast cancer screening, it is the appropriate end point in a breast cancer screening trial. All-cause mortality is a poor and inefficient surrogate for breast cancer mortality.


Increased infectivity of HIV type 1 particles bound to cell surface and solid-phase ICAM-1 and VCAM-1 through acquired adhesion molecules LFA-1 and VLA-4.
HIV-1 incorporates a variety of host membrane proteins during budding. We have previously shown that adhesion molecules are acquired by the virus in their activated or functional states. Our studies and those of others indicate that adhesion molecules can have profound effects on virus infectivity and its resistance to neutralization by antiviral antibodies. In this study we have examined the effect on infectivity of immobilization or margination of HIV-1 through acquired integrins LFA-1 and VLA-4 onto nonsusceptible cells and solid-phase adhesion ligands (ICAM-1 and VCAM-1, respectively). LFA-1- and VLA-4-mediated HIV-1 binding was supported by ICAM-1 and VCAM-1 immunoglobulin Fc chimeras, respectively. Integrin-mediated HIV-1 binding was also supported by 293 cells transfected with ICAM-1. In both cases the specificity of binding was confirmed with the appropriate blocking monoclonal antibodies or soluble adhesion ligands. We used a sensitive single-cycle infection assay based on a cell line expressing an LTR-luciferase cDNA construct to compare the infectivity of bound virus with that of free virus. Our results show that the binding of HIV-1 to nonsusceptible cells or immobilized adhesion ligands through acquired integrins can increase its infectivity by as much as two orders of magnitude. These results have implications for in vivo dissemination and transmission of HIV-1 and may also explain the high level of virus replication seen in solid lymphoid organs.


The EnzymeTracker: an open-source laboratory information management system for sample tracking.
In many laboratories, researchers store experimental data on their own workstation using spreadsheets. However, this approach poses a number of problems, ranging from sharing issues to inefficient data-mining. Standard spreadsheets are also error-prone, as data do not undergo any validation process. To overcome spreadsheets inherent limitations, a number of proprietary systems have been developed, which laboratories need to pay expensive license fees for. Those costs are usually prohibitive for most laboratories and prevent scientists from benefiting from more sophisticated data management systems. In this paper, we propose the EnzymeTracker, a web-based laboratory information management system for sample tracking, as an open-source and flexible alternative that aims at facilitating entry, mining and sharing of experimental biological data. The EnzymeTracker features online spreadsheets and tools for monitoring numerous experiments conducted by several collaborators to identify and characterize samples. It also provides libraries of shared data such as protocols, and administration tools for data access control using OpenID and user/team management. Our system relies on a database management system for efficient data indexing and management and a user-friendly AJAX interface that can be accessed over the Internet. The EnzymeTracker facilitates data entry by dynamically suggesting entries and providing smart data-mining tools to effectively retrieve data. Our system features a number of tools to visualize and annotate experimental data, and export highly customizable reports. It also supports QR matrix barcoding to facilitate sample tracking. The EnzymeTracker was designed to be easy to use and offers many benefits over spreadsheets, thus presenting the characteristics required to facilitate acceptance by the scientific community. It has been successfully used for 20 months on a daily basis by over 50 scientists. The EnzymeTracker is freely available online at http://cubique.fungalgenomics.ca/enzymedb/index.html under the GNU GPLv3 license.


Growth patterns and conformation in broilers: influence of genotype and management on isometry of growth.
Log-linear regression equations of log-transformed weekly broiler growth data and allometric growth equations (in actual measure) were fitted with body weight as the predictor variable and shank length, keel length, breast width, and thigh width as response variables. Data were obtained on two commercial broiler genotypes (G1 and G2) reared on litter floor and in wire cages. Growth of each of the structural body components relative to growth of the body as a whole during a 12-wk growth period was similar in both cage and floor-reared groups. Analysis of the 12-wk pooled data from both cage and floor groups indicated the occurrence of isometric growth of the shank and breast in G1 and of the breast only in G2 and allometric growth of the thigh and keel in both genotypes. When starter and finisher growth phases were considered separately, data showed growth patterns generally similar to those of the different body parameters in the 12-wk period. This suggests that characterization of individuals on the basis of relative growth response for selection purposes can be done equally accurately during any phase of growth.


