Comparison of oxygen uptake during a conventional treadmill test and the shuttle walking test in chronic airflow limitation.
The purpose of this study was to investigate the relationship between performance on the shuttle walking test and maximal oxygen uptake (VO2max) during a conventional treadmill test in patients with chronic airflow limitation. Two different techniques were used to measure oxygen consumption, i.e. conventional Douglas bag techniques (treadmill test) and a portable oxygen consumption meter (shuttle test). Initially, 19 patients performed a shuttle walking test (after one practice walk) and a maximal treadmill walking test, in a randomized, balanced design. Subsequently, 10 patients, (after one practice) completed an unencumbered shuttle walking test and one supporting the portable oxygen consumption meter, in random order. The results of the first experiment revealed a strong relationship between performance during the shuttle walking test and VO2max during the treadmill walking test (r = 0.88). The results of the second experiment consistently demonstrated an incremental increase in oxygen consumption and ventilation in response to the increasing intensity of the shuttle walking test. Again, a strong relationship between VO2max and performance on the shuttle test was demonstrated (r = 0.81). We concluded that the shuttle walking test is a valid field exercise test of functional capacity. Performance on the test relates strongly to VO2max, the traditional indicator of cardiorespiratory capacity.


Influence of multiple scattering on subwavelength imaging: transverse electric case.
This paper uses the Cramér-Rao bound (CRB) to investigate the role of multiple scattering in the framework of transverse electric (TE) electromagnetic inverse scattering. The surface mode in the TE scattering case enables a strong multiple scattering effect even if the scatterers are widely separated. We show that multiple scattering does not always improve the accuracy of the estimation, compared with that expected with a fictitious single scattering model. The reason for the aforementioned conclusion is discussed. Two scenarios that favor the multiple scattering effect are discussed, and the differences between these scenarios and the CRB analysis are highlighted.


Nonlinear integration of sensory responses in the rat barrel cortex: an intracellular study in vivo.
To study integration of converging sensory inputs on single cortical neurons, we performed intracellular recordings in vivo in the barrel cortex of the barbiturate-anesthetized rat. We deflected the principal whisker (PW) for each cell either alone or preceded (at 20, 50, and 100 msec) by the deflection of a small number of remote whiskers (RWs) far from the PW. The synaptic responses to both the PW and the RW were similar qualitatively and consisted of excitation followed by inhibition that comprised an early and a late component. The RW response was of smaller amplitude and more often subthreshold for action potential generation. The main effect of the RW deflection was a suppression of the subsequent response to the PW that was most pronounced at the 20 msec interval and decreased progressively at the 50 and 100 msec intervals. Suppression of the spike output of the cell was not caused by hyperpolarization (subtractive inhibition) but by a reduction in the EPSP amplitude (divisive inhibition), resulting in a highly sublinear summation of the two responses. The small decrease in input resistance caused by the RW responses is not consistent with synaptic shunting as the main cause of the reduction of the EPSP amplitude. Instead, our results suggest that suppression results from a decrease in the amount of synaptic input triggered by the PW, particularly the early excitation. We suggest that this process involves a reduction in reverberant granular cell excitation that is induced by PW deflection.


Atmospheric turbulence in optical surveillance systems.
The limitations imposed by atmospheric turbulence in the design of optical surveillance systems with slant optical paths are developed. Image blurring effects which determine scene contrast ratio are separated from spot dancing effects which determine signal-to-noise ratio. The relative position of each turbulent eddy with respect to scene and observer is considered. The effects of turbulence in ground-to-ground, air-to-ground, and ground-to-air optical surveillance systems are compared.


Biomechanical Characterization of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Use of Atomic Force Microscopy.
Atomic force microscopy (AFM) is not only a high-resolution imaging technique but also a sensitive tool able to study biomechanical properties of bio-samples (biomolecules, cells) in native conditions-i.e., in buffered solutions (culturing media) and stable temperature (mostly 37 °C). Micromechanical transducers (cantilevers) are often used to map surface stiffness distribution, adhesion forces, and viscoelastic parameters of living cells; however, they can also be used to monitor time course of cardiomyocytes contraction dynamics (e.g. beating rate, relaxation time), together with other biomechanical properties. Here we describe the construction of an AFM-based biosensor setup designed to study the biomechanical properties of cardiomyocyte clusters, through the use of standard uncoated silicon nitride cantilevers. Force-time curves (mechanocardiograms, MCG) are recorded continuously in real time and in the presence of cardiomyocyte-contraction affecting drugs (e.g., isoproterenol, metoprolol) in the medium, under physiological conditions. The average value of contraction force and the beat rate, as basic biomechanical parameters, represent pharmacological indicators of different phenotype features. Robustness, low computational requirements, and optimal spatial sensitivity (detection limit 200 pN, respectively 20 nm displacement) are the main advantages of the presented method.


The Alberta Hip and Knee Replacement Project: a model for health technology assessment based on comparative effectiveness of clinical pathways.
The Alberta Hip and Knee Replacement Project developed a new evidence-based clinical pathway (NCP) for total hip (THR) and knee (TKR) replacement. The aim was to facilitate the delivery of services in a timely and cost-effective manner while achieving the highest quality of care for the patient across the full continuum of care from patient referral to an orthopedic surgeon through surgery, recovery, and rehabilitation. The purpose of this article is to provide an overview of the study design, rationale, and execution of this project as a model for health technology assessment based on comparative effectiveness of alternative clinical pathways. A pragmatic randomized controlled trial study design was used to evaluate the NCP compared with the standard of care (SOC) for these procedures. The pragmatic study design was selected as a rigorous approach to produce high quality evidence suitable for informing decisions between relevant interventions in real clinical practice. The NCP was evaluated in three of the nine regional health authorities (RHAs) in Alberta with dedicated central intake clinics offering multidisciplinary care teams, constituting 80 percent of THR and TKR surgeries performed annually in Alberta. Patients were identified in the offices of twenty orthopedic surgeons who routinely performed THR or TKR surgeries. Evaluation outcome measures were based on the six dimensions of the Alberta Quality Matrix for Health (AQMH): acceptability, accessibility, appropriateness, effectiveness, efficiency and safety. Data were collected prospectively through patient self-completed questionnaires at baseline and 3 and 12 months after surgery, ambulatory and inpatient chart reviews, and electronic administrative data. The trial design was successful in establishing similar groups for rigorous evaluation. Of the 4,985 patients invited to participate, 69 percent of patients consented. A total of 3,434 patients were randomized: 1,712 to SOC and 1,722 to the NCP. The baseline characteristics of patients in the two study arms, including demographics, comorbidity as measured by CDS and exposure to pain medications, and health-related quality of life, as measured by Western Ontario and McMaster Universities Osteoarthritis Index and Short Form-36, were similar. The Alberta Hip and Knee Replacement Project demonstrates the feasibility and advantages of applying a pragmatic randomized controlled trial to ascertain comparative effectiveness. This is a model for health technology assessment that incorporates how clinical pathways can be effectively evaluated.


Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome.
Andersen's syndrome, an autosomal dominant disorder related to mutations of the potassium channel Kir2.1, is characterized by cardiac arrhythmias, periodic paralysis, and dysmorphic bone structure. The aim of our study was to find out whether heteromerization of Kir2.1 channels with wild-type Kir2.2 and Kir2.3 channels contributes to the phenotype of Andersen's syndrome. The following results show that Kir2.x channels can form functional heteromers: (i) HEK293 cells transfected with Kir2.x-Kir2.y concatemers expressed inwardly rectifying K(+) channels with a conductance of 28-30 pS. (ii) Expression of Kir2.x-Kir2.y concatemers in Xenopus oocytes produced inwardly rectifying, Ba(2+) sensitive currents. (iii) When Kir2.1 and Kir2.2 channels were coexpressed in Xenopus oocytes the IC(50) for Ba(2+) block of the inward rectifier current differed substantially from the value expected for independent expression of homomeric channels. (iv) Coexpression of nonfunctional Kir2.x constructs, in which the GYG region of the pore region was replaced by AAA, with wild-type Kir2.x channels produced both homomeric and heteromeric dominant-negative effects. (v) Kir2.1 and Kir2.3 channels could be coimmunoprecipitated in membrane extracts from isolated guinea pig cardiomyocytes. (vi) Yeast two-hybrid analysis showed interaction between the N- and C-terminal intracellular domains of different Kir2.x subunits. Coexpression of Kir2.1 mutants related to Andersen's syndrome with wild-type Kir2.x channels showed a dominant negative effect, the extent of which varied between different mutants. Our results suggest that differential tetramerization of the mutant allele of Kir2.1 with wild-type Kir2.1, Kir2.2, and Kir2.3 channels represents the molecular basis of the extraordinary pleiotropy of Andersen's syndrome.


Improved antioxidative defence protects insulin-producing cells against homocysteine toxicity.
Homocysteine (HC) is considered to play an important role in the development of metabolic syndrome complications. Insulin-producing cells are prone to HC toxicity and this has been linked to oxidative stress. However, the exact mechanisms remain unknown. Therefore it was the aim of this study to determine the nature of reactive oxygen species responsible for HC toxicity. Chronic exposure of RINm5F and INS1E insulin-producing cells to HC decreased cell viability and glucose-induced insulin secretion in a concentration-dependent manner and led to a significant induction of hydrogen peroxide generation in the cytosolic, but not the mitochondrial compartment of the cell. Cytosolic overexpression of catalase, a hydrogen peroxide detoxifying enzyme, provided a significant protection against viability loss and hydrogen peroxide generation, while mitochondrial overexpression of catalase did not protect against HC toxicity. Overexpression of CuZnSOD, a cytosolic superoxide dismutating enzyme, also protected against HC toxicity. However, the best protection was achieved in the case of a combined overexpression of CuZnSOD and catalase. Incubation of cells in combination with alloxan resulted in a significant increase of HC toxicity and an increase of hydrogen peroxide generation. Overexpression of CuZnSOD or catalase protected against the toxicity of HC plus alloxan, with a superior protection achieved again by combined overexpression. The results indicate that HC induces oxidative stress in insulin-producing cells by stimulation of superoxide radical and hydrogen peroxide generation in the cytoplasm. The low antioxidative defence status makes the insulin-producing cells very vulnerable to HC toxicity.


NRF IRES activity is mediated by RNA binding protein JKTBP1 and a 14-nt RNA element.
The mRNA of human NF-kappaB repressing factor (NRF) contains a long 5'-untranslated region (UTR) that directs ribosomes to the downstream start codon by a cap-independent mechanism. Comparison of the nucleotide (nt) sequences of human and mouse NRF mRNAs reveals a high degree of identity throughout a fragment of 150 nt proximal to the start codon. Here, we show that this region constitutes a minimal internal ribosome entry segment (IRES) module. Enzymatic RNA structure analysis reveals a secondary structure model of the NRF IRES module. Point mutation analysis of the module determines a short, 14-nt RNA element (nt 640-653) as a mediator of IRES function. Purification of IRES binding cellular proteins and subsequent ESI/MS/MS sequence analysis led to identification of the RNA-binding protein, JKTBP1. EMSA experiments show that JKTBP1 binds upstream to the 14-nt RNA element in the NRF IRES module (nt 579-639). Over-expression of JKTBP1 significantly enhances activity of the NRF IRES module in dicistronic constructs. Moreover, siRNA experiments demonstrate that down-regulation of endogenous JKTBP1 decreases NRF IRES activity and the level of endogenous NRF protein. The data of this study show that JKTBP1 and the 14-nt element act independently to mediate NRF IRES activity.


Purification and refolding of anti-T-antigen single chain antibodies (scFvs) expressed in Escherichia coli as inclusion bodies.
T-antigen (Galβ1-3GalNAcα-1-Ser/Thr) is an oncofetal antigen that is commonly expressed as a carbohydrate determinant in many adenocarcinomas. Since it is associated with tumor progression and metastasis, production of recombinant antibodies specific for T-antigen could lead to the development of cancer diagnostics and therapeutics. Previously, we isolated and characterized 11 anti-T-antigen phage clones from a phage library displaying human single-chain antibodies (scFvs) and purified one scFv protein, 1G11. More recently, we purified and characterized 1E8 scFv protein using a Drosophila S2 expression system. In the current study, four anti-T-antigen scFv genes belonging to Groups 1-4 were purified from inclusion bodies expressed in Escherichia coli cells. Inclusion bodies isolated from E. coli cells were denatured in 3.5 M Gdn-HCl. Solubilized His-tagged scFv proteins were purified using Ni(2+)-Sepharose column chromatography in the presence of 3.5 M Gdn-HCl. Purified scFv proteins were refolded according to a previously published method of step-wise dialysis. Two anti-T-antigen scFv proteins, 1E6 and 1E8 that belong to Groups 1 and 2, respectively, were produced in sufficient amounts, thus allowing further characterization of their binding activity with T-antigen. Specificity and affinity constants determined using enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR), respectively, provided evidence that both 1E8 and 1E6 scFv proteins are T-antigen specific and suggested that 1E8 scFv protein has a higher affinity for T-antigen than 1E6 scFv protein.


Use of mycelial-phase Sporothrix schenckii exoantigens in an enzyme-linked immunosorbent assay for diagnosis of sporotrichosis by antibody detection.
An enzyme-linked immunosorbent assay (ELISA) was developed for specific antibody detection in serum specimens of patients with sporotrichosis. The assay was made with mycelial-phase Sporothrix schenckii exoantigens and was tested against 90 sera from patients with different clinical forms of sporotrichosis. Potential cross-reactions were analyzed with 72 heterologous sera from patients with paracoccidioidomycosis, cryptococcosis, aspergillosis, histoplasmosis, tuberculosis, and American tegumentary leishmaniasis, as well as 76 sera from healthy controls. We found a sensitivity of 97% and a specificity of 89% in this assay. Some cross-reactions were seen, as observed in other immunoassays for the diagnosis of sporotrichosis. The ELISA appears to be especially useful for cutaneous forms of disease, since these are not promptly diagnosed with available immunoprecipitation or agglutination techniques. These results suggest that the ELISA using mycelial-phase S. schenckii exoantigens is a very sensitive diagnostic tool for the serodiagnosis of sporotrichosis and can be used in conjunction with conventional methods of diagnosis, particularly in cases where cross-reactions or false-positive results are experienced with the serodiagnosis.


Role of calcium ions in the positive interaction between TRPA1 and TRPV1 channels in bronchopulmonary sensory neurons.
Both transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are abundantly expressed in bronchopulmonary C-fiber sensory nerves and can be activated by a number of endogenous inflammatory mediators. A recent study has reported a synergistic effect of simultaneous TRPA1 and TRPV1 activations in vagal pulmonary C-fiber afferents in anesthetized rats, but its underlying mechanism was not known. This study aimed to characterize a possible interaction between these two TRP channels and to investigate the potential role of Ca(2+) as a mediator of this interaction in isolated rat vagal pulmonary sensory neurons. Using the perforated patch-clamp recording technique, our study demonstrated a distinct positive interaction occurring abruptly between TRPA1 and TRPV1 when they were activated simultaneously by their respective agonists, capsaicin (Cap) and allyl isothiocyanate (AITC), at near-threshold concentrations in these neurons. AITC at this low concentration evoked only minimal or undetectable responses, but it markedly amplified the Cap-evoked current in the same neurons. This potentiating effect was eliminated when either AITC or Cap was replaced by non-TRPA1 and non-TRPV1 chemical activators of these neurons, demonstrating the selectivity of the interaction between these two TRP channels. Furthermore, when Ca(2+) was removed from the extracellular solution, the synergistic effect of Cap and AITC on pulmonary sensory neurons was completely abrogated, clearly indicating a critical role of Ca(2+) in mediating the action. These results suggest that this TRPA1-TRPV1 interaction may play a part in regulating the sensitivity of pulmonary sensory neurons during airway inflammatory reaction.


The effects of mind-body therapies on the immune system: meta-analysis.
Psychological and health-restorative benefits of mind-body therapies have been investigated, but their impact on the immune system remain less defined. To conduct the first comprehensive review of available controlled trial evidence to evaluate the effects of mind-body therapies on the immune system, focusing on markers of inflammation and anti-viral related immune responses. Data sources included MEDLINE, CINAHL, SPORTDiscus, and PsycINFO through September 1, 2013. Randomized controlled trials published in English evaluating at least four weeks of Tai Chi, Qi Gong, meditation, or Yoga that reported immune outcome measures were selected. Studies were synthesized separately by inflammatory (n = 18), anti-viral related immunity (n = 7), and enumerative (n = 14) outcomes measures. We performed random-effects meta-analyses using standardized mean difference when appropriate. Thirty-four studies published in 39 articles (total 2, 219 participants) met inclusion criteria. For inflammatory measures, after 7 to 16 weeks of mind-body intervention, there was a moderate effect on reduction of C-reactive protein (effect size [ES], 0.58; 95% confidence interval [CI], 0.04 to 1.12), a small but not statistically significant reduction of interleukin-6 (ES, 0.35; 95% CI, -0.04 to 0.75), and negligible effect on tumor necrosis factor-α (ES, 0.21; 95% CI, -0.15 to 0.58). For anti-viral related immune and enumerative measures, there were negligible effects on CD4 counts (ES, 0.15; 95% CI, -0.04 to 0.34) and natural killer cell counts (ES, 0.12, 95% CI -0.21 to 0.45). Some evidence indicated mind-body therapies increase immune responses to vaccination. Mind-body therapies reduce markers of inflammation and influence virus-specific immune responses to vaccination despite minimal evidence suggesting effects on resting anti-viral or enumerative measures. These immunomodulatory effects, albeit incomplete, warrant further methodologically rigorous studies to determine the clinical implications of these findings for inflammatory and infectious disease outcomes.


Local pH tracking in living cells.
Continuous and simultaneous 3D single-particle movement and local pH detection in HeLa cells were demonstrated for the first time by combining fluorescent mesoporous silica nanoparticles (FMSNs) and a single-particle tracking (SPT) technique with a precision of ∼10 nm. FMSNs, synthesized by the co-condensation of both pH-sensitive and reference dyes with a silica/surfactant source, allow long-term reliable ratiometric pH measurements with a precision better than 0.3 pH unit because of their excellent brightness and stability. pH variation in the surrounding area of FMSNs during endocytosis was monitored in real-time. Acidification and low mobility of FMSNs were observed at the early endocytic stage, whereas basification and high mobility of FMSNs were observed at the late stage. Our results indicate that it is possible to monitor local pH changes in the environments surrounding nanoparticles during the cellular uptake process of FMSNs, which provides much needed information for designing an efficient drug delivery nanosystem.


Quality of life impact and recovery after ureteroscopy and stent insertion: insights from daily surveys in STENTS.
Our objective was to describe day-to-day evolution and variations in patient-reported stent-associated symptoms (SAS) in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS), a prospective multicenter observational cohort study, using multiple instruments with conceptual overlap in various domains. In a nested cohort of the STENTS study, the initial 40 participants having unilateral ureteroscopy (URS) and stent placement underwent daily assessment of self-reported measures using the Brief Pain Inventory short form, Patient-Reported Outcome Measurement Information System measures for pain severity and pain interference, the Urinary Score of the Ureteral Stent Symptom Questionnaire, and Symptoms of Lower Urinary Tract Dysfunction Research Network Symptom Index. Pain intensity, pain interference, urinary symptoms, and bother were obtained preoperatively, daily until stent removal, and at postoperative day (POD) 30. The median age was 44 years (IQR 29,58), and 53% were female. The size of the dominant stone was 7.5 mm (IQR 5,11), and 50% were located in the kidney. There was consistency among instruments assessing similar concepts. Pain intensity and urinary symptoms increased from baseline to POD 1 with apparent peaks in the first 2 days, remained elevated with stent in situ, and varied widely among individuals. Interference due to pain, and bother due to urinary symptoms, likewise demonstrated high individual variability. This first study investigating daily SAS allows for a more in-depth look at the lived experience after URS and the impact on quality of life. Different instruments measuring pain intensity, pain interference, and urinary symptoms produced consistent assessments of patients' experiences. The overall daily stability of pain and urinary symptoms after URS was also marked by high patient-level variation, suggesting an opportunity to identify characteristics associated with severe SAS after URS.


Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.
Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.


Surgical Results of Common Peroneal Nerve Neuroplasty at Lateral Fibular Neck.
Common peroneal nerve (CPN) compressive neuropathy is the most common lower-extremity entrapment neuropathy. A retrospective review of a prospectively maintained single-institution database of all patients with CPN palsy who underwent decompression and neuroplasty over a 5-year period was performed. Thirty patients underwent a neuroplasty of the CPN over a 5-year period (2010-2015) at our institution. The median age was 45 years, and there was a male preponderance. The average time between first onset of symptoms to surgery was 122.9 weeks and between first clinic visit and surgery was 21 weeks. The etiology of the CPN neuropathy was as follows: in 12 patients, it followed a surgical procedure and in 14 patients, it occurred after a trauma to the lower extremity. In 2 patients, it occurred as a result of a mass lesion compromising the nerve and in 1 patient, a local infection predisposed to CPN palsy. Right and left lower extremities were equally involved. The median body mass index was 28.6. The most common presentation was weakness of the tibialis anterior (TA) and extensor hallucis longus (EHL) and loss of sensation in the distribution of the CPN or one of its major branches. Pain was a presenting symptom in 16 patients. Only 12 of the 30 patients had a positive Tinel's sign at the site of compression over the lateral fibular neck. Preoperative electrophysiologic confirmation of CPN neuropathy was available in all patients. Mean follow-up was 52 weeks. Prone positioning and selective use of the operating microscope provided excellent visualization and surgical exposure of the CPN from the lower popliteal region to the peroneal tunnel. Average operating room time was 170 minutes and average skin-to-skin time 91 minutes. Clinical improvement after surgery in terms of motor function was noted in 24 of the 26 patients who presented with a motor deficit. The most consistent improvement was noted in the TA and EHL; a trend toward greater improvement with shorter time to surgery was noted. No complications related to the surgical site or CPN were encountered, and no patient had a decline in their neurologic examination as a consequence of the surgery. One patient developed a positioning-related right upper-extremity brachial plexus neuropraxic injury after surgery that recovered completely. Common peroneal neuropathy usually presents with weakness of the TA and EHL and decreased sensation or pain in the distribution of the CPN. Microscope-assisted surgical neuroplasty of the CPN at the lateral fibular neck with the patient in a prone position allows decompression of the nerve from the lower popliteal region to the peroneal tunnel. Significant improvement in motor strength after surgery, particularly of the TA and EHL, was observed in this series.


A review of technology-based interventions to maintain weight loss.
For many decades, healthcare providers and researchers have developed weight-loss interventions to help people achieve weight loss. Unfortunately, it is typical for people to lose weight quickly during the intervention period but then slowly regain weight until they return to their approximate baseline. Technology-based maintenance interventions are among the newest approaches to long-term weight loss. Several advantages make technology helpful for maintaining weight loss. The purpose of this article was to review and critique the randomized controlled trials of technology-based weight-loss maintenance interventions (WLMIs) for adults. A systematic search through electronic databases and a manual citation search were conducted. Limited numbers of controlled trials published since 2000 that included randomization, and technology-based WLMIs were identified. The characteristics of the eight studies were diverse. The average score of study design quality was moderate. The results of the effectiveness of technology-based WLMIs were mixed. Technology-based WLMIs are more likely to be effective than usual care but not more effective than personal contact. Based on the review, guidelines were established for the selection and potential success of technology-based WLMIs. The effectiveness of technology-based maintenance interventions for weight loss varied, and potential strategies and approaches are discussed to improve their effectiveness. Further studies are needed to better evaluate and refine the efficacy of technology-based WLMIs.


Deterioration of high-moisture corn.
Two small, leaky silos were filled with normal high-moisture corn (HMC), and two with HMC severely infested by Helminthosporium maydis. Counts of mesophilic bacteria, lactobacilli, coliforms, yeasts, and molds were made on corn samples as received and periodically thereafter during 220 days of storage. Temperature and gas levels also were monitored. Sequential changes in the populations of lactobacilli, yeasts, and molds were determined during spoilage of HMC. These population changes were compared on the basis of the variables encountered in the present study as well as with the results of previous studies conducted on normal HMC stored under adequate conditions. Heavy infestation by H. maydis had no appreciable effect on HMC preservation.


Approach to the diagnosis and management of suspected exercise-induced bronchoconstriction by primary care physicians.
Exercise-related respiratory symptoms in the diagnosis of exercise-induced bronchoconstriction (EIB) have poor predictive value. The aim of this study was to evaluate how athletes presenting with these symptoms are diagnosed and managed in primary care. An electronic survey was distributed to a random selection of family practitioners in England. The survey was designed to assess the frequency with which family practitioners encounter adults with exercise-related respiratory symptoms and how they would approach diagnostic work-up and management. The survey also evaluated awareness of and access to diagnostic tests in this setting and general knowledge of prescribing asthma treatments to competitive athletes. 257 family practitioners completed the online survey. One-third of respondents indicated they encountered individuals with this problem at a frequency of more than one case per month. Over two-thirds of family practitioners chose investigation as an initial management strategy, while one-quarter would initiate treatment based on clinical information alone. PEFR pre- and post-exercise was the most commonly selected test for investigation (44%), followed by resting spirometry pre- and post-bronchodilator (35%). Short-acting beta2-agonists were the most frequently selected choice of treatment indicated by respondents (90%). Family practitioners encounter individuals with exercise-related respiratory symptoms commonly and although objective testing is often employed in diagnostic work-up, the tests most frequently utilised are not the most accurate for diagnosis of EIB. This diagnostic approach may be dictated by the reported lack of access to more precise testing methods, or may reflect a lack of dissemination or awareness of current evidence. Overall the findings have implications both for the management and hence welfare of athletes presenting with this problem to family practitioners and also for the competitive athletes requiring therapeutic use exemption.


Structural brain correlates of adolescent resilience.
Despite calls for integration of neurobiological methods into research on youth resilience (high competence despite high adversity), we know little about structural brain correlates of resilient functioning. The aim of the current study was to test for brain regions uniquely associated with positive functioning in the context of adversity, using detailed phenotypic classification. 1,870 European adolescents (Mage = 14.56 years, SDage = 0.44 years, 51.5% female) underwent MRI scanning and completed behavioral and psychological measures of stressful life events, academic competence, social competence, rule-abiding conduct, personality, and alcohol use. The interaction of competence and adversity identified two regions centered on the right middle and superior frontal gyri; grey matter volumes in these regions were larger in adolescents experiencing adversity who showed positive adaptation. Differences in these regions among competence/adversity subgroups were maintained after controlling for several covariates and were robust to alternative operationalization decisions for key constructs. We demonstrate structural brain correlates of adolescent resilience, and suggest that right prefrontal structures are implicated in adaptive functioning for youth who have experienced adversity.


A methodological approach for the on-site quantification of food losses in primary production: Austrian and German case studies using the example of potato harvest.
In the last decade, in many European Countries more and more measures have been initiated aiming at the prevention of food losses and wastes along the entire value chain. In order to evaluate or monitor such important measures it is crucial to obtain quantitative information on generated food waste amounts, subsequently enabling the quantitative evaluation of the measure's outcomes and efficiency. Currently there is a paucity of quantitative information, particularly on food losses that are directly generated during harvesting processes. Up to date, no method is available or standardised aiming at the in-situ or on-site quantification of food losses during harvest. Using the example of the potato harvest, this study presents a practical approach for determining potato losses. To test the applicability of the developed method, on-site measurements were conducted directly on the field at five different locations in Austria and Germany. Our method enables the quantification of food losses based on defined areas along the harvested potato rows, where the analyser manually collects potatoes during their harvest. Hereby, two types of potato losses needs to be considered: non-harvested, under-sized potatoes that remain under the earth and the harvested ones, which are rejected on-site because of quality requirements regarding their size, shape, and state of health. Our study shows that between 1 and 9% of field losses (based on yield potential) can be generated during the potato harvest. In future, this method may be the basis for standardised protocols in order to be able to derive cultivar-specific benchmarks and, consequently, to develop measures for preventing food losses. In general, more case studies and evidence-based ground-up measurements on other cultivars and for other regions are needed focusing on the on-site quantification of post-harvest losses.


Overlapping and parallel cerebello-cerebral networks contributing to sensorimotor control: an intrinsic functional connectivity study.
In concert with sensorimotor control areas of the cerebrum, the cerebellum shows differential activation patterns during a variety of sensorimotor-related tasks. However, the spatial details and extent of the complex and heterogeneous cerebello-cerebral systems involved in action control remain uncertain. In this study, we use intrinsic functional connectivity (iFC) to examine cerebello-cerebral networks of five cerebellar lobules (I-IV, V, VI, and VIIIa/b) that have been empirically identified to form the functional basis of sensorimotor processes. A refined cerebellar seed-region selection allowed us to identify a network of primary sensorimotor and supplementary motor areas (I-V), a network of prefrontal, premotor, occipito-temporal and inferior-parietal regions (VI), and two largely overlapping networks involving premotor and superior parietal regions, the temporo-parietal junction as well as occipito-temporal regions (VIIIa/b). All networks involved the medial prefrontal/cingulate cortex. These cerebral clusters were used in a partial correlation analysis to systematically map cerebral connectivity throughout the entire cerebellum. We discuss these findings in the framework of affective and cognitive control, sensorimotor, multisensory systems, and executive/language systems. Within the cerebellum we found that cerebro-cerebellar systems seem to run in parallel, as indicated by distinct sublobular functional topography of prefrontal, parietal, sensorimotor, cingulate, and occipito-temporal regions. However, all areas showed overlapping connectivity to various degrees in both hemispheres. The results of both analyses demonstrate that different sublobular parts of the cerebellar lobules may dominate in different aspects of primary or higher-order sensorimotor processing. This systems-level cerebellar organization provides a more detailed structure for cerebello-cerebral interaction which contributes to our understanding of complex motor behavior.


Replication protein A-mediated recruitment and activation of Rad17 complexes.
The human Rad17-Rfc2-5 and Rad9-Rad1-Hus1 complexes play crucial roles in the activation of the ATR-mediated DNA damage and DNA replication stress response pathways. In response to DNA damage, Rad9 is recruited to chromatin in a Rad17-dependent manner in human cells. However, the DNA structures recognized by the Rad17-Rfc2-5 complex during the damage response have not been defined. Here, we show that replication protein A (RPA) stimulates the binding of the Rad17-Rfc2-5 complex to single-stranded DNA (ssDNA), primed ssDNA, and a gapped DNA structure. Furthermore, RPA facilitates the recruitment of the Rad9-Rad1-Hus1 complex by the Rad17-Rfc2-5 complex to primed and gapped DNA structures in vitro. These findings suggest that RPA-coated ssDNA is an important part of the structures recognized by the Rad17-Rfc2-5 complex. Unlike replication factor C (RFC), which uses the 3' primer/template junction to recruit proliferating cell nuclear antigen (PCNA), the Rad17-Rfc2-5 complex can use both the 5' and the 3' primer/template junctions to recruit the Rad9-Rad1-Hus1 complex, and it shows a preference for gapped DNA structures. These results explain how the Rad17-Rfc2-5 complex senses DNA damage and DNA replication stress to initiate checkpoint signaling.


Rhizoxin analogs contribute to the biocontrol activity of a newly isolated pseudomonas strain.
Two strains of Pseudomonas sp., Os17 and St29, were newly isolated from the rhizosphere of rice and potato, respectively, by screening for 2,4-diacetylphloroglucinol producers. These strains were found to be the same species and were the closest to but different from Pseudomonas protegens among the sequenced pseudomonads, based on 16S ribosomal RNA gene and whole-genome analyses. Strain Os17 was as effective a biocontrol agent as reported for P. protegens Cab57, whereas strain St29 was less effective. The whole-genome sequences of these strains were obtained: the genomes are organized into a single circular chromosome with 6,885,464 bp, 63.5% G+C content, and 6,195 coding sequences for strain Os17; and with 6,833,117 bp, 63.3% G+C content, and 6,217 coding sequences for strain St29. Comparative genome analysis of these strains revealed that the complete rhizoxin analog biosynthesis gene cluster (approximately 79 kb) found in the Os17 genome was absent from the St29 genome. In an rzxB mutant, which lacks the polyketide synthase essential for the production of rhizoxin analogs, the growth inhibition activity against fungal and oomycete pathogens and the plant protection efficacy were attenuated compared with those of wild-type Os17. These findings suggest that rhizoxin analogs are important biocontrol factors of this strain.


Current situation of Leishmania infantum infection in shelter dogs in northern Spain.
Canine leishmaniosis (CanL) caused by Leishmania infantum is a widespread endemic disease in the Mediterranean basin, though, so far, the north of Spain has been considered a non-endemic area. The aim of the present study was to determine the prevalence of specific antibodies to L. infantum among stray dogs living in shelters in this area, and to evaluate the clinical status (both clinical signs and clinico-pathological abnormalities) of seropositive dogs. Besides L. infantum infection, the epidemiological role of variables like sex, breed and age was also assessed. Over the year 2011 a cross-sectional study was conducted on a total of 418 stray dogs. A preliminary entomological survey was carried out using CDC-light traps. The chi-squared test was used to examine relationships between L. infantum seroprevalence and the remaining variables. The overall seroprevalence of L. infantum infection detected was 3% in the Cantabrian coast. In Orense the seroprevalence was 35.6%. In this latter region, the presence of sand fly, Phlebotomus perniciosus was also detected.In general, seropositivity for L. infantum was related to size (large breed dogs versus small) and age, with a significantly higher seroprevalence recorded in younger (0-3 years) and older dogs (> 7 years) than adult dogs. Clinical signs of CanL were observed in 41.3% of the seropositive dogs. The seropositivity for L. infantum infection associated with the presence of clinical signs and/or abnormal laboratory findings shows a prevalence of 4.5%. Our data provide new insight into the prevalence of CanL across northern Spain. The situation observed in Orense seems to be worsening compared to the few reports available, with figures being similar to those cited for known endemic areas of Spain. Besides, the presence of P. perniciosus in Orense points out to a risk of the spread of this zoonotic disease in this geographical area. These findings identify a need for an active search for the sand fly vectors of L. infantum across the entire northern spanish region including the rest of Galicia, Asturias, Cantabria and the Basque Country.


(1)H NMR metabolite profiling of feces as a tool to assess the impact of nutrition on the human microbiome.
Current research increasingly recognizes the human gut microbiome as a metabolically versatile biological 'digester' that plays an essential role in regulating the host metabolome. Gut microbiota recover energy and biologically active molecules from food that would otherwise be washed out of the intestinal tract without benefit. In this study, a protocol for NMR-based metabolite profiling has been developed to access the activity of the microbiome. The physicochemical properties of fecal metabolites have been found to strongly affect the reproducibility and coverage of the profiles obtained. Metabolite profiles generated by water and methanol extraction of lyophilized feces are reproducible and comprise a variety of different compounds including, among others, short-chain fatty acids (e.g. acetate, propionate, butyrate, isobutyrate, isovalerate, malate), organic acids (e.g. succinate, pyruvate, fumarate, lactate), amino acids, uracil, trimethylamine, ethanol, glycerol, glucose, phenolic acids, cholate, and lipid components. The NMR profiling approach was validated on fecal samples from a double-blinded, placebo-controlled, randomized cross-over study, in which healthy human subjects consumed a placebo and either a grape juice extract or a mix of grape juice and wine extract over a period of 4 weeks, each. The considerable inter- and intra-individual variability observed originates in the first instance from variable metabolite concentrations rather than from variable metabolite compositions, suggesting that different colonic flora share general biochemical characteristics metabolizing different substrates to specific metabolic patterns. Whereas the grape juice extract did not induce changes in the metabolite profiles as compared with the placebo, the mixture of grape juice and wine extract induced a reduction in isobutyrate, which may indicate that polyphenols are able to modulate the microbial ecology of the gut.


Different colors of light lead to different adaptation and activation as determined by high-density EEG.
Light adaptation is crucial for coping with the varying levels of ambient light. Using high-density electroencephalography (EEG), we investigated how adaptation to light of different colors affects brain responsiveness. In a within-subject design, sixteen young participants were adapted first to dim white light and then to blue, green, red, or white bright light (one color per session in a randomized order). Immediately after both dim and bright light adaptation, we presented brief light pulses and recorded event-related potentials (ERPs). We analyzed ERP response strengths and brain topographies and determined the underlying sources using electrical source imaging. Between 150 and 261 ms after stimulus onset, the global field power (GFP) was higher after dim than bright light adaptation. This effect was most pronounced with red light and localized in the frontal lobe, the fusiform gyrus, the occipital lobe and the cerebellum. After bright light adaptation, within the first 100 ms after light onset, stronger responses were found than after dim light adaptation for all colors except for red light. Differences between conditions were localized in the frontal lobe, the cingulate gyrus, and the cerebellum. These results indicate that very short-term EEG brain responses are influenced by prior light adaptation and the spectral quality of the light stimulus. We show that the early EEG responses are differently affected by adaptation to different colors of light which may contribute to known differences in performance and reaction times in cognitive tests.


Climate change vulnerability of native and alien freshwater fishes of California: a systematic assessment approach.
Freshwater fishes are highly vulnerable to human-caused climate change. Because quantitative data on status and trends are unavailable for most fish species, a systematic assessment approach that incorporates expert knowledge was developed to determine status and future vulnerability to climate change of freshwater fishes in California, USA. The method uses expert knowledge, supported by literature reviews of status and biology of the fishes, to score ten metrics for both (1) current status of each species (baseline vulnerability to extinction) and (2) likely future impacts of climate change (vulnerability to extinction). Baseline and climate change vulnerability scores were derived for 121 native and 43 alien fish species. The two scores were highly correlated and were concordant among different scorers. Native species had both greater baseline and greater climate change vulnerability than did alien species. Fifty percent of California's native fish fauna was assessed as having critical or high baseline vulnerability to extinction whereas all alien species were classified as being less or least vulnerable. For vulnerability to climate change, 82% of native species were classified as highly vulnerable, compared with only 19% for aliens. Predicted climate change effects on freshwater environments will dramatically change the fish fauna of California. Most native fishes will suffer population declines and become more restricted in their distributions; some will likely be driven to extinction. Fishes requiring cold water (<22°C) are particularly likely to go extinct. In contrast, most alien fishes will thrive, with some species increasing in abundance and range. However, a few alien species will likewise be negatively affected through loss of aquatic habitats during severe droughts and physiologically stressful conditions present in most waterways during summer. Our method has high utility for predicting vulnerability to climate change of diverse fish species. It should be useful for setting conservation priorities in many different regions.


Initial orthostatic hypotension: review of a forgotten condition.
Several studies have shown that standing up is a frequent (3-10%) trigger of loss of consciousness both in young and old subjects. An exaggerated transient BP (blood pressure) fall upon standing is the underlying cause. IOH (initial orthostatic hypotension) is defined as a transient BP decrease within 15 s after standing, >40 mmHg SBP (systolic BP) and/or >20 mmHg DBP (diastolic BP) with symptoms of cerebral hypoperfusion. It differs distinctly from typical orthostatic hypotension (i.e. BP decrease >20 mmHg SBP and/or >10 mmHg DBP after 3 min of standing) as the BP decrease is transient. Only continuous beat-to-beat BP measurement during an active standing-up manoeuvre can document this condition. As IOH is only associated with active rising, passive tilting is of no diagnostic value. The pathophysiology of IOH is thought to be a temporal mismatch between cardiac output and vascular resistance. The marked decrease of vascular resistance during rising is similar to that observed at the onset of leg exercise and is absent during head-up tilting. It is attributed to vasodilatation in the working muscle through local mechanisms. Standing up causes an initial increase in venous return through the effects of contraction of leg and abdominal muscles. The consequent sudden increase in right atrial pressure may contribute to the fall in systemic vascular resistance through a reflex effect. This review alerts clinicians and clinician scientists to a common, yet often neglected, condition that occurs only upon an active change of posture and discusses its epidemiology, pathophysiology and management.


Interleukin-10 and antigen-presenting cells actively suppress Th1 cells in BALB/c mice infected with the filarial parasite Brugia pahangi.
Infection with the third-stage larvae (L3) of the filarial nematode Brugia results in a Th2-biased immune response in mice and humans. Previously we have shown that the production of interleukin 4 (IL-4) is critical for down-regulating polyclonal Th1 responses in L3-infected mice. However, the in vitro neutralization of IL-4 did not fully recover the defective polyclonal Th1 responses, nor did it result in the production of any antigen (Ag)-specific Th1 cytokines, suggesting that perhaps infection with L3 does not result in priming of Th1 cells in vivo. In this study, we analyzed the role of IL-10 and Ag-presenting cells (APCs) in the spleen as additional factors controlling the Th2 bias in infected mice. Our data show that IL-10 and APCs also contribute to the suppression of mitogen-driven Th1 responses of spleen cells from infected mice. In addition, the neutralization of IL-10 or the replacement of the resident APC population from spleen cell cultures resulted in the production of Ag-specific Th1 cytokines. Irradiated spleen cells from either L3-infected or uninfected mice were able to restore Ag-specific Th1 responses in vitro. Therefore, it appears that Brugia-reactive Th1 cells are primed following infection with L3, but are actively suppressed in vivo by a mechanism that involves IL-10 and the resident APC population, but not IL-4. These results indicate that a complex interplay of cytokines and cell populations underscores the Th2-polarized response in L3-infected mice.


Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.
Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.


Putative cis-regulatory drivers in colorectal cancer.
The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Using the changes in ASE in matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effects in CRC, suggesting a cancer driver role. We correlate genotypes and gene expression to identify expression quantitative trait loci (eQTLs) and find 1,693 and 948 eQTLs in normal samples and tumours, respectively. We estimate that 36% of the tumour eQTLs are exclusive to CRC and show that this specificity is partially driven by increased expression of specific transcription factors and changes in methylation patterns. We show that tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) P values than shared eQTLs, which suggests that some of the GWAS variants are tumour specific regulatory variants. Importantly, tumour-specific eQTL genes also accumulate more somatic mutations when compared to the shared eQTL genes, raising the possibility that they constitute germline-derived cancer regulatory drivers. Collectively the integration of genome and the transcriptome reveals a substantial number of putative somatic and germline cis-regulatory cancer changes that may have a role in tumorigenesis.


The Role of Radiotherapy and Surgery in the Management of Aggressive Vertebral Hemangioma: A Retrospective Study of 20 Patients.
BACKGROUND Vertebral hemangioma is usually a benign and asymptomatic tumor of blood vessels, but can be aggressive (symptomatic) with expansion, pain, and spinal cord compression. The aim of this study was to review the effects of radiotherapy, surgery, and other treatment approaches in patients with aggressive vertebral hemangioma. MATERIAL AND METHODS Retrospective clinical review included 20 patients who underwent radiotherapy as their first-line treatment for aggressive vertebral hemangioma with mild or slowly developing neurological deficit. External radiation was divided into 20-25 fractions with a total dose of 40-50 Gy. Minimum clinical follow-up after treatment was 20 months. RESULTS The 20 patients included eight men and 12 women (mean age, 46.6 years), with aggressive vertebral hemangioma located in the cervical, thoracic, and lumbar vertebrae in four, 14, and two patients, respectively. Following radiotherapy treatment, 65.0% of patients (13/20) were symptom-free, without recurrence or malignant transformation at the time of last clinical follow-up (average, 75.2 months). Due to minor post-radiation vertebral re-ossification, two of the 13 patients who were initially symptom-free after radiotherapy requested percutaneous vertebroplasty. A further seven patients required surgery after radiotherapy, due to increasing neurological deficit in three patients, and persistent neurological deficit in four patients. At the last follow-up (average, 63.6 months), six patients were symptom-free, and one patient still had slight residual symptoms. CONCLUSIONS Radiotherapy was a safe and effective treatment choice for aggressive vertebral hemangioma, but in case with severe spinal cord compression and neurological deficit, surgical intervention was required.


High-Sugar, High-Saturated-Fat Dietary Patterns Are Not Associated with Depressive Symptoms in Middle-Aged Adults in a Prospective Study.
The consumption of unhealthy "Western" dietary patterns has been previously associated with depressive symptoms in different populations. We examined whether high-sugar and high-saturated-fat dietary patterns are associated with depressive symptoms over 5 y in a British cohort of men and women. We used data from the Whitehall II study in 5044 individuals (aged 35-55 y). Diet was assessed at phase 7 (2003-2004) using a validated food-frequency questionnaire. Dietary patterns were derived by using reduced rank regression with sugar, saturated fat, and total fat as response variables. The Center for Epidemiological Studies-Depression (CES-D) scale was used to assess depressive symptoms (CES-D sum score ≥16 and/or use of antidepressant medication) at phase 7 and at phase 9 (2008-2009). We applied logistic regression analyses to test the association between dietary patterns and depressive symptoms. All analyses were stratified by sex. In total, 398 cases of recurrent and 295 cases of incident depressive symptoms were observed. We identified 2 dietary patterns: a combined high-sugar and high-saturated-fat (HSHF) and a high-sugar dietary pattern. No association was observed between the dietary patterns and either incidence of or recurrent depressive symptoms in men or women. For example, higher consumption of the HSHF dietary pattern was not associated with recurrent depressive symptoms in men (model 3, quartile 4: OR: 0.67; 95% CI: 0.36, 1.23; P-trend = 0.13) or in women (model 3, quartile 4: OR: 1.26; 95% CI: 0.58, 2.77; P-trend = 0.97). Among middle-aged men and women living in the United Kingdom, dietary patterns containing high amounts of sugar and saturated fat are not associated with new onset or recurrence of depressive symptoms.


Breech repositioning unresponsive to Webster technique: coexistence of oligohydramnios.
The purpose of this report is to describe the results of a pregnant woman demonstrating breech fetal presentation who was managed with Webster technique in the presence of oligohydramnios. A 23-year-old primigravida woman sought chiropractic care for the management of breech presentation and bilateral sacroiliac arthralgia at 34 weeks' gestation. Sacral manipulation and abdominal effleurage (Webster Technique) was used to address breech presentation and sacroiliac arthralgia for a total of 7 treatments over a 3 1/2-week duration. The patient's sacroiliac pain reduced from 8/10 to 3/10. However, breech presentation was unchanged at each treatment. At a scheduled prenatal surveillance during the 37th week of gestation, the midwife detected vaginal bleeding and reduced fundal height, which resulted in hospitalization, diagnosis of oligohydramnios, and an emergency cesarean delivery. For this particular patient, the breech presentation was not corrected using the Webster technique. Clinicians who use the Webster technique to manage breech fetal presentation should be aware of undiagnosed comorbidities as a complicating factor in clinical presentation. Screening for previously undiagnosed comorbidities, such as oligohydramnios, must be considered.


Geriatrics and the Legal System.
Correctional systems, already struggling to meet the basic and functional requirements of older prisoners, will be further challenged by the increasing medical and psychiatric needs of this population. Mental health and general medical care for older adults requires specific on-site or consultation expertise in geriatric medicine and psychiatry, as well as potential changes in infrastructure, both of which may be prohibitively expensive. However, compassionate and effective treatment of older prisoners requires that prison and legal systems facilitate this expert care. To address this situation, strategic revisions of the criminal justice system are needed to alleviate prison overcrowding and consequent inadequate medical care for inmates, especially the elder ones. The unique, age-related demands of this older population predict an increased need for forensic psychiatrists with a thorough knowledge and expertise in geriatrics, as more forensic psychiatric evaluations will be needed before trial in both civil and criminal cases, during incarceration, and at the time of parole. In this article, we review the current state of elder inmates in correctional institutions and advocate for increased geriatric training for forensic psychiatrists in anticipation of this growing need.


Methoxy-derivatization of alkyl chains increases the in vivo efficacy of cationic Mn porphyrins. Synthesis, characterization, SOD-like activity, and SOD-deficient E. coli study of meta Mn(III) N-methoxyalkylpyridylporphyrins.
Cationic Mn(III) N-alkylpyridylporphyrins (MnPs) are potent SOD mimics and peroxynitrite scavengers and diminish oxidative stress in a variety of animal models of central nervous system (CNS) injuries, cancer, radiation, diabetes, etc. Recently, properties other than antioxidant potency, such as lipophilicity, size, shape, and bulkiness, which influence the bioavailability and the toxicity of MnPs, have been addressed as they affect their in vivo efficacy and therapeutic utility. Porphyrin bearing longer alkyl substituents at pyridyl ring, MnTnHex-2-PyP(5+), is more lipophilic, thus more efficacious in vivo, particularly in CNS injuries, than the shorter alkyl-chained analog, MnTE-2-PyP(5+). Its enhanced lipophilicity allows it to accumulate in mitochondria (relative to cytosol) and to cross the blood-brain barrier to a much higher extent than MnTE-2-PyP(5+). Mn(III) N-alkylpyridylporphyrins of longer alkyl chains, however, bear micellar character, and when used at higher levels, become toxic. Recently we showed that meta isomers are ∼10-fold more lipophilic than ortho species, which enhances their cellular accumulation, and thus reportedly compensates for their somewhat inferior SOD-like activity. Herein, we modified the alkyl chains of the lipophilic meta compound, MnTnHex-3-PyP(5+) via introduction of a methoxy group, to diminish its toxicity (and/or enhance its efficacy), while maintaining high SOD-like activity and lipophilicity. We compared the lipophilic Mn(III) meso-tetrakis(N-(6'-methoxyhexyl)pyridinium-3-yl)porphyrin, MnTMOHex-3-PyP(5+), to a hydrophilic Mn(III) meso-tetrakis(N-(2'-methoxyethyl)pyridinium-3-yl)porphyrin, MnTMOE-3-PyP(5+). The compounds were characterized by uv-vis spectroscopy, mass spectrometry, elemental analysis, electrochemistry, and ability to dismute O(2)˙(-). Also, the lipophilicity was characterized by thin-layer chromatographic retention factor, R(f). The SOD-like activities and metal-centered reduction potentials for the Mn(III)P/Mn(II)P redox couple were similar-to-identical to those of N-alkylpyridyl analogs: log k(cat) = 6.78, and E(1/2) = +68 mV vs. NHE (MnTMOHex-3-PyP(5+)), and log k(cat) = 6.72, and E(1/2) = +64 mV vs. NHE (MnTMOE-3-PyP(5+)). The compounds were tested in a superoxide-specific in vivo model: aerobic growth of SOD-deficient E. coli, JI132. Both MnTMOHex-3-PyP(5+) and MnTMOE-3-PyP(5+) were more efficacious than their alkyl analogs. MnTMOE-3-PyP(5+) is further significantly more efficacious than the most explored compound in vivo, MnTE-2-PyP(5+). Such a beneficial effect of MnTMOE-3-PyP(5+) on diminished toxicity, improved efficacy and transport across the cell wall may originate from the favorable interplay of the size, length of pyridyl substituents, rotational flexibility (the ortho isomer, MnTE-2-PyP(5+), is more rigid, while MnTMOE-3-PyP(5+) is a more flexible meta isomer), bulkiness and presence of oxygen.


New Doppler echocardiographic applications for the study of diastolic function.
Doppler echocardiography is one of the most useful clinical tools for the assessment of left ventricular (LV) diastolic function. Doppler indices of LV filling and pulmonary venous (PV) flow are used not only for diagnostic purposes but also for establishing prognosis and evaluating the effect of therapeutic interventions. The utility of these indices is limited, however, by the confounding effects of different physiologic variables such as LV relaxation, compliance and filling pressure. Since alterations in these variables result in changes in Doppler indices of opposite direction, it is often difficult to determine the status of a given variable when a specific Doppler filling pattern is observed. Recently, color M-mode and tissue Doppler have provided useful insights in the study of diastolic function. These new Doppler applications have been shown to provide an accurate estimate of LV relaxation and appear to be relatively insensitive to the effects of preload compensation. This review will focus on the complementary role of color M-mode and tissue Doppler echocardiography and traditional Doppler indices of LV filling and PV flow in the assessment of diastolic function.


Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma.
Exosomes are 40-nm to 100-nm membrane vesicles that are secreted by various cells, and they play a major role in cell-cell communication. The objective of this study was to clarify the significance of the levels of microRNA in exosomes extracted from the sera of patients with esophageal squamous cell cancer (ESCC). The authors isolated exosomes in serum samples from patients who had ESCC and from patients who had benign diseases without systemic inflammation. Total RNA was purified from the exosomes, and expression levels of microRNA-21 (miR-21) were analyzed by quantitative real-time polymerase chain reaction. Serum exosomes from patients with ESCC induced the proliferation of ESCC cells in vitro. The expression levels of exosomal miR-21 were significantly higher in patients with ESCC than those with benign diseases with and without (C-reactive protein <0.3 mg/dL) systemic inflammation. MiR-21 was not detected in serum that remained after exosome extraction. Exosomal miR-21 expression was correlated with advanced tumor classification, positive lymph node status, and the presence of metastasis with inflammation or and clinical stage without inflammation (C-reactive protein <0.3 mg/dL). The current results confirmed that exosomal miR-21 expression is up-regulated in serum from