PHI and PCA3 improve the prognostic performance of PRIAS and Epstein criteria in predicting insignificant prostate cancer in men eligible for active surveillance.
To assess the performance of prostate health index (PHI) and prostate cancer antigen 3 (PCA3) when added to the PRIAS or Epstein criteria in predicting the presence of pathologically insignificant prostate cancer (IPCa) in patients who underwent radical prostatectomy (RP) but eligible for active surveillance (AS). An observational retrospective study was performed in 188 PCa patients treated with laparoscopic or robot-assisted RP but eligible for AS according to Epstein or PRIAS criteria. Blood and urinary specimens were collected before initial prostate biopsy for PHI and PCA3 measurements. Multivariate logistic regression analyses and decision curve analysis were carried out to identify predictors of IPCa using the updated ERSPC definition. At the multivariate analyses, the inclusion of both PCA3 and PHI significantly increased the accuracy of the Epstein multivariate model in predicting IPCa with an increase of 17 % (AUC = 0.77) and of 32 % (AUC = 0.92), respectively. The inclusion of both PCA3 and PHI also increased the predictive accuracy of the PRIAS multivariate model with an increase of 29 % (AUC = 0.87) and of 39 % (AUC = 0.97), respectively. DCA revealed that the multivariable models with the addition of PHI or PCA3 showed a greater net benefit and performed better than the reference models. In a direct comparison, PHI outperformed PCA3 performance resulting in higher net benefit. In a same cohort of patients eligible for AS, the addition of PHI and PCA3 to Epstein or PRIAS models improved their prognostic performance. PHI resulted in greater net benefit in predicting IPCa compared to PCA3.


Principles for designing and delivering psychosocial and mental healthcare.
The development of the UK's military policy includes the potential for military organisations to deploy in support of humanitarian aid operations. This paper offers an overview of the risks to people's mental health of their exposure to emergencies, major incidents, disasters, terrorism, displacement, postconflict environments in which humanitarian aid is delivered, and deployments to conflict zones. It summarises the psychosocial approach recommended by many contemporary researchers and practitioners. It differentiates the extremely common experience of distress from the mental disorders that people who are affected may develop and introduces the construct of psychosocial resilience. The authors recognise the importance of trajectories of response in separating people who are distressed and require psychosocial care from those who require mental healthcare. Finally, this paper summarises a strategic approach to designing, planning and providing psychosocial and mental healthcare, provides a model of care and outlines the principles for early psychosocial interventions that do not require training in mental healthcare to deliver them.


The origin of reactive oxygen species in mouse embryos cultured in vitro.
The increase in production of reactive oxygen species such as H2O2 at the G2/M phase of the second cell cycle may be related to the in vitro block to development of mouse 2-cell embryos. The occurrence of the H2O2 rise is independent of the activation of the embryonic genome and of passage through the S, G2 and M phases of the first cell cycle and G1 and M phases of the second cell cycle, but does require the activation of the unfertilized oocyte. The H2O2 is produced via dismutation of superoxide by the enzyme superoxide dismutase. Production of superoxide via mitochondrial, NADPH-oxidase and xanthine/xanthine oxidase systems has been investigated. The evidence suggests that superoxide, and thereby H2O2, is produced by the xanthine/xanthine oxidase system, but an involvement of the other superoxide generating systems has not been excluded. The relation between H2O2 and development in vitro is discussed.


Conduction velocity and spike configuration in myelinated fibres: computed dependence on internode distance.
It has been argued theoretically and confirmed experimentally that conduction velocity (theta) should be proportional to nerve fibre diameter for myelinated fibre tracts, such as normal peripheral nerve, exhibiting 'structural' similarity'. In some axons, however, the nodes of Ranvier are more closely spaced than in normal peripheral nerve. Analytic arguments have suggested that when internodal distance (L) alone is changed, the plot of theta versus L should have a relatively flat maximum. This was confirmed by several previous computer simulations of myelinated axons, but internode lengths of less than half the normal case were not examined. In order to gain insight into impulse propagation in myelinated and remyelinated fibres with short internodal lengths, the present study examines the conduction velocity and spike configuration for a wide range of internodal lengths. As L becomes large, theta falls and finally propagation is blocked; as L becomes small, theta decreases more and more steeply. From this, it is predicted that for fibres with very short internodal lengths, small local changes in L should affect substantially the conduction velocity.


[UCP2 and UCP3 gene expression, heart function and oxygen cost of myocardial work changes during aging and ischemia-reperfusion].
To examine the effects of ischemia/reperfusion on UCPs genes expression, heart function and oxygen cost of myocardial work, hearts of adult (6 mo) and old (24 mo) rats were perfused by Langendorf preparation and subjected to 20 min ischemia followed by 40 min reperfusion. Mitochondrial permeability transition due to ischemic stimuli was evaluated by release of mitochondrial factor (lambda 250 nm) which was previously shown as a marker of MPTP opening. Expression of UCPs was detected by reverse transcriptional polymerase chain reaction. Mitochondrial membrane potential (deltaphi(m)) and oxygen consumption in isolated heart mitochondria of adult and old rats were measured. It was shown that impaired function of aging rat hearts was accompanied with an increased oxygen cost of myocardial work and lower mitochondrial membrane potential compared with adult rats. Reperfusion disturbances of cardiodynamic, contractile activity of myocardium and noneffective oxygen utilization in early period of reperfusion were less intensive in aged hearts than in adult ones. Therefore, the levels of mRNA of UCP2 in aging hearts were higher and mRNA levels of UCP3 were tended to increase. At the same time ischemia/reperfusion increased the expression of UCP2 and UCP3 in adult myocardium: mRNA levels of UCPs were significantly higher that those in control, whereas there was no such effect in aging hearts. It is concluded that uncoupling proteins are implicated in the age-depended heart dysfunction and development of the pathological mechanisms during ischemia-reperfusion.


Trichomonal urethritis in Nigerian males.
The incidence and mode of presentation of trichomonal urethritis in Nigerian males have benn investigated. Nineteen (10.6%) out of 179 patients presenting with non-gonococcal urethritis were found to harbour the parasite. The commonest symptoms were urethral discharge and/or urethral irritation. The usefulness of examining wet preparations of the urethral exudate in diagnosis is stressed. No significant difference has been found between the incidence of the condition in Nigerians as compared with other ethnic groups. Attention is drawn to the possibility of T. vaginalis playing a role in male infertility, its superinfection in longstanding urethritis is stressed, and the therapeutic efficacy of metronidazole is appraised.


Semi-automated protein binding methodology using equilibrium dialysis and a novel mixed-matrix cassette approach.
A semi-automated protein binding assay using equilibrium dialysis (ED) and a novel mixed-matrix methodology has been developed. This method decreases mass spectrometer run time and reduces the likelihood of experimental artifacts. In this cassette-based approach, a single matrix is prepared following dialysis by mixing dialyzed plasma and buffer containing different test compounds from the same dialysis plate. This approach differs from the traditional mixed-matrix method where fresh plasma and fresh buffer are mixed with opposing dialyzed samples. This new mixed-matrix methodology is compatible with various high-throughput ED and ultrafiltration devices, many liquid handling systems, and can be used for plasma, serum, albumin, alpha-1 acid glycoprotein, microsomal, and fine tissue homogenate binding studies. The utility of the method can be further enhanced by varying the number of replicates, concentrations, and matrices with simple modifications. Using 29 structurally diverse marketed drugs with a wide range of protein binding values reported in the literature, we have shown the new procedure reduces the total number of samples by nearly half compared to traditional methods, eliminates the need for standard curves, and increases the uniformity of the sample matrix for LC/MS/MS analysis.


Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism.
A -double-blind crossover trial of a combined preparation of triiodothyronine and thyroxine (1:4 ratio) compared with thyroxine alone was conducted with 99 patients previously stabilized on. thyroxine as treatment for hypothyroidism. Four patients were excluded during the trial and eight afterwards owing to gross deficiencies in taking the tablets. Of the remaining 87 patients 42 (48%) had no -preference for either medication, 29 (33%) preferred thyroxine alone, and 16 (18%) the combination. A high incidence of unpleasant symptoms was experienced during the two months' treatment with the combined preparation. The serum protein-bound iodine levels were lowered (mean reduction 1.8 mug./100 ml.) on the combination, but the labelled T(3)-resin sponge uptake values were not altered and remained in the normal range. on both treatments.


Oligomerization of anthrax toxin protective antigen and binding of lethal factor during endocytic uptake into mammalian cells.
The protective antigen (PA) protein of anthrax toxin binds to a cellular receptor and is cleaved by cell surface furin to produce a 63-kDa fragment (PA63). The receptor-bound PA63 oligomerizes to a heptamer and acts to translocate the catalytic moieties of the toxin, lethal factor (LF) and edema factor (EF), from endosomes to the cytosol. In this report, we used nondenaturing gel electrophoresis to show that each PA63 subunit in the heptamer can bind one LF molecule. Studies using PA immobilized on a plastic surface showed that monomeric PA63 is also able to bind LF. The internalization of PA and LF by cells was studied with radiolabeled and biotinylated proteins. Uptake was relatively slow, with a half-time of 30 min. The number of moles of LF internalized was nearly equal to the number of moles of PA subunit internalized. The essential role of PA oligomerization in LF translocation was shown with PA protein cleaved at residues 313-314. The oligomers formed by these proteins during uptake into cells were not as stable when subjected to heat and detergent as were those formed by native PA. The results show that the structure of the toxin proteins and the kinetics of proteolytic activation, LF binding, and internalization are balanced in a way that allows each PA63 subunit to internalize an LF molecule. This set of proteins has evolved to achieve highly efficient internalization and membrane translocation of the catalytic components, LF and EF.


Utility of measuring CSF hypocretin-1 level in patients with suspected narcolepsy.
The patho-aetiology of narcolepsy Type I (NT1) is the loss of hypocretin-1 secreting neurons in the hypothalamus. Diagnostic criteria for NT1 include excessive daytime sleepiness (EDS) for at least three months not explained by any other condition, cataplexy and cerebrospinal fluid (CSF) hypocretin-1 concentrations lower than 110 pg/ml. In this study we evaluated the utility of measuring CSF hypocretin-1 levels in patients with suspected narcolepsy (N). The study included 29 consecutively recruited patients at a tertiary sleep centre presenting with EDS for exclusion of N. All patients were examined using an extensive clinical interview followed by two weeks of actigraphy and sleep diary recordings, polysomnography (PSG) and multiple sleep latency testing (MSLT). Additionally, HLA-typing, urinary screening for substances of abuse and a lumbar puncture to measure CSF hypocretin-1 expression using radioimmunoassay were carried out. In sum, 19 patients (66%) had a CSF hypocretin-1 level <110 pg/ml, of whom two had current severe depression without any features of narcolepsy except EDS. The predictive potential of hypocretin-1 measurement in diagnosing narcolepsy revealed a positive predictive value (PPV) of 89%, a specificity of 83%, with both negative predictive value (NPV) and sensitivity equal to 100%. Despite a high sensitivity and specificity, the MSLT is not always a reliable diagnostic test for narcolepsy and where this uncertainty exits, CSF hypocretin-1 concentrations <110 pg/ml can be useful. However, due to a lower PPV and specificity at this cut-off, it may also not be entirely reliable as a stand-alone diagnostic test, particularly in the context of severe depression.


Relevance of parameters related to fertility and reproduction in toxicity testing.
Toxicity data of 37 compounds tested in both a subchronic study and one or more studies focused on reproduction were evaluated to obtain information on the significance of fertility and reproduction parameters in setting no-effect levels (NEL). It appeared that a) the test system aimed at reproduction and development was more sensitive than the subchronic study for 35% of the selected compounds and was equally sensitive for another 35%; b) for 65% of these compounds parameters related to reproduction and development were at least codecisive in determining the minimal-effect level (MEL); c) for 21% of all compounds, parameters related to reproduction were the most sensitive and therefore decisive for the MEL. It was concluded that reproduction in its broadest sense is a very sensitive tool in toxicity testing. The possibilities of either applying a simple screen of fertility and reproduction at an early stage of toxicity testing or incorporating fertility and reproduction parameters in the current subchronic study are discussed.


Attitudes to aging in older carers - do they have a role in their well-being?
Attitudes to aging have been investigated in non-carer populations and found to have important relationships with physical and mental health. However, these have not been explored in an older carer sample, although it is becoming increasingly important to clarify variables which are linked with positive carer outcomes. This is one of the first studies to report on older carers, their attitudes to aging, and the relationship with carer-related factors. A cross-sectional study of 202 carers with a mean age of 70.8 years was conducted in Victoria, Australia, using carer demographic data, carer factors such as depression (using the Geriatric Depression Scale), burden (using the Zarit Burden Inventory, ZBI), physical health, personality, and attitudes to aging (using the Attitudes to Aging Questionnaire, AAQ). Spearman rank correlation and hierarchical regression analyses were used. This study showed that carers had overall positive attitudes to aging inspite of their caring role. It also identified that carer factors including depression and burden contributed a significant amount of the variance to attitudes to aging in terms of physical change and psychosocial loss. Personality traits, specifically neuroticism, and extraversion, were also important contributors to attitudes to aging. Results from this study demonstrated that inspite of moderate levels of depression and spending significant time caring, carers reported positive attitudes to aging. Treating depression, decreasing burden, and investigating the benefits of caring may assist older carers maintain their well-being.


Differential retention of metabolic genes following whole-genome duplication.
Classical studies in Metabolic Control Theory have shown that metabolic fluxes usually exhibit little sensitivity to changes in individual enzyme activity, yet remain sensitive to global changes of all enzymes in a pathway. Therefore, little selective pressure is expected on the dosage or expression of individual metabolic genes, yet entire pathways should still be constrained. However, a direct estimate of this selective pressure had not been evaluated. Whole-genome duplications (WGDs) offer a good opportunity to address this question by analyzing the fates of metabolic genes during the massive gene losses that follow. Here, we take advantage of the successive rounds of WGD that occurred in the Paramecium lineage. We show that metabolic genes exhibit different gene retention patterns than nonmetabolic genes. Contrary to what was expected for individual genes, metabolic genes appeared more retained than other genes after the recent WGD, which was best explained by selection for gene expression operating on entire pathways. Metabolic genes also tend to be less retained when present at high copy number before WGD, contrary to other genes that show a positive correlation between gene retention and preduplication copy number. This is rationalized on the basis of the classical concave relationship relating metabolic fluxes with enzyme expression.


Dermatology residency selection criteria with an emphasis on program characteristics: a national program director survey.
Background. Dermatology residency programs are relatively diverse in their resident selection process. The authors investigated the importance of 25 dermatology residency selection criteria focusing on differences in program directors' (PDs') perception based on specific program demographics. Methods. This cross-sectional nationwide observational survey utilized a 41-item questionnaire that was developed by literature search, brainstorming sessions, and online expert reviews. The data were analyzed utilizing the reliability test, two-step clustering, and K-means methods as well as other methods. The main purpose of this study was to investigate the differences in PDs' perception regarding the importance of the selection criteria based on program demographics. Results. Ninety-five out of 114 PDs (83.3%) responded to the survey. The top five criteria for dermatology residency selection were interview, letters of recommendation, United States Medical Licensing Examination Step I scores, medical school transcripts, and clinical rotations. The following criteria were preferentially ranked based on different program characteristics: "advanced degrees," "interest in academics," "reputation of undergraduate and medical school," "prior unsuccessful attempts to match," and "number of publications." Conclusions. Our survey provides up-to-date factual data on dermatology PDs' perception in this regard. Dermatology residency programs may find the reported data useful in further optimizing their residency selection process.


The epidemiology of notified genital Chlamydia trachomatis infection in Victoria, Australia: a survey of diagnosing providers.
Data on 259 notified cases of genital chlamydia infection diagnosed in Victoria Australia in January and February 1995 were augmented by call-back. Risk factor data was available for 221. Patients were primarily adolescents or young adults (median age 23 years); 66% were women. Men were more commonly symptomatic. Persons without symptoms were tested as a result of partner notification, sexual risk, termination of pregnancy, or because of abnormalities on genital examination. Limitations of antigen-based screening tests in low prevalence populations were rarely considered. Although antimicrobial treatment usually accorded with available guidelines, case management was not well geared to reducing the broader issue of risk of this infection in the community. Data management systems for handling name-coded data, and systems for recall and follow-up of diagnosed patients and their partners were often inadequate. Sexual history taking had not generally identified details of sexual partners. Partner notification was generally regarded as the patient's responsibility and professional help with contact tracing was rarely sought. Control of chlamydia will require much greater attention to management issues, particularly contact tracing.


A study of severe domestic squalor: 173 cases referred to an old age psychiatry service.
Although community psychiatric services commonly encounter cases where intervention is needed due to persons' unclean or cluttered living conditions, evidence concerning the referral rate and prevalence of severe domestic squalor is sparse. Between 2000 and 2009, ratings of cleanliness and clutter have been made in all cases of people living in squalor who have been referred to an old age psychiatry service in Central Sydney. Where possible, one-year follow-up was arranged. 173 persons aged 65 years or more were referred to the service during the ten years and assessed as living in squalor (120 moderate or severe, two thirds of whom showed a moderate or severe degree of hoarding/clutter). Of 157 followed up after one year, 47% were still at home, 32% were in long-term care homes, 12% had moved elsewhere, and 9% had died. The annual new referral rate was close to 1 per 1000 elderly people in the catchment area, and of moderate or severe squalor was 0.66 per 1000. Limiting follow-up to those in moderate or severe squalor, 41% were still at home one year later. Current findings suggest that the minimum prevalence in the community of older people living in moderate or severe squalor in Sydney is 1 per 1000. The costs of intervening in cases of severe domestic squalor are considerable. Increased attention and funding are warranted, as the incidence and prevalence are higher than had previously been estimated.


Long-Term Progress and Behavior Complexification in Competitive Coevolution.
The possibility of using competitive evolutionary algorithms to generate long-term progress is normally prevented by the convergence on limit cycle dynamics in which the evolving agents keep progressing against their current competitors by periodically rediscovering solutions adopted previously. This leads to local but not to global progress (i.e., progress against all possible competitors). We propose a new competitive algorithm that produces long-term global progress by identifying and filtering out opportunistic variations, that is, variations leading to progress against current competitors and retrogression against other competitors. The efficacy of the method is validated on the coevolution of predator and prey robots, a classic problem that has been used in related researches. The accumulation of global progress over many generations leads to effective solutions that involve the production of articulated behaviors. The complexity of the behavior displayed by the evolving robots increases across generations, although progress in performance is not always accompanied by behavior complexification.


The impact of economic considerations on clinical decisionmaking: the case of thrombolytic therapy.
This study examines the intravenous use of two thrombolytic agents [streptokinase (SK) and tissue plasminogen activator (tPA)] in the acute phase of myocardial infarction (MI). These two agents have very different costs and offer an excellent opportunity to study both the impact of economic factors on clinical decisionmaking and the potential for cost savings by limiting the use of expensive new therapeutic agents. A nationwide survey of the 5,792 acute care general hospitals listed in the American Hospital Association's 1988 data file was responded to by 2,651 hospitals (46%) and revealed that 2,384 of these responding hospitals (90%) were using thrombolytic therapy. For 2,200 of these 2,384 hospitals (92%), the respondent was a physician who primarily used one of the two drugs. Eight hundred eighty-six of these 2,200 physicians (40%) primarily used SK while 1,314 (60%) primarily used tPA. SK users were more concentrated in federal public hospitals (69% used SK) than in nonfederal public hospitals (47% used SK), and were least concentrated in private hospitals (36% used SK). There was no difference between the rate of SK vs tPA use in investor-owned and not-for-profit private hospitals. SK users most often (62%) cited various economic factors as the reason for their choice. The users of tPA primarily (73%) cited clinical preferability as the reason for their choice even though trials are still ongoing to see which drug is preferable. Several multivariate analyses shed light upon the association between choice of thrombolytic agent and various additional physician and hospital characteristics. These data clearly indicate that while new therapies are rapidly implemented by the medical community, considerations of cost have a substantial impact upon the pattern of implementation and reflect a desire to implement cost savings in the use of new drugs.


Investigation of Potassium Chloride for Euthanasia of Anesthetized African Clawed Frogs (Xenopus laevis).
Euthanasia is frequently performed in amphibians, but techniques are currently limited in number and variable in effectiveness. The current study examined the use of potassium chloride (KCl) for euthanasia of anesthetized African clawed frogs (Xenopus laevis). Twenty adult, female African clawed frogs were anesthetized by immersion in buffered tricaine methanesulfonate (MS-222) for 5 min beyond loss of righting reflex. Frogs were then randomly assigned to receive one of 4 treatments: KCl via intracardiac injection (10 mEq/kg; IC, n = 5), intracoelomic injection (100 mEq/kg; ICe, n = 5), immersion (4,500 mEq/L; IMS, n = 5), or no treatment (C, n = 5). After treatment, serial heart rate was measured via Doppler device until either the loss of Doppler sounds, a 60-min endpoint (IC, ICe, IMS), or recovery (C). Times to loss of righting reflex, loss of Doppler sounds, and/or recovery were recorded. Plasma potassium concentrations were measured immediately after Doppler sound cessation in frogs in IC (n = 1), ICe (n = 2), and IMS (n = 5). Injection failure occurred in 1 IC frog, and 1 Ice frog regained spontaneous movement 4 min after treatment administration. Data from these 2 frogs were not included in statistical analysis. Doppler sound cessation occurred in 4 of 4, 4 of 4, 0 of 5, and 0 of 5 frogs in IC, ICe, IMS, and C, respectively. Median (range) times to Doppler sound cessation in IC and ICe were 6 (0 to 16) s and 18 (10 to 25) min, respectively. Plasma potassium concentration was greater than 9.0 mmol/L in sampled frogs. Intracardiac KCl at 10 mEq/kg and intracoelomic KCl at 100 mEq/kg were effective for euthanasia of anesthetized African clawed frogs. Return to MS-222 solution after KCl administration may be warranted to prevent unintended, premature anesthetic recovery prior to death.


Seronegative spondyloarthropathies: what radiologists should know.
Inflammatory involvement of the spine and sacroiliac joints is the most peculiar feature of seronegative spondyloarthropathies (SpA), which include ankylosing spondylitis, psoriatic arthritis, reactive arthritis (Reiter's syndrome), enteropathic spondylitis (related to inflammatory bowel diseases) and undifferentiated spondyloarthropathies. SAPHO syndrome may also be considered a SpA, but there is no clear agreement in this respect. Imaging, along with clinical and laboratory evaluation, is an important tool to reach a correct diagnosis and to provide a precise grading of disease progression, influencing both clinical management and therapy. Conventional radiography, which is often the first-step imaging modality in SpA, does not allow an early diagnosis. Computed tomography (CT) demonstrates with a very high spatial resolution the tiny structural alterations of cortical and spongy bone before they become evident on plain film radiographs. Magnetic resonance imaging (MRI) is the only modality that provides demonstration of bone marrow oedema, which reflects vasodilatation and inflammatory hyperaemia. The primary aim of this review article was to examine the involvement of the spine and sacroiliac joints in SpA using a multimodal radiological approach (radiography, CT, MRI), providing a practical guide for the differential diagnosis of these conditions.


[Atheroembolic renal disease: a cause of acute renal failure not much explored].
Atheroembolism is a multisytemic disease which affects many organs, including the kidneys, by the release of cholesterol emboli to tissues from an erosed atherosclerotic plaque, causing vascular obstruction in many tissues. The atheroembolic renal disease (AERD) is histologically represented by cholesterol crystals in renal arterioles with an inflammatory infiltrate around the vessels, and causes acute renal failure that may be severe and prolonged, weeks or even months after the embolic episode. The AERD carries a bad prognosis, with a high mortality. We herein report a case of a patient presenting AERD which was manifested two months after he was submitted to a cardiac catheterism and coronary angioplasty. The prevalence, clinical findings, renal histology, treatment and prognosis of AERD are discussed.


How the turtle forms its shell: a paracrine hypothesis of carapace formation.
We propose a two-step model for the evolutionary origin of the turtle shell. We show here that the carapacial ridge (CR) is critical for the entry of the ribs into the dorsal dermis. Moreover, we demonstrate that the maintenance of the CR and its ability to attract the migrating rib precursor cells depend upon fibroblast growth factor (FGF) signaling. Inhibitors of FGF allow the CR to degenerate, with the consequent migration of ribs along the ventral body wall. Beads containing FGF10 can rearrange rib migration in the chick, suggesting that the CR FGF10 plays an important role in attracting the rib rudiments. The co-ordinated growth of the carapacial plate and the ribs may be a positive feedback loop (similar to that of the limbs) caused by the induction of Fgf8 in the distal tips of the ribs by the FGF10-secreting mesenchyme of the CR. Once in the dermis, the ribs undergo endochrondral ossification. We provide evidence that the ribs act as signaling centers for the dermal ossification and that this ossification is due to bone morphogenetic proteins secreted by the rib. Thus, once the ribs are within the dermis, the ossification of the dermis is not difficult to achieve. This relatively rapid means of carapace formation would allow for the appearance of turtles in the fossil record without obvious intermediates.


Genetic diversity of Ehrlichia canis in Brazil.
Canine monocytic ehrlichiosis is a highly prevalent disease in Brazil, where the genetic diversity of Ehrlichia canis remains undefined. In this study, we used the TRP36 gene to examine the genetic diversity of E. canis strains from naturally infected dogs residing in five distinct geographic regions in Brazil. E. canis DNA was detected in 82/126 (65%) dogs by dsb-specific PCR and E. canis was isolated in cell culture from 13 dogs. Sequences obtained from dsb genes amplified from the isolates were identical to the US E. canis strain. An extended molecular characterization based on the TRP36 gene identified two major genogroups based on differences among eight isolates. Isolates with tandem repeat amino acid sequence (TEDSVSAPA) identical to the previously reported TRP36 sequence were found in the midwest, northeast and southeast regions of Brazil, and classified into the US genogroup. A novel Brazilian genotype with a different tandem repeat sequence (ASVVPEAE) was also identified in midwest, northern and southern regions. Similarity in the N-terminal sequence of a US genogroup member with the Brazilian genogroup suggested that genomic recombination between the two genogroups may have occurred. Other subtypes within the Brazilian genogroup were also identified using C-terminal amino acid divergence. We identified two distinct major Brazilian genogroups and several subtypes based on analysis of TRP36, and such information will be useful for further genotyping and possible associations with disease severity, understanding of the genetic and antigenic variability of E. canis, and for developing strain-specific vaccines and diagnostic methods based on TRP36.


Pharmacokinetic and Bioequivalence Evaluation of Single-Tablet and Separate-Tablet Regimens for Ainuovirine, Lamivudine, and Tenofovir Disoproxil Fumarate in Chinese Healthy Subjects.
This was a single-dose, randomized, open-label, 2-period crossover study to evaluate the bioequivalence of the ACC008 (test formulation [T]) versus coadministered ainuovirine (ANV) 150 mg, lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate 300 mg (reference formulation [R]) in the fasted state among the Chinese healthy adults. Eligible subjects were randomized into 2 cohorts to received treatment in 1 of 2 sequences (T → R, R → T). PK samples were collected from 1 hour before dosing to 144 hours after dosing in each period. The concentrations of ANV, 3TC, and tenofovir in plasma were determined by liquid chromatography-tandem mass spectrometry. Phoenix WinNonlin software was used for pharmacokinetic parameter calculation and bioequivalence evaluation. All the 90% confidence intervals of maximum concentration, area under the concentration-time curve from time zero to the last detectable time, and area under the concentration-time curve from time zero to infinity fell within the bioequivalence range. The safety was comparable between the 2 treatments, with no Grade III/VI or serious adverse events. ACC008 was bioequivalent to administration of its individual components, including ANV 150 mg, 3TC 300 mg, and tenofovir disoproxil fumarate 300 mg with favorable safety profile.


Vascular assessment of liver disease-towards a new frontier in MRI.
Complex haemodynamic phenomena underpin the pathophysiology of chronic liver disease. Non-invasive MRI-based assessment of hepatic vascular parameters therefore has the potential to yield meaningful biomarkers for chronic liver disease. In this review, we provide an overview of vascular sequelae of chronic liver disease amenable to imaging evaluation and describe the current supportive evidence, strengths and the limitations of MRI methodologies, including dynamic contrast-enhanced, dynamic hepatocyte-specific contrast-enhanced, phase-contrast, arterial spin labelling and MR elastography in the assessment of hepatic vascular parameters. We review the broader challenges of quantitative hepatic vascular MRI, including the difficulties of motion artefact, complex post-processing, long acquisition times, validation and limitations of pharmacokinetic models, alongside the potential solutions that will shape the future of MRI and deliver this new frontier to the patient bedside.


Aerobic endospore-forming bacteria from geothermal environments in northern Victoria Land, Antarctica, and Candlemas Island, South Sandwich archipelago, with the proposal of Bacillus fumarioli sp. nov.
Aerobic endospore-forming bacteria were isolated from soils taken from active fumaroles on Mount Rittmann and Mount Melbourne in northern Victoria Land, Antarctica, and from active and inactive fumaroles on Candlemas Island, South Sandwich archipelago. The Mt Rittmann and Mt Melbourne soils yielded a dominant, moderately thermophilic and acidophilic, aerobic endospore-former growing at pH 5.5 and 50 degrees C, and further strains of the same organism were isolated from a cold, dead fumarole at Clinker Gulch, Candlemas Island. Amplified rDNA restriction analysis, SDS-PAGE and routine phenotypic tests show that the Candlemas Island isolates are not distinguishable from the Mt Rittmann strains, although the two sites are 5600 km apart, and 16S rDNA sequence comparisons and DNA relatedness data support the proposal of a new species, Bacillus fumarioli, the type strain of which is LMG 17489T.


GATA3 frameshift mutation promotes tumor growth in human luminal breast cancer cells and induces transcriptional changes seen in primary GATA3 mutant breast cancers.
The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. Heterozygous mutations, mostly frameshifts, are seen in 15% of estrogen receptor positive breast cancers, the subtype in which these mutations are almost exclusively found. Mouse studies have shown that Gata3 is critical for breast development and that GATA3 gene dosage affects breast tumor progression. Human patient data have shown that high Gata3 expression, a feature of luminal subtype breast cancers, is associated with a better prognosis. Although the frequency of GATA3 mutation suggests an important role in breast cancer development or progression, there is little understanding of how mutations in GATA3 affect its function in luminal breast epithelial cells and what gene expression changes result as a consequence of the mutations. Here, using gene editing, we have created two sets of isogenic human luminal breast cancer cell lines with and without a hotspot truncating GATA3 mutation. GATA3 mutation enhanced tumor growth in vivo but did not affect sensitivity to clinically used hormonal therapies or chemotherapeutic agents. We identified genes with upregulated and downregulated expression in GATA3 mutant cells, a subset of which was concordantly differentially expressed in GATA3 mutant primary luminal breast cancers. Addback of mutant GATA3 recapitulated mutation-specific gene expression changes and enhanced soft agar colony formation, suggesting a gain of function for the mutant protein.


The Influence of Diabetes Mellitus on the Outcome of Superficial Femoral Artery Recanalization is Debatable.
Notwithstanding technological improvements in endovascular devices treatment of steno-obstructive lesions of the superficial femoral artery (SFA) remains a challenge for today's vascular surgeon. Current opinion dictates that the diabetic population may have worse outcome after revascularization of the lower extremities. Herein we examine the effects of endovascular treatment on steno-obstructive lesions of the SFA in diabetic and non-diabetic patients. A retrospective analysis was carried out on 110 patients who had undergone endovascular treatment of the SFA from 2010 to 2017 comparing outcomes in diabetic (DM) vs non-diabetic patients (nDM). 56 (50.9%) of the patients were diabetic and 54 were non-diabetic (49.1%). 52.7% (62.7% DM vs 35.2% nDM, p = 0.0003) were patients with critical limb ischemia. SFA occlusion was present in 65.5% (60.7% DM vs 70.4% nDM, p = 0.29) of all patients. All had undergone PTA of the SFA and 40.9% had received adjunctive stenting (44.6% DM vs 37.0% nDM, p = 0.41). A multilevel treatment was executed in 39.1% (51.8% DM vs 25.9% nDM) of the cases whereas an infra-popliteal procedure was associated in 27.3% (37.5% DM vs 16.7% nDM). In both groups the presence of diabetes was significantly associated (p = 0.005 e p = 0.014, respectively). Reintervention rate was 22.7%; 13 in the diabetic group (23.2%) and 12 in the non-diabetic group (22.2%). Of those who had had reintervention (p = 0.77); 9 patients (8.2%) had undergone an open surgical operation, 6 of whom had diabetes (p = 0.32). 5 patients (4.5%) had had major amputation, 4 of whom were diabetic (p = 0.20). Curves assessing freedom from target lesion restenosis were substantially overlapping between the two groups. No statistical associations between diabetes and reintervention or amputation rates were found. Indication to treat the SFA were not influenced by the presence of diabetes but further investigation is required to verify our hypothesis.


Morphological diversity at different spatial scales in a Neotropical bat assemblage.
The morphology of species can be used to represent their ecological position and infer potential processes determining the structure of species assemblages. This ecomorphological approach has been widely applied to the study of bat assemblages which mainly focuses on a single spatial scale and particular guilds. We extended such an ecomorphological approach to a multi-scale analysis of a Neotropical bat assemblage and its constituent guilds (aerial and gleaning insectivores, frugivores, and nectarivores) to describe their structure at different spatial scales and determine the relative importance of inter-specific competition, habitat filtering, or stochastic processes shaping such structures. We measured the occupied morphological space (size) defined by wing and skull morphology independently and the nearest-neighbour distance (structure) among species within these spaces at each spatial scale. Observed patterns were compared with random expectations derived from null models for statistical inference. When controlling for species richness and regional sampling effects in the null models, we did not find a significant effect of spatial scale in the morphological structure of the studied bat assemblage and guilds. Morphological structure followed the same patterns across scales as those expected from random drawings of sample size alone. Similar results were obtained regardless of morphological complex (wing and skull) and guilds. At both the assemblage and guild levels, bat morphological structure seems to be determined by regional, abiotic processes (e.g. habitat filtering) shaping the composition and organization of the species pool.


[Revision of autism spectrum disorder diagnosis in three women].
Increasing attention has arisen for autism spectrum disorders (asd) in adults, especially women. To ensure the specificity of the diagnostic process, careful consideration of the differential diagnosis is necessary, in order to optimise treatment.
 AIM: To offer practical recommendations to increase the specificity of the diagnostic process for asd.
 RESULTS: The asd diagnoses of the three women were reconsidered and eventually removed in favor of new diagnoses, which opened the door to more suitable therapeutic possibilities.
 CONCLUSION: The asd diagnoses of the three women must always be considered. During the diagnostic process, it must be considered whether there are distinctive symptoms of asd present that justify the need for an asd diagnosis, or whether the symptoms can be explained more suitably by another psychiatric disorder.


Cardiac PET: metabolic and functional imaging of the myocardium.
Cardiac PET has evolved over the past 30 years to gain wider acceptance as a valuable modality for a variety of cardiac conditions. Wider availability of scanners as well as changes in reimbursement policies in more recent years has further increased its use. Moreover, with the emergence of novel radionuclides as well as further advances in scanner technology, the use of cardiac PET can be expected to increase further in both clinical practice and the research arena. PET has demonstrated superior diagnostic accuracy for the diagnosis of coronary artery disease in comparison with single-photon emission tomography while it provides robust prognostic value. The addition of absolute flow quantification increases sensitivity for 3-vessel disease as well as providing incremental functional and prognostic information. Metabolic imaging using (18)F-fluorodeoxyglucose can be used to guide revascularization in the setting of heart failure and also to detect active inflammation in conditions such as cardiac sarcoidosis and within atherosclerotic plaque, improving our understanding of the processes that underlie these conditions. However, although the pace of new developments is rapid, there remains a gap in evidence for many of these advances and further studies are required.


Identification of Bacillus anthracis by API tests.
API and morphological tests were examined for their ability to distinguish between 37 Bacillus anthracis strains (virulent and avirulent) and 194 strains of closely related Bacillus species (B. cereus, B. mycoides and B. thuringiensis). In addition, 34 strains of B. anthracis and four of B. cereus were tested by several other methods that included capsule formation, ability to grow on a selective medium, and sensitivity to phage. It was found that virulent strains of B. anthracis were easily separated from the closely related Bacillus species by most of the test methods; but separation of slightly virulent and avirulent strains of B. anthracis from the closely related species could be done only by API and phage-sensitivity tests.


THE FUNCTIONAL ACTIVITY OF SINGLE UNITS IN THE CENTRAL NERVOUS SYSTEM.
Single motor units, i.e., anterior horn cells plus the muscle fibers they innervate, have recently been placed under direct observation while responding to a normal reflex stimulus. Details such as the normal rate of discharge, latent period, refractory period, influence of fatigue, etc., have been carefully studied. The work of Denny-Brown, Adrian and Bronk, Eccles and Sherrington have all indicated that the natural rate of discharge of the anterior horn cell is slow, i.e., 5 to 25 per sec., and never more than 80 to 90 per sec. under intense stimulation. A motor unit discharging at 10 per sec. may continue in activity for indefinite periods of time without fatigue. Tonic responses are maintained by such rates of discharge and therefore no special tonic mechanisms need be postulated to explain the absence of fatigue.


Epidermal growth factor mimics insulin effects in rat hepatocytes.
Epidermal growth factor (EGF) mimicked the effect of insulin to activate glycogen synthase and stimulate glycogen synthesis in isolated rat hepatocytes. Both agents required glucose (greater than 5 mM) and had similar time courses of action. The maximum effect of EGF was approx. 70% of that of insulin, and the half-maximally effective concentrations were 9 nM and 4 nM respectively. Combinations of the two agents produced additive responses. EGF also resembled insulin in its ability to inhibit the effects of 0.1-1.0 nM-glucagon on cyclic AMP and glycogen phosphorylase in hepatocytes. The maximum effect of EGF was approx. 70% of that of insulin, and the half-maximally effective concentrations were approx. 5 nM and 0.5 nM respectively. EGF and insulin inhibited phosphorylase activation by exogenous cyclic AMP, and inhibited cyclic AMP accumulation induced by forskolin. They also inhibited phosphorylase activation provoked by phenylephrine, but not by vasopressin. EGF added alone rapidly activated phosphorylase and increased cytosolic [Ca2+], but the effects were no longer apparent at 5 min and were smaller than those of vasopressin. Insulin did not induce these changes. In hepatocytes previously incubated with myo-[3H]inositol, EGF did not significantly increase myo-inositol 1,4,5-trisphosphate. However, its ability to increase cytosolic [Ca2+] was blocked by neomycin, an inhibitor of phosphatidylinositol bisphosphate hydrolysis. It is concluded that some, but not all, of the effects of EGF in liver are strikingly similar to those exerted by insulin, suggesting that these agents may have some similar mechanisms of action in this tissue.


Bilateral laryngeal paralysis associated with hepatic dysfunction and hepatic encephalopathy in six ponies and four horses.
Six ponies and four horses with a mean (sd) age of 15.9 (6.0) years developed sudden-onset bilateral laryngeal paralysis (BLP) in association with hepatic dysfunction. Nine of them had been referred for the investigation of respiratory distress, and one pony had been referred for weight loss before BLP developed. Nine of the animals had clinicopathological evidence of liver disease, and nine had histological evidence of liver disease. All of the animals had one or more of the following: hepatic encephalopathy (in eight), hyperammonaemia (in six) and endoscopic evidence of BLP (in nine). Three of the animals had signs of pituitary pars intermedia dysfunction, a diagnosis supported in two by endocrine function testing, and in two by histopathological examination. Histopathological examination of the intrinsic laryngeal musculature and recurrent laryngeal nerves of four of the horses and of the region of the nucleus ambiguus of two did not reveal any abnormalities. Three of the animals were euthanased after they had first been examined, and one improved temporarily before the condition recurred. A temporary tracheostomy was performed in six of the animals, five of which subsequently died or were euthanased; one pony recovered.


Antibacterial screening of anthocyanic and proanthocyanic fractions from cranberry juice.
The effect of anthocyanin- and proanthocyanidin-rich fractions isolated from cranberry juice was studied for their antibacterial activity against nine bacterial strains. Activity was assessed by the agar diffusion assay. Staphylococcus aureus ATCC 6538 was the only strain to exhibit some susceptibility to four out of 10 anthocyanin-rich fractions tested. A variable susceptibility of S. aureus, Enterococcus faecalis ATCC 10541, and Micrococcus luteus ATCC 9341 to proanthocyanidin- rich fractions was also observed. Streptococcus mutans strains as well as Escherichia coli ATCC 10538 and Pseudomonas aeruginosa ATCC 27853 were not susceptible to any of the cranberry juice samples or fractions at the tested concentrations. There was no clear correlation between Gram-positive or Gram-negative bacterial susceptibility to cranberry juice. In this work, the role of cranberry juice anthocyanic and proanthocyanic fractions upon bacterial viability is discussed.


Lipedema and the Evolution to Lymphedema With the Progression of Obesity.
The aim of the present study was to evaluate the prevalence of subclinical and clinical systemic lymphedema in patients with lipedema and different body mass index (BMI) values. A cross-sectional study was conducted to determine the prevalence of subclinical systemic lymphedema and clinical lymphedema of the lower limbs detected by bioimpedance (InBody S10 device, Seoul, Korea) in 258 women with clinically diagnosed lipedema. The patients were divided into three groups based on BMI: Group I - BMI below 30 kg/m2; Group II - BMI between 30 and 40 kg/m2; and Group III - BMI 40 to 50 kg/m2. Fisher's exact test revealed a statistically significant difference between Group I and both Groups II and III (p = 0.0001) regarding the occurrence of lower limb lymphedema. Patients with lipedema can develop edema even when their weight is within the standards of normality. However, obesity is an aggravating factor, as the prevalence of lipedema increases progressively with the increase in weight.


Design of Tunable Ultrasonic Receivers for Efficient Powering of Implantable Medical Devices With Reconfigurable Power Loads.
Miniaturized ultrasonic receivers are designed for efficient powering of implantable medical devices with reconfigurable power loads. Design parameters that affect the efficiency of these receivers under highly variable load conditions, including piezoelectric material, geometry, and operation frequency, are investigated. Measurements were performed to characterize electrical impedance and acoustic-to-electrical efficiency of ultrasonic receivers for off-resonance operation. Finally, we propose, analyze, and demonstrate adaptive matching and frequency tuning techniques using two different reconfigurable matching networks for typical implant loads from 10 [Formula: see text] to 1 mW. Both simulations and measurements show a significant increase in total implant efficiency (up to 50 percentage points) over this load power range when operating off-resonance with the proposed matching networks.


Lack of pharmacokinetic interaction between pantoprazole and diclofenac.
The new H+/K+ ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles may potentially interact with the cytochrome P450 system, the influence of pantoprazole on the pharmacokinetics of the NSAID diclofenac was investigated. Diclofenac is widely used in the treatment of rheumatic diseases and is mainly metabolized in the liver by CYP2C9. Twenty-four healthy volunteers (13 male/11 female) completed a randomized crossover study. As test they received orally 40 mg pantoprazole and concomitantly 100 mg diclofenac. As respective references 100 mg diclofenac or 40 mg pantoprazole were given alone. Diclofenac and pantoprazole serum concentrations were measured. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90% confidence intervals (CI) of the ratios of the primary characteristic AUC and the secondary characteristic C(max) of diclofenac were entirely within the equivalence range of 0.8 - 1.25. Hence, no influence of pantoprazole on the pharmacokinetics of diclofenac was concluded, either by competition with the CYP2C9 or by the reduction of gastric acid secretion. Vice versa, diclofenac did not affect the pharmacokinetics of pantoprazole. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with diclofenac and pantoprazole.


Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT.
Quantitative cortical microarchitectural end points are important for understanding structure-function relations in the context of fracture risk and therapeutic efficacy. This technique study details new image-processing methods to automatically segment and directly quantify cortical density, geometry, and microarchitecture from HR-pQCT images of the distal radius and tibia. An automated segmentation technique was developed to identify the periosteal and endosteal margins of the distal radius and tibia and detect intracortical pore space morphologically consistent with Haversian canals. The reproducibility of direct quantitative cortical bone indices based on this method was assessed in a pooled data set of 56 subjects with two repeat acquisitions for each site. The in vivo precision error was characterized using root mean square coefficient of variation (RMSCV%) from which the least significant change (LSC) was calculated. Bland-Altman plots were used to characterize bias in the precision estimates. The reproducibility of cortical density and cross-sectional area measures was high (RMSCV <1% and <1.5%, respectively) with good agreement between young and elder medians. The LSC for cortical porosity (Ct.Po) was somewhat smaller in the radius (0.58%) compared with the distal tibia (0.84%) and significantly different between young and elder medians in the distal tibia (LSC: 0.75% vs. 0.92%, p<0.001). The LSC for pore diameter and distribution (Po.Dm and Po.Dm.SD) ranged between 15 and 23 microm. Bland-Altman analysis revealed moderate bias for integral measures of area and volume but not for density or microarchitecture. This study indicates that HR-pQCT measures of cortical bone density and architecture can be measured in vivo with high reproducibility and limited bias across a biologically relevant range of values. The results of this study provide informative data for the design of future clinical studies of bone quality.


The Roles of Calcineurin B-like Proteins in Plants under Salt Stress.
Salinity stands as a significant environmental stressor, severely impacting crop productivity. Plants exposed to salt stress undergo physiological alterations that influence their growth and development. Meanwhile, plants have also evolved mechanisms to endure the detrimental effects of salinity-induced salt stress. Within plants, Calcineurin B-like (CBL) proteins act as vital Ca2+ sensors, binding to Ca2+ and subsequently transmitting signals to downstream response pathways. CBLs engage with CBL-interacting protein kinases (CIPKs), forming complexes that regulate a multitude of plant growth and developmental processes, notably ion homeostasis in response to salinity conditions. This review introduces the repercussions of salt stress, including osmotic stress, diminished photosynthesis, and oxidative damage. It also explores how CBLs modulate the response to salt stress in plants, outlining the functions of the CBL-CIPK modules involved. Comprehending the mechanisms through which CBL proteins mediate salt tolerance can accelerate the development of cultivars resistant to salinity.


Endosomolytic anionic polymer for the cytoplasmic delivery of siRNAs in localized in vivo applications.
The use of small interfering RNAs (siRNAs) to down-regulate the expression of disease-associated proteins carries significant promise for the treatment of a variety of clinical disorders. One of the main barriers to the widespread clinical use of siRNAs, however, is their entrapment and degradation within the endolysosomal pathway of target cells. Here we report the trafficking and function of PP75, a non-toxic, biodegradable, lipid membrane disruptive anionic polymer composed of phenylalanine derivatized poly(L-lysine iso-phthalamide). PP75 is readily endocytosed by cells, safely permeabilizes endolysosomes in a pH dependent manner and facilitates the transfer of co-endocytosed materials directly into the cytoplasm. The covalent attachment of siRNAs to PP75 using disulfide linkages generates conjugates that effectively traffic siRNAs to the cytoplasm of target cells both in vitro and in vivo. In a subcutaneous malignant glioma tumor model, a locally delivered PP75-stathmin siRNA conjugate decreases stathmin expression in tumor cells and, in combination with the nitrosourea chemotherapy carmustine, is highly effective at inhibiting tumor growth. PP75 may be clinically useful for the local delivery of siRNAs, in particular for the treatment of solid tumors.


Long Exciton Dephasing Time and Coherent Phonon Coupling in CsPbBr2Cl Perovskite Nanocrystals.
Fully inorganic cesium lead halide perovskite nanocrystals (NCs) have shown to exhibit outstanding optical properties such as wide spectral tunability, high quantum yield, high oscillator strength as well as blinking-free single photon emission, and low spectral diffusion. Here, we report measurements of the coherent and incoherent exciton dynamics on the 100 fs to 10 ns time scale, determining dephasing and density decay rates in these NCs. The experiments are performed on CsPbBr2Cl NCs using transient resonant three-pulse four-wave mixing (FWM) in heterodyne detection at temperatures ranging from 5 to 50 K. We found a low-temperature exciton dephasing time of 24.5 ± 1.0 ps, inferred from the decay of the photon-echo amplitude at 5 K, corresponding to a homogeneous line width (fwhm) of 54 ± 5 μeV. Furthermore, oscillations in the photon-echo signal on a picosecond time scale are observed and attributed to coherent coupling of the exciton to a quantized phonon mode with 3.45 meV energy.


Influence of feeding various quantities of wet and dry distillers grains to finishing steers on carcass characteristics, meat quality, retail-case life of ground beef, and fatty acid profile of longissimus muscle.
Two hundred forty Angus crossbred steers were used to determine the influence of feeding various quantities of wet and dry distillers grains to finishing steers on carcass characteristics, meat quality, retail-case life of ground beef, and fatty acid profile of LM. Three replications of 5 dietary treatments were randomly applied to 15 pens in each of 2 yr. A finishing diet containing dry-rolled corn, soybean meal, and alfalfa hay was fed as the control diet. Wet distillers grains with solubles (DGS) or dry DGS was added to the finishing diets at either 20.0 or 40.0% of the dietary DM to replace all soybean meal and part of the cracked corn in treatment diets. Carcasses of steers fed DGS had greater (P < 0.05) fat thickness (1.47 vs. 1.28 cm), greater (P < 0.05) USDA yield grades (3.23 vs. 2.94), and smaller (P < 0.05) percentage of yield grades 1 and 2 (41.1 vs. 60.4%) than carcasses of steers fed the control diet. Longissimus muscle from steers fed dry DGS had greater (P < 0.05) ultimate pH values (5.52 vs. 5.49) than LM from steers fed wet DGS. Ground beef from steers fed DGS had greater (P < 0.05) concentrations of α-tocopherol (1.77 vs. 1.43 μg/g) than ground beef from steers fed the control diet. Ground beef from steers fed 40% DGS had greater (P < 0.05) thiobarbituric acid-reactive substances (2.84 vs. 2.13 mg/kg) on d 2 of retail display than ground beef from steers fed 20% DGS. Longissimus muscle of steers fed DGS had less (P < 0.05) C17:0 and more (P < 0.05) C18:0, C18:1t, C16:1c9, C18:2c9c12 (where t is trans and c is cis), and total PUFA than LM of steers fed the control diet. Feedlot steers fed DGS may need to be marketed earlier than normal to avoid excess external fat and carcasses with a greater numerical yield grade. These data suggest feeding DGS to finishing steers will have no adverse or beneficial effects on glycolytic variables (dark cutters), retail display life of ground beef, or meat tenderness. However, beef from cattle finished on diets containing DGS will likely have a greater proportion of PUFA and therefore may be more susceptible to oxidative rancidity.


Optimizing the linearity in high-speed photodiodes.
Analog photonic links require high-fidelity, high-speed optical-to-electrical conversion for applications such as radio-over-fiber, synchronization at kilometer-scale facilities, and low-noise electronic signal generation. Photodetector nonlinearity is a particularly vexing problem, causing signal distortion and excess noise, especially in systems utilizing ultrashort optical pulses. Here we show that photodetectors designed for high power handling and high linearity can perform optical-to-electrical conversion of ultrashort optical pulses with unprecedented linearity over a large photocurrent range. We also corroborate and expand upon the physical understanding of how the broadband, complex impedance of the circuit following the photodiode modifies the linearity - in some cases quite significantly. By externally manipulating the circuit impedance, we extend the detector's linear range to higher photocurrents, with over 50 dB rejection of amplitude-to-phase conversion for photocurrents up to 40 mA. This represents a 1000-fold improvement over state-of-the-art photodiodes and significantly extends the attainable microwave power by a factor of four. As such, we eliminate the long-standing requirement in ultrashort pulse detection of precise tuning of the photodiode's operating parameters to coincide with a nonlinearity minimum. These results should also apply more generally to reduce nonlinear distortion in a range of other microwave photonics applications.


Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib.
The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors. Furthermore, the data presented here provide rationale for further clinical development of delanzomib.


Effects of an entertainment-education radio soap opera on family planning behavior in Tanzania.
An entertainment-education radio soap opera introduced in Tanzania in 1993 was evaluated by means of a field experimental design in which the radio program was broadcast by seven mainland stations of Radio Tanzania. An eighth station broadcast alternative programming from 1993 to 1995, its listenership serving as a comparison area in which contemporaneous changes in family planning adoption were measured. The soap opera was subsequently broadcast nationwide from 1995 to 1997. Data about the effects of the radio soap opera were gathered in five annual surveys of about 2,750 households in the comparison and the treatment areas and from a sample of new family planning adopters in 79 health clinics. The soap opera had strong behavioral effects on family planning adoption; it increased listeners' self-efficacy regarding family planning adoption and influenced listeners to talk with their spouses and peers about contraception.


Noise-induced temporal regularity and signal amplification in an optomechanical system with parametric instability.
Noise usually has an unwelcome influence on system performance. For instance, noise inevitably affects the low-frequency mechanical freedom in optomechanical experiments. However, we investigate here the beneficial effects of thermal noise on a basic optomechanical system with parametric instability. In a regime near parametric instability, it is found that thermal noise in the mechanical freedom can sustain long-term quasi-coherent oscillations when the system would otherwise remain in the equilibrium state. In an overlapping regime of parametric instability and bistability, intermittent switching between a self-sustained oscillating state and an equilibrium can be induced by adding a certain amount of noise. When a subthreshold periodic signal is applied to the mechanics, the switching between the self-sustained oscillations and the equilibrium exhibits good periodicity at a rate that is synchronized to the signal frequency, resulting in a significant amplification of the signal. Our results deepen the understanding of the interplay between optomechanical nonlinearity and noise and provide theoretical guidance for experimental observation of noise-induced beneficial phenomena in optomechanics.


Transduction of interphase cells by avian sarcoma virus.
It has been generally believed that oncoretroviruses are dependent on mitosis for efficient nuclear entry of viral DNA. We previously identified a nuclear localization signal in the integrase protein of an oncoretrovirus, avian sarcoma virus (ASV), suggesting an active import mechanism for the integrase-DNA complex (G. Kukolj, R. A. Katz, and A. M. Skalka, Gene 223:157-163, 1998). Here, we have evaluated the requirement for mitosis in nuclear import and integration of ASV DNA. Using a modified ASV encoding a murine leukemia virus amphotropic env gene and a green fluorescent protein (GFP) reporter gene, DNA nuclear import was measured in cell cycle-arrested avian (DF-1) as well as human (HeLa) and mouse cells. The results showed efficient accumulation of nuclear forms of ASV DNA in gamma-irradiation-arrested cells. Efficient transduction of a GFP reporter gene was also observed after infection of cells that were arrested with gamma-irradiation, mitomycin C, nocodazole, or aphidicolin, confirming that nuclear import and integration of ASV DNA can occur in the absence of mitosis. By monitoring GFP expression in individual cells, we also obtained evidence for nuclear import of viral DNA during interphase in cycling cells. Lastly, we observed that ASV can transduce postmitotic mouse neurons. These results support an active nuclear import mechanism for the oncoretrovirus ASV and suggest that this mechanism can operate in both nondividing and dividing cells.


Evaluation of in vivo bioequivalence methodology for topical clobetasol 17-propionate based on pharmacodynamic modeling using Chinese skin.
The United States Food and Drug Administration recommends pilot dose duration-response and pivotal bioequivalence studies to be conducted using reflectance colorimetry for assessment of the in vivo bioequivalence of topical dermatologic corticosteroids. The major objectives of the present studies were to examine the applicability of the standardized pharmacodynamic modeling-based methodology to super-potent clobetasol 17-propionate (CP) in the Chinese population and to evaluate the bioequivalence of two generic ointments and four generic creams containing 0.05% (w/w) CP with respect to Dermovate formulations using such methodology. In the pilot dose duration-response study, although the E(max) model (where E(max) is the maximum fitted value of AUEC, which is the area under the baseline-corrected, untreated control-site-corrected a* scale data from 0 to 24 h after drug removal) did not provide acceptable model fits, E(max) parameter estimates of -38.97 +/- 3.62 and -41.89 +/- 11.28 a*-scale. h, and ED(50) (dose duration required to achieve 50% of the fitted E(max) value) estimates of 0.40 +/- 0.37 and 0.42 +/- 0.16 h were obtained for Dermovate ointment and cream, respectively, by population analyses. The estimates for the two formulations were not statistically different, so in vivo bioequivalence studies were conducted at an ED(50)dose duration of approximately 0.5 h for both Dermovate formulations. The results demonstrated that one generic ointment was bioequivalent to Dermovate, whereas the other was not. None of the generic creams were shown to be bioequivalent to Dermovate cream. The in vivo bioequivalence data from the vasoconstriction assay were linearly correlated with stratum corneum uptake of the drug at the same dose duration until the maximal vasoconstriction response was achieved. The studies illustrated the applicability of the standardized pharmacodynamic modeling-based methodology in detecting the product differences between a variety of generic 0.05% CP formulations and reference Dermovate formulations in Chinese skin.


Collagenase-3 (MMP-13) and integral membrane protein 2a (Itm2a) are marker genes of chondrogenic/osteoblastic cells in bone formation: sequential temporal, and spatial expression of Itm2a, alkaline phosphatase, MMP-13, and osteocalcin in the mouse.
Endochondral bone formation requires the action of cells of the chondrocytic and osteoblastic lineage, which undergo continuous differentiation during this process. To identify subpopulations of resting, proliferating, and hypertrophic chondrocytes and osteoblasts involved in bone formation, we have identified here two novel marker genes present in endochondral and intramembranous ossification. Using Northern blot analysis and in situ hybridization on parallel sections of murine embryos and bones of newborn mice we compared the expression pattern of the recently cloned Itm2a and MMP-13 (collagenase-3) genes with that of established marker genes for bone formation, such as alkaline phosphatase (ALP), osteocalcin (OC), and collagen type X, during endochondral and intramembranous ossification. During embryonic development expression of Itm2a and ALP was detectable at midgestation (11.5 days postcoitum [dpc]) and increased up to 16.5 dpc. MMP-13 and OC expression started at 14.5 dpc and 16.5 dpc, respectively. This temporal expression was reflected in the spatial distribution of these markers in the growth plate of long bones. In areas undergoing endochondral ossification Itm2a expression was found in chondrocytes of the resting and the proliferating zones. Expression of ALP and MMP-13 are mutually exclusive: ALP transcripts were found only in collagen type X positive hypertrophic chondrocytes of the upper zone. MMP-13 expression was restricted to chondrocytes of the lower zone of hypertrophic cartilage also expressing collagen type X. In osteoblasts involved in endochondral and intramembranous ossification Itm2a was not present. ALP, MMP-13, and OC were mutually exclusively expressed in these cells suggesting a differentiation-dependent sequential expression of ALP, MMP-13, and OC. The identification of the continuum of sequential expression of Itm2a, ALP, MMP-13, and OC will now allow us to establish a series of marker genes that are highly suitable to characterize bone cells during chondrocytic and osteoblastic differentiation in vivo.


Spectral domain optical coherence tomography as an adjunctive tool for screening Behçet uveitis.
This study investigated the association of central macular thickness (CMT) and macular volume (MV) with severity of Behçet uveitis in the absence of macular edema (ME). This retrospective, interventional study included a total 131 treatment-naïve Behçet patients with varying degree of uveitis in the absence of ME. The mean CMT and MV were obtained by spectral domain optical coherence tomography (SD ODT). The patients were classified according to the anatomical classification of Behçet uveitis. The main outcome measure was comparison of mean CMT and MV with the types of Behçet uveitis. Sixty patients (45.8%) with no uveitis, 41 patients (31.3%) with anterior uveitis, 18 patients (13.7%) with posterior uveitis, and 12 patients (9.2%) with panuveitis. The mean CMT were 261.6±22.2 μm in no uveitis, 268.1±17.8 μm in anterior uveitis, 306.4±32.9 μm in posterior uveitis, and 300.4±44.0 μm in panuveitis (P < 0.001). The mean MV was 8.7±0.3 mm3 in those without uveitis, 8.8±0.3 mm3 in anterior uveitis, 9.9±1.1 mm3 in those with posterior uveitis, and 9.7±0.4 mm3 in panuveitis (P < 0.001). Types of Behçet uveitis was the only significant factor correlated with the mean CMT (B = 18.170, β = 0.408, P < 0.001) and the mean MV (B = 0.328, β = 0.652, P < 0.001). The mean CMT and MV were significantly thicker in the Behçet uveitis with posterior involvement. SD OCT can be used for an adjunctive tool for screening Behçet uveitis, especially for the presence of posterior involvement.


Performance comparison between 8- and 14-bit-depth imaging in polarization-sensitive swept-source optical coherence tomography.
Recently the effects of reduced bit-depth acquisition on swept-source optical coherence tomography (SS-OCT) image quality have been evaluated by using simulations and empirical studies, showing that image acquisition at 8-bit depth allows high system sensitivity with only a minimal drop in the signal-to-noise ratio compared to higher bit-depth systems. However, in these studies the 8-bit data is actually 12- or 14-bit ADC data numerically truncated to 8 bits. In practice, a native 8-bit ADC could actually possess a true bit resolution lower than this due to the electronic jitter in the converter etc. We compare true 8- and 14-bit-depth imaging of SS-OCT and polarization-sensitive SS-OCT (PS-SS-OCT) by using two hardware-synchronized high-speed data acquisition (DAQ) boards. The two DAQ boards read exactly the same imaging data for comparison. The measured system sensitivity at 8-bit depth is comparable to that for 14-bit acquisition when using the more sensitive of the available full analog input voltage ranges of the ADC. Ex-vivo structural and birefringence images of equine tendon indicate no significant differences between images acquired by the two DAQ boards suggesting that 8-bit DAQ boards can be employed to increase imaging speeds and reduce storage in clinical SS-OCT/PS-SS-OCT systems. One possible disadvantage is a reduced imaging dynamic range which can manifest itself as an increase in image artifacts due to strong Fresnel reflection.


Platinum-catalyzed hydroformylation of terminal and internal octenes.
A brief historic overview of Pt/Sn-catalyzed hydroformylation as well as recent advances in the hydroformylation of internal alkenes is provided. This serves as background for the results obtained with the [Pt(Sixantphos)Cl(2)] system, for which the molecular structure and the spectroscopic data are described. Insitu UV/Vis-spectroscopic studies have revealed rapid formation of the corresponding Pt-stannate complex upon reaction with SnCl(2), whereas high-pressure insitu IR-spectroscopy showed formation of a Pt-CO species and a short-lived Pt-H species under syngas, as well as rapid evolution of aldehyde product upon addition of 1-octene to the preformed catalyst in the IR autoclave. The hydroformylation of 1-octene and the i-octenes has been performed. For the internal alkenes, selective tandem isomerization/hydroformylation towards n-nonanal is observed with this catalyst system.


Developing Program Performance Measures for Rural Emergency Medical Services.
The development of measures to monitor and evaluate the performance and quality of emergency medical services (EMS) systems has been a focus of attention for many years. The Medicare Rural Hospital Flexibility Program (Flex Program), established by Congress in 1997, provides grants to states to implement initiatives to strengthen rural healthcare delivery systems, including better integration of EMS into those systems of care. Building on national efforts to develop EMS performance measures, we sought to identify measures relevant to the rural communities and hospitals supported by the Flex Program. The measures are intended for use in monitoring rural EMS performance at the community level as well as for use by State Flex Programs and the Federal Office of Rural Health Policy (FORHP) to demonstrate the impact of the Flex Program. To evaluate the performance of EMS in rural communities, we conducted a literature search, reviewed research on performance measures conducted by key EMS organizations, and recruited a panel of EMS experts to identify and rate rurally-relevant EMS performance measures as well as emergent protocols for episodes of trauma, ST Elevation Myocardial Infarction (STEMI), and stroke. The rated measures were assessed for inclusion in the final measure set. The Expert Panel identified 17 program performance measures to support EMS services in rural communities. These measures monitor the capacity of local agencies to collect and report quality and financial data, use the data to improve agency performance, and train rural EMS employees in emergent protocols for all age groups. The system of care approach on which this rural EMS measures set is based can support the FORHP's goal of better focusing State Flex Program activity to improve program impact on the performance of rural EMS services in the areas of financial viability, quality improvement, and local/regional health system performance.


The impact of antipsychotic side effects on attitudes towards medication in people with schizophrenia and related disorders.
This research aimed to: (i) investigate the prevalence and perceived severity of antipsychotic side effects in people with schizophrenia and related disorders living in communities in Singapore; (ii) examine the relationship between antipsychotic variables (type, dose, route, prescription duration) and side effects; and (iii) examine the relationship between side effects and attitudes towards medication. Antipsychotics are the mainstay treatment in schizophrenia and other psychotic disorders. However, antipsychotics are associated with a wide range of side effects, which potentially have adverse effects on patients' functioning. A lack of studies comparing the frequency of side effects and their associated levels of distress across multiple antipsychotics and different medication variables has been noted. Additionally, it is essential to assess patients' attitudes towards antipsychotics in relation to their experience of side effects. A cross-sectional, non-experimental research design was used. A convenience sample of 96 adults with schizophrenia and related disorders on antipsychotic treatment and attending the hospital's outpatient clinic was recruited. Variables collected included antipsychotic type, dose, route, prescription duration and side effects, attitudes towards medication and demographic and clinical variables. They were analysed with descriptive statistics and correlational analyses. Many participants experienced psychic (80·2%), extrapyramidal (69·8%) and miscellaneous side effects (61·5%). Side effects positively correlated with dose (p = 0·016) and negatively correlated with prescription duration (p = 0·014). Negative attitudes towards medication were positively correlated with side effects in general (p = 0·023), along with hormonal (p = 0·013) and psychic side effects (p = 0·008). Findings revealed that majority of the participants experienced and were distressed over psychic, extrapyramidal and weight gain, which may be related to high doses and treatment duration. Additionally, patients experiencing psychic and hormonal side effects are at risk of developing negative attitudes towards medication. Findings guide the development of appropriate nursing interventions that aim to alleviate side effects, reduce negative attitudes towards medication and prevent compliance problems.


[The motivation for mental patients' attending industrial medical clinics].
In order to define the possibilities and approaches to the humanization and democratization of labour rehabilitation of mental patients, to reveal and consider individual requirements constituting each patient's personality, a study was made of the motives of attending the treatment and industrial shops (TIS) by them and preferable types of labour activities. Use was made of special formalized maps devised for the given study purposes. All the possible motives of attending TIS and preferable labour activities were registered in those maps as was an objective assessment of the output per man-hour. 221 patients were examined. The results of the examination were assessed in accordance with distribution of the patients by the clinical parameters. The hierarchy of the motives and preferences and output per man-hour depended on the patients' clinical characteristics. Still, it has been established on the whole that attending TIS, 91% were willing to work, 85% to change the environment, 70% to speed up the discharge, 65% to enhance the treatment efficacy, 45% to communicate with new people, 33% to earn money. 46% of the patients reported to work passively, under the influence of persuasions. 71% preferred performing collective work, 68% unsophisticated, 63% very simple work without any responsibility, 53% mobile, 51% sedentary, 49% physical, 32% complicated, 25% individual, 7% intellectual. Only 85% of the patients attending TIS worked. The highest productivity was recorded in patients with borderline mental disorders, the lowest in patients with actual psychotic disorders.


Near-misses and future disaster preparedness.
Disasters garner attention when they occur, and organizations commonly extract valuable lessons from visible failures, adopting new behaviors in response. For example, the United States saw numerous security policy changes following the September 11 terrorist attacks and emergency management and shelter policy changes following Hurricane Katrina. But what about those events that occur that fall short of disaster? Research that examines prior hazard experience shows that this experience can be a mixed blessing. Prior experience can stimulate protective measures, but sometimes prior experience can deceive people into feeling an unwarranted sense of safety. This research focuses on how people interpret near-miss experiences. We demonstrate that when near-misses are interpreted as disasters that did not occur and thus provide the perception that the system is resilient to the hazard, people illegitimately underestimate the danger of subsequent hazardous situations and make riskier decisions. On the other hand, if near-misses can be recognized and interpreted as disasters that almost happened and thus provide the perception that the system is vulnerable to the hazard, this will counter the basic "near-miss" effect and encourage mitigation. In this article, we use these distinctions between resilient and vulnerable near-misses to examine how people come to define an event as either a resilient or vulnerable near-miss, as well as how this interpretation influences their perceptions of risk and their future preparedness behavior. Our contribution is in highlighting the critical role that people's interpretation of the prior experience has on their subsequent behavior and in measuring what shapes this interpretation.


Chain Conformation Control of Fluorene-Benzothiadiazole Copolymer Light-Emitting Diode Efficiency and Lifetime.
The β-phase, in which the intermonomer torsion angle of a fraction of chain segments approaches ∼180°, is an intriguing conformational microstructure of the widely studied light-emitting polymer poly(9,9-dioctylfluorene) (PFO). Its generation can in turn be used to significantly improve the performance of PFO emission-layer-based light-emitting diodes (LEDs). Here, we report the generation of β-phase chain segments in a copolymer, 90F8:10BT, containing 90% 9,9-dioctylfluorene (F8) and 10% 2,1,3-benzothiadiazole (BT) units and show that significant improvements in performance also ensue for LEDs with β-phase 90F8:10BT emission layers, generalizing the earlier PFO results. The β-phase was induced by both solvent vapor annealing and dipping copolymer thin films into a solvent/nonsolvent mixture. Subsequent absorption spectra show the characteristic fluorene β-phase peak at ∼435 nm, but luminescence spectra (∼530 nm peak) and quantum yields barely change, with the emission arising following efficient energy transfer to the lowest-lying excited states localized in the vicinity of the BT units. For ∼5% β-phase chain segment fraction relative to 0% β-phase, the LED luminance at 10 V increased by ∼25% to 5940 cd m-2, the maximum external quantum efficiency by ∼61 to 1.91%, and the operational stability from 64% luminance retention after 20 h of operation to 90%. Detailed studies addressing the underlying device physics identify a reduced hole injection barrier, higher hole mobility, correspondingly more balanced electron and hole charge transport, and decreased carrier trapping as the dominant factors. These results confirm the effectiveness of chain conformation control for fluorene-based homo- and copolymer device optimization.


Differential contribution of superior parietal and dorsal-lateral prefrontal cortices in copying.
In this study we examined the differential contribution of superior parietal cortex (SPC) and caudal dorsal-lateral prefrontal cortex (dlPFC) to drawing geometrical shapes. Monkeys were trained to draw triangles, squares, trapezoids and inverted triangles while we recorded the activity of small ensembles of neurons in caudal area 46 and areas 5 and 2 of parietal cortex. We analyzed the drawing factors encoded by individual neurons by fitting a step-wise general-linear model using as our dependent variable the firing rate averaged over segments of the produced trajectories. This analysis demonstrated that both cognitive (shape and segment serial position) and motor (maximum speed, position and direction of segment) factors modulated the activity of individual neurons. Furthermore, SPC had an enriched representation of both shape and motor factors, with the motor enrichment being stronger than the shape enrichment. Following this we used the activity in the simultaneously recorded neural ensembles to predict the hand velocity. In these analyses we found that the prediction of the hand velocity was better when we estimated different linear decoding functions for each shape than when we estimated a single function across shapes, although it was a subtle effect. Furthermore, we also found that ensembles of caudal dlPFC neurons carried considerable information about hand velocity, a purely motor factor. However, the SPC ensembles carried more information at the ensemble level as a function of the ensemble size than the caudal dlPFC ensembles, although the differences were not dramatic. Finally, an analysis of the response latencies of individual neurons showed that the caudal dlPFC representation was more sensory than the SPC representation, which was equally sensory and motor. Thus, this neurophysiological evidence suggests that both SPC and caudal dlPFC have a role in drawing, but that SPC plays a larger role in both the cognitive and the motor components.


The comprehensive neuro-oncology data repository (CONDR): a research infrastructure to develop and validate imaging biomarkers.
Advanced imaging methods have the potential to serve as quantitative biomarkers in neuro-oncology research. However, a lack of standardization of image acquisition, processing, and analysis limits their application in clinical research. Standardization of these methods and an organized archival platform are required to better validate and apply these markers in research settings and, ultimately, in clinical practice. The primary objective of the Comprehensive Neuro-oncology Data Repository (CONDR) is to develop a data set for assessing and validating advanced imaging methods in patients diagnosed with brain tumors. As a secondary objective, informatics resources will be developed to facilitate the integrated collection, processing, and analysis of imaging, tissue, and clinical data in multicenter clinical trials. Finally, CONDR data and informatics resources will be shared with the research community for further analysis. CONDR will enroll 200 patients diagnosed with primary brain tumors. Clinical, imaging, and tissue-based data are obtained from patients serially, beginning with diagnosis and continuing over the course of their treatment. The CONDR imaging protocol includes structural and functional sequences, including diffusion- and perfusion-weighted imaging. All data are managed within an XNAT-based informatics platform. Imaging markers are assessed by correlating image and spatially aligned pathological markers and a variety of clinical markers. CONDR will generate data for developing and validating imaging markers of primary brain tumors, including multispectral and probabilistic maps. CONDR implements a novel, open-research model that will provide the research community with both open-access data and open-source informatics resources.


Overlap Extension Barcoding for the Next Generation Sequencing and Genotyping of Plasmodium falciparum in Individual Patients in Western Kenya.
Large-scale molecular epidemiologic studies of Plasmodium falciparum parasites have provided insights into parasite biology and transmission, can identify the spread of drug resistance, and are useful in assessing vaccine targets. The polyclonal nature infections in high transmission settings is problematic for traditional genotyping approaches. Next-generation sequencing (NGS) approaches to parasite genotyping allow sensitive detection of minority variants, disaggregation of complex parasite mixtures, and scalable processing of large samples sets. Therefore, we designed, validated, and applied to field parasites an approach that leverages sequencing of individually barcoded samples in a multiplex manner. We utilize variant barcodes, invariant linker sequences and modular template-specific primers to allow for the simultaneous generation of high-dimensional sequencing data of multiple gene targets. This modularity permits a cost-effective and reproducible way to query many genes at once. In mixtures of reference parasite genomes, we quantitatively detected unique haplotypes comprising as little as 2% of a polyclonal infection. We applied this genotyping approach to field-collected parasites collected in Western Kenya in order to simultaneously obtain parasites genotypes at three unlinked loci. In summary, we present a rapid, scalable, and flexible method for genotyping individual parasites that enables molecular epidemiologic studies of parasite evolution, population structure and transmission.


Intracerebral delivery of 5-iodo-2'-deoxyuridine in combination with synchrotron stereotactic radiation for the therapy of the F98 glioma.
Iodine-enhanced synchrotron stereotactic radiotherapy takes advantage of the radiation dose-enhancement produced by high-Z elements when irradiated with mono-energetic beams of synchrotron X-rays. In this study it has been investigated whether therapeutic efficacy could be improved using a thymidine analogue, 5-iodo-2'-deoxyuridine (IUdR), as a radiosentizing agent. IUdR was administered intracerebrally over six days to F98 glioma-bearing rats using Alzet osmotic pumps, beginning seven days after tumor implantation. On the 14th day, a single 15 Gy dose of 50 keV synchrotron X-rays was delivered to the brain. Animals were followed until the time of death and the primary endpoints of this study were the mean and median survival times. The median survival times for irradiation alone, chemotherapy alone or their combination were 44, 32 and 46 days, respectively, compared with 24 days for untreated controls. Each treatment alone significantly increased the rats' survival in comparison with the untreated group. Their combination did not, however, significantly improve survival compared with that of X-irradiation alone or chemotherapy alone. Further studies are required to understand why the combination of chemoradiotherapy was no more effective than X-irradiation alone.


Exploring Mediators of a Guided Web-Based Self-Help Intervention for People With HIV and Depressive Symptoms: Randomized Controlled Trial.
Cognitive behavioral therapy (CBT) is frequently used to treat depressive symptoms in people living with HIV. We developed an internet-based cognitive behavioral intervention for people with HIV and depressive symptoms, which was based on an effective self-help booklet. The Web-based intervention was previously found to be effective. The objective of this study was to investigate potential mediators of the Web-based intervention. This study was part of a randomized controlled trial, in which the intervention was compared with an attention-only waiting list control condition. Participants were 188 (97 in intervention group and 91 in control group) people with HIV and mild to moderate depressive symptoms recruited in HIV treatment centers in the Netherlands. A total of 22 participants (22/188, 11.7%) in the study were female and 166 (166/188, 88.3%) were male. The average age of the participants was 46.30 years (SD 10.63). The intervention comprised Web-based self-help CBT for 8 weeks, 1 to 2 hours a week, including minimal telephone support from a coach. The participants received Web-based questionnaires at pretest, 3 times during the intervention/or waiting period, and post intervention. The outcome was depressive symptoms. Factors tested as potential mediators were changes in behavioral activation, relaxation, the cognitive coping strategies catastrophizing and positive refocusing, goal re-engagement, and coping self-efficacy. Using multilevel structural equation modeling, changes in behavioral activation (P=.006) and goal re-engagement (P=.009) were found to be significant mediators of the intervention effect. The mediation effect seemed to occur between weeks 3 and 5 for behavioral activation and weeks 1 and 3 for goal re-engagement. Using (bivariate) autoregressive latent trajectory analysis, we found a return effect (from the dependent variable to the mediator) for goal re-engagement but not for behavioral activation, which suggested that the mediation effect of changes in behavioral activation was stronger than that in goal re-engagement. The results suggest that changes in behavioral activation and goal re-engagement may mediate the effect of the Web-based intervention for people with HIV and depressive symptoms. The results may lead to possible mechanisms of change of the intervention and improvement of therapy outcomes. Netherlands Trial Register NTR5407; https://www.trialregister.nl/trial/5298.


Foraging mode constrains the evolution of cephalic horns in lizards and snakes.
A phylogenetically diverse minority of snake and lizard species exhibit rostral and ocular appendages that substantially modify the shape of their heads. These cephalic horns have evolved multiple times in diverse squamate lineages, enabling comparative tests of hypotheses on the benefits and costs of these distinctive traits. Here, we demonstrate correlated evolution between the occurrence of horns and foraging mode. We argue that although horns may be beneficial for various functions (e.g. camouflage, defence) in animals that move infrequently, they make active foragers more conspicuous to prey and predators, and hence are maladaptive. We therefore expected horns to be more common in species that ambush prey (entailing low movement rates) rather than in actively searching (frequently moving) species. Consistent with that hypothesis, our phylogenetic comparative analysis of published data on 1939 species reveals that cephalic horns occur almost exclusively in sit-and-wait predators. This finding underlines how foraging mode constrains the morphology of squamates and provides a compelling starting point for similar studies in other animal groups.