Bacillus thuringiensis var. israelensis delta-endotoxin. Cloning and expression of the toxin in sporogenic and asporogenic strains of Bacillus subtilis.
A plasmid-borne gene from Bacillus thuringiensis var. israelensis encoding a 27,340 Mr insecticidal delta-endotoxin has been cloned on a bifunctional multicopy plasmid in a wild-type sporogenic strain and two asporogenic mutants of Bacillus subtilis. The delta-endotoxin gene is expressed at a low level during vegetative growth in all three strains, but the synthesis of the toxin increases markedly during the third hour of stationary phase for both the sporogenic strain and an asporogenic mutant containing the OJ lesion. However, in a stage OA mutant, this increase in delta-endotoxin synthesis is not observed. In both the wild-type sporogenic B. subtilis and the asporogenic OJ strain, phase-bright inclusions, resembling the israelensis crystal in appearance, are visible during late stationary phase. The insoluble inclusions from the B. subtilis transformants, consisting solely of the 27,340 Mr polypeptide, were purified by density gradient centrifugation and found to be extremely toxic to Aedes aegypti larvae. After solubilization in alkaline buffer, this polypeptide was also shown to be haemolytic for human erythrocytes and to lyse Aedes albopictus cells with the same LC50 value as native israelensis delta-endotoxin crystals. During stationary phase, novel mRNA species appear in both the wild-type strain and the OJ mutant, but not in the OA mutant, and these appear to be the major gene-specific transcripts. Transcriptional mapping of delta-endotoxin-specific mRNA has shown that the same region of initiation is used at a relatively low level in all three strains during vegetative growth.


Role of myosin-II phosphorylation in V12Cdc42-mediated disruption of Drosophila cellularization.
Microinjection of constitutively active Cdc42 (V12Cdc42) disrupts the actomyosin cytoskeleton during cellularization (Crawford et al., Dev. Biol., 204, 151-164 (1998)). The p21-activated kinase (PAK) family of Ser/Thr kinases are effectors of GTP-bound forms of the small GTPases, Cdc42 and Rac. Drosophila PAK, which colocalizes with actin and myosin-II during cellularization, concentrates at sites of V12Cdc42-induced actomyosin disruption. In vitro biochemical analyses demonstrate that PAK phosphorylates the regulatory light chain (RLC) of Drosophila nonmuscle myosin-II on Ser21, a site known to activate myosin-II function. Although activated PAK does not disrupt the actomyosin cytoskeleton, it induces increased levels of Ser21 phosphorylated RLC. These findings suggest that increased levels of RLC phosphorylation do not contribute to disruption of the actomyosin hexagonal array.


The small molecule NSM00191 specifically represses the TNF-α/NF-кB axis in foot and ankle rheumatoid arthritis.
The activation of TNF-α/NF-кB signaling is involved in the regulation of a wide range of biological processes, such as cell proliferation, differentiation and apoptosis, eventually causing a number of diseases, such as cancer and inflammation. Here, we found that TNF-α/NF-кB signaling was activated in a large number of blood samples taken from foot and ankle rheumatoid arthritis (RA) patients. By applying a microarray assay to the human synovial sarcoma cell line SW982 and the human fibroblast-like synoviocyte cell line HFLS-RA, as well as in their corresponding p65 knockdown and -overexpressing cells, we identified and verified the activation of many p65 targets, including cytokines (e.g., TNF-α and IL-6), chemokines (e.g., MCP-1 and PANTES), protein receptors (e.g., CD-40 and MHC-1), and inducible enzymes (e.g., COX2). In addition, we subjected microRNAs from foot and ankle RA patients to a microRNA-specific microarray and found that miR-7-5p targeted the 3'-UTR of p65, negatively regulating its expression. By applying an in vitro screen to identify small molecules that specifically inhibited the interaction between TRADD and TNFR2, we found that NSM00191 strongly inhibited the activation of TNF-α/NF-кB signaling in vitro and in vivo, causing the downregulation of NF-кB targets and the decrease of arthritis scores. Collectively, our findings shed new light on the regulation of the TNF-α/NF-кB axis and might provide a new avenue for RA treatment.


[Economic evaluation of healthcare technologies: an introduction for physicians].
Economic evaluation of healthcare interventions is becoming increasingly important and are seen by decision makers as a useful tool on how best to allocate scarce resources efficiently by maximising the health of the population. It is therefore important that health care professionals understand the fundamentals of an economic analysis so that they can understand, evaluate and critically appraise published economic evaluations. This article presents an introduction to the economic analysis of health care interventions and describes the basic concepts of an economic evaluation. The authors introduce the concept of efficiency to defend the use of economic tools to guide or help decisions in healthcare. The article presents the cost-effectiveness plane as a useful instrument when presenting the results of an economic evaluation, and summarises the main ways on how costs and outcomes are measured. To help readers understand the concepts presented in this introduction, we draw on published examples of economic analyses undertaken in the field of stroke.


Highlights from the ecancer Future Horizons in Lung Cancer conference, 1-2 September 2016: Focusing on the future of treatment for NSCLC and SCLC.
The 'Future Horizons in Lung Cancer' meeting was designed to bring leading scientists together alongside clinicians to discuss the most recent advances in lung cancer pathophysiology and treatment. The aim was to take those attending the event on a journey through decades of lung cancer research and understanding, with topics spanning from screening and surgical care to "omics" approaches for drug target and biomarker discovery. There were also several talks describing the role of radiotherapy in lung cancer and advancements in imaging techniques, aiding surgeons in their attempts to resect early lesions. Current standards of care were both challenged and celebrated, while new and innovative immunotherapies also came into the spotlight. The meeting, held over two days, attracted a high calibre of speakers and delegates from across the globe. There were 10 sessions in total focusing on the latest therapeutic advances and predictions for the future of lung cancer treatment. Highlights included a key note lecture from Dr Frances Shepherd packing 40 years of lung cancer research into a 40-minute presentation. Heated debates were had regarding the validity of maintenance therapy and immune checkpoint inhibitors that have taken the research community by storm. The latest developments in imaging, surgery, systemic and radiotherapy were presented over 10 sessions of exciting, innovative and stimulating presentations, leaving the audience lively yet pensive.


Regularization of deep neural networks with spectral dropout.
The big breakthrough on the ImageNet challenge in 2012 was partially due to the 'Dropout' technique used to avoid overfitting. Here, we introduce a new approach called 'Spectral Dropout' to improve the generalization ability of deep neural networks. We cast the proposed approach in the form of regular Convolutional Neural Network (CNN) weight layers using a decorrelation transform with fixed basis functions. Our spectral dropout method prevents overfitting by eliminating weak and 'noisy' Fourier domain coefficients of the neural network activations, leading to remarkably better results than the current regularization methods. Furthermore, the proposed is very efficient due to the fixed basis functions used for spectral transformation. In particular, compared to Dropout and Drop-Connect, our method significantly speeds up the network convergence rate during the training process (roughly ×2), with considerably higher neuron pruning rates (an increase of ∼30%). We demonstrate that the spectral dropout can also be used in conjunction with other regularization approaches resulting in additional performance gains.


Single-Cell Multi-omics: An Engine for New Quantitative Models of Gene Regulation.
Cells in a multicellular organism fulfill specific functions by enacting cell-type-specific programs of gene regulation. Single-cell RNA sequencing technologies have provided a transformative view of cell-type-specific gene expression, the output of cell-type-specific gene regulatory programs. This review discusses new single-cell genomic technologies that complement single-cell RNA sequencing by providing additional readouts of cellular state beyond the transcriptome. We highlight regression models as a simple yet powerful approach to relate gene expression to other aspects of cellular state, and in doing so, gain insights into the biochemical mechanisms that are necessary to produce a given gene expression output.


Phosphorescence monitoring of hypoxic microenvironment in solid-tumors to evaluate chemotherapeutic effects using the hypoxia-sensitive iridium (III) coordination compound.
To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo. A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti-angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results. BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice. We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis.


One-year outcomes of infants born with congenital diaphragmatic hernia: a national population cohort study.
To report outcomes to 1 year, in infants born with congenital diaphragmatic hernia (CDH), explore factors associated with infant mortality and examine the relationship between surgical techniques and postoperative morbidity. Prospective national population cohort study. Paediatric surgical centres in the UK and Ireland. Data were collected to 1 year for infants with CDH live-born between 1 April 2009 to 30 September 2010. Factors associated with infant mortality are explored using logistic regression. Postoperative morbidity following patch versus primary closure, minimally invasive versus open surgery and biological versus synthetic patch material is described. Data are presented as n (%) and median (IQR). Overall known survival to 1 year was 75%, 95% CI 68% to 81% (138/184) and postoperative survival 93%, 95% CI 88% to 97% (138/148). Female sex, antenatal diagnosis, use of vasodilators or inotropes, being small for gestational age, patch repair and use of surfactant were all associated with infant death. Infants undergoing patch repair had a high incidence of postoperative chylothorax (11/54 vs 2/96 in infants undergoing primary closure) and a long length of hospital stay (41 days, IQR 24-68 vs 16 days, IQR 10-25 in primary closure group). Infants managed with synthetic patch material had a high incidence of chylothorax (11/34 vs 0/19 with biological patch). The majority of infant deaths in babies born with CDH occur before surgical correction. Female sex, being born small for gestational age, surfactant use, patch repair and receipt of cardiovascular support were associated with a higher risk of death. The optimum surgical approach, timing of operation and choice of patch material to achieve lowest morbidity warrants further evaluation.


Characterization of monoclonal antibodies to avian Escherichia coli Iss.
Colibacillosis accounts for annual multimillion dollar losses in the poultry industry, and control of this disease is hampered by limited understanding of the virulence mechanisms used by avian pathogenic Escherichia coli (APEC). Previous work in our laboratory has found that the presence of the increased serum survival gene (iss) is strongly associated with APEC but not commensal E. coli, making iss and the protein it encodes (Iss) candidate targets of colibacillosis-control procedures. Previously, we produced monoclonal antibodies (MAbs) against Iss to be used as a reagent in studies of APEC virulence and colibacillosis pathogenesis. Unfortunately, the utility of these MAbs was limited because these MAbs exhibited nonspecific binding. It was thought that the lack of specificity might be related to the fact that these MAbs were of the immunoglobulin M (IgM) isotype. In the present study, new MAbs were produced using a different immunization strategy in an effort to generate MAbs of a different isotype. Also, because Iss bears strong similarity to Bor, a lambda-derived protein that occurs commonly among E. coli, MAbs were assessed for their ability to distinguish Iss and Bor. For these studies, the bor gene from an APEC isolate was cloned into an expression vector. The fusion protein expressed from this construct was used to assess the potential of the anti-Iss MAbs produced in the past and present studies to distinguish Bor and Iss. The MAbs produced in this study were of the IgG1 isotype, which appeared to bind more specifically to Iss than previously generated antibodies in certain immunologic procedures. These results suggested that the MAbs generated in this study might prove superior to the previous MAbs as a reagent for study of APEC. However, both MAbs recognized recombinant Iss and Bor, suggesting that any results obtained using anti-Iss MAbs would need to be interpreted with this cross-reactivity in mind.


EJE PRIZE 2017: Hypothalamic AMPK: a golden target against obesity?
AMP-activated protein kinase (AMPK) is a cellular gauge that is activated under conditions, such as low energy, increasing energy production and reducing energy waste. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. Current evidence links hypothalamic AMPK with feeding, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), as well as muscle metabolism, hepatic function and glucose homeostasis. The relevance of these data is interesting from a therapeutic point of view as several agents with potential anti-obesity and/or antidiabetic effects, some currently in clinical use, such as nicotine, metformin and liraglutide are known to act through AMPK, either peripherally or centrally. Furthermore, the orexigenic and weight-gaining effects of the worldwide use of antipsychotic drugs (APDs), such as olanzapine, are also mediated by hypothalamic AMPK. Overall, this evidence makes hypothalamic AMPK signaling an interesting target for the drug development, with its potential for controlling both sides of the energy balance equation, namely feeding and energy expenditure through defined metabolic pathways.


Sequences expressed sex-specifically in Drosophila melanogaster adults.
To obtain probes for sex-specific gene regulation during development in D. melanogaster, sequences expressed sex-specifically in adult flies were isolated by differential cDNA hybridization screens of a genomic library. Ten clones define new sex-specifically expressed genes. The remaining three isolates correspond to previously cloned genes encoding female-specific yolk proteins and chorion proteins. The pattern of expression of these genes in sex determination mutants and in germlineless flies, as well as their tissue specificities, permitted us to distinguish transcripts whose expression is dependent on correct sexual development of the soma or the germline. One of the female transcripts is expressed in nurse cells and oocytes. Five of the male-specific sequences are expressed in the testis during spermatogenesis: the remaining one is expressed in the soma. Experiments using a temperature-sensitive allele of tra-2 show that the presence of this male-specific transcript, found only in the adult paragonia, is not affected by temperature shift of X/X; tra-2ts2 adults. This is in contrast to yolk protein genes, which require tra-2 function in the adult for their expression in the female fat body.


Back-seeding of higher order gain processes in picosecond supercontinuum generation.
In photonic crystal fibers with closely spaced zero dispersion wavelengths it is possible to have two pairs of four-wave mixing (FWM) gain peaks. Here, we demonstrate both numerically and experimentally how the outer four-wave mixing gain peaks can be used to produce a strong amplification peak in a picosecond supercontinuum. The method involves feeding back part of the output light of a SC source and time matching it with the pump light. In this way it is possible to produce a gain of over 20 dB near the FWM gain wavelengths.


Frequency generation within the forbidden band gap: all optical Rabi-like splitting in photonic crystals and microcavities.
Based on three-dimensional time domain numerical simulations of the nonlinear dispersive Maxwell equations, we find evidence of all optical splitting of defect states in a photonic band gap structure. The result is analogous to the well known Rabi splitting and optical nutation in atomic two-level systems, and can be used for controlled in-gap generation of optical frequencies. Photon-echo-like behavior and third harmonic generation are also investigated.


Higher hospitalization and mortality rates among SARS-CoV-2-infected persons in rural America.
Rural communities are among the most underserved and resource-scarce populations in the United States. However, there are limited data on COVID-19 outcomes in rural America. This study aims to compare hospitalization rates and inpatient mortality among SARS-CoV-2-infected persons stratified by residential rurality. This retrospective cohort study from the National COVID Cohort Collaborative (N3C) assesses 1,033,229 patients from 44 US hospital systems diagnosed with SARS-CoV-2 infection between January 2020 and June 2021. Primary outcomes were hospitalization and all-cause inpatient mortality. Secondary outcomes were utilization of supplemental oxygen, invasive mechanical ventilation, vasopressor support, extracorporeal membrane oxygenation, and incidence of major adverse cardiovascular events or hospital readmission. The analytic approach estimates 90-day survival in hospitalized patients and associations between rurality, hospitalization, and inpatient adverse events while controlling for major risk factors using Kaplan-Meier survival estimates and mixed-effects logistic regression. Of 1,033,229 diagnosed COVID-19 patients included, 186,882 required hospitalization. After adjusting for demographic differences and comorbidities, urban-adjacent and nonurban-adjacent rural dwellers with COVID-19 were more likely to be hospitalized (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI], 1.16-1.21 and aOR 1.29, CI 1.24-1.1.34) and to die or be transferred to hospice (aOR 1.36, CI 1.29-1.43 and 1.37, CI 1.26-1.50), respectively. All secondary outcomes were more likely among rural patients. Hospitalization, inpatient mortality, and other adverse outcomes are higher among rural persons with COVID-19, even after adjusting for demographic differences and comorbidities. Further research is needed to understand the factors that drive health disparities in rural populations.


Localized and transient transcription of Hox genes suggests a link between patterning and the segmentation clock.
During development, Hox gene transcription is activated in presomitic mesoderm with a time sequence that follows the order of the genes along the chromosome. Here, we show that Hoxd1 and other Hox genes display dynamic stripes of expression within presomitic mesoderm. The underlying transcriptional bursts may reflect the mechanism that coordinates Hox gene activation with somitogenesis. This mechanism appears to depend upon Notch signaling, as mice deficient for RBPJk, the effector of the Notch pathway, showed severely reduced Hoxd gene expression in presomitic mesoderm. These results suggest a molecular link between Hox gene activation and the segmentation clock. Such a linkage would efficiently keep in phase the production of novel segments with their morphological specification.


The binding of inosine monophosphate to Escherichia coli carbamoyl phosphate synthetase.
Carbamoyl phosphate synthetase (CPS) from Escherichia coli catalyzes the formation of carbamoyl phosphate, which is subsequently employed in both the pyrimidine and arginine biosynthetic pathways. The reaction mechanism is known to proceed through at least three highly reactive intermediates: ammonia, carboxyphosphate, and carbamate. In keeping with the fact that the product of CPS is utilized in two competing metabolic pathways, the enzyme is highly regulated by a variety of effector molecules including potassium and ornithine, which function as activators, and UMP, which acts as an inhibitor. IMP is also known to bind to CPS but the actual effect of this ligand on the activity of the enzyme is dependent upon both temperature and assay conditions. Here we describe the three-dimensional architecture of CPS with bound IMP determined and refined to 2.1 A resolution. The nucleotide is situated at the C-terminal portion of a five-stranded parallel beta-sheet in the allosteric domain formed by Ser(937) to Lys(1073). Those amino acid side chains responsible for anchoring the nucleotide to the polypeptide chain include Lys(954), Thr(974), Thr(977), Lys(993), Asn(1015), and Thr(1017). A series of hydrogen bonds connect the IMP-binding pocket to the active site of the large subunit known to function in the phosphorylation of the unstable intermediate, carbamate. This structural analysis reveals, for the first time, the detailed manner in which CPS accommodates nucleotide monophosphate effector molecules within the allosteric domain.


Operational seasonal forecasting of crop performance.
Integrated, interdisciplinary crop performance forecasting systems, linked with appropriate decision and discussion support tools, could substantially improve operational decision making in agricultural management. Recent developments in connecting numerical weather prediction models and general circulation models with quantitative crop growth models offer the potential for development of integrated systems that incorporate components of long-term climate change. However, operational seasonal forecasting systems have little or no value unless they are able to change key management decisions. Changed decision making through incorporation of seasonal forecasting ultimately has to demonstrate improved long-term performance of the cropping enterprise. Simulation analyses conducted on specific production scenarios are especially useful in improving decisions, particularly if this is done in conjunction with development of decision-support systems and associated facilitated discussion groups. Improved management of the overall crop production system requires an interdisciplinary approach, where climate scientists, agricultural scientists and extension specialists are intimately linked with crop production managers in the development of targeted seasonal forecast systems. The same principle applies in developing improved operational management systems for commodity trading organizations, milling companies and agricultural marketing organizations. Application of seasonal forecast systems across the whole value chain in agricultural production offers considerable benefits in improving overall operational management of agricultural production.


Effect of Inorganic and Organic Carbon Enrichments (DIC and DOC) on the Photosynthesis and Calcification Rates of Two Calcifying Green Algae from a Caribbean Reef Lagoon.
Coral reefs worldwide are affected by increasing dissolved inorganic carbon (DIC) and organic carbon (DOC) concentrations due to ocean acidification (OA) and coastal eutrophication. These two stressors can occur simultaneously, particularly in near-shore reef environments with increasing anthropogenic pressure. However, experimental studies on how elevated DIC and DOC interact are scarce and fundamental to understanding potential synergistic effects and foreseeing future changes in coral reef function. Using an open mesocosm experiment, the present study investigated the impact of elevated DIC (pHNBS: 8.2 and 7.8; pCO2: 377 and 1076 μatm) and DOC (added as 833 μmol L-1 of glucose) on calcification and photosynthesis rates of two common calcifying green algae, Halimeda incrassata and Udotea flabellum, in a shallow reef environment. Our results revealed that under elevated DIC, algal photosynthesis decreased similarly for both species, but calcification was more affected in H. incrassata, which also showed carbonate dissolution rates. Elevated DOC reduced photosynthesis and calcification rates in H. incrassata, while in U. flabellum photosynthesis was unaffected and thalus calcification was severely impaired. The combined treatment showed an antagonistic effect of elevated DIC and DOC on the photosynthesis and calcification rates of H. incrassata, and an additive effect in U. flabellum. We conclude that the dominant sand dweller H. incrassata is more negatively affected by both DIC and DOC enrichments, but that their impact could be mitigated when they occur simultaneously. In contrast, U. flabellum can be less affected in coastal eutrophic waters by elevated DIC, but its contribution to reef carbonate sediment production could be further reduced. Accordingly, while the capacity of environmental eutrophication to exacerbate the impact of OA on algal-derived carbonate sand production seems to be species-specific, significant reductions can be expected under future OA scenarios, with important consequences for beach erosion and coastal sediment dynamics.


Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 radioembolization.
Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ((90)Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of (90)Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the second cycle, whole-liver (90)Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after (90)Y infusion. If a DLT was not observed, the (90)Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of (90)Y with full-dose capecitabine. Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing (90)Y MTD were not met, indicating an MTD of >170 Gy. The MTD of (90)Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest (90)Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.


Specific Conditions for Resveratrol Neuroprotection against Ethanol-Induced Toxicity.
Aims. 3,5,4'-Trihydroxy-trans-stilbene, a natural polyphenolic compound present in wine and grapes and better known as resveratrol, has free radical scavenging properties and is a potent protector against oxidative stress induced by alcohol metabolism. Today, the mechanism by which ethanol exerts its toxicity is still not well understood, but it is generally considered that free radical generation plays an important role in the appearance of structural and functional alterations in cells. The aim of this study was to evaluate the protective action of resveratrol against ethanol-induced brain cell injury. Methods. Primary cultures of rat astrocytes were exposed to ethanol, with or without a pretreatment with resveratrol. We examined the dose-dependent effects of this resveratrol pretreatment on cytotoxicity and genotoxicity induced by ethanol. Cytotoxicity was assessed using the MTT reduction test. Genotoxicity was evidenced using single cell gel electrophoresis. In addition, DNA staining with fluorescent dyes allowed visualization of nuclear damage using confocal microscopy. Results. Cell pretreatment with low concentrations of trans-resveratrol (0.1-10 μM) slowed down cell death and DNA damage induced by ethanol exposure, while higher concentrations (50-100 μM) enhanced these same effects. No protection by cis-resveratrol was observed. Conclusion. Protection offered by trans-resveratrol against ethanol-induced neurotoxicity was only effective for low concentrations of this polyphenol.


Empathy and bullying: exploring the influence of callous-unemotional traits.
Although knowing and feeling the emotions of other people might result in less bullying, we argue that not caring about these feelings will also be important. That is, what good is empathy, if one does not care about the feelings or values of others? We examined self-reports of callous-unemotional traits (CU: Inventory of Callous-Unemotional Traits), bullying, and empathy in 201 children (ages 11-12 years). Results show children high on CU to be lowest in affective empathy and highest in direct bullying. While all subscales of the ICU were related to affective empathy, only the uncaring subscale was uniquely related to cognitive empathy. Empathy did not explain differences in bullying when taking into account CU traits. Therefore, failing to care about others is more important than empathy for explaining the direct and indirect bullying these children take part in. Implications for targeting different forms of empathy in treatment are considered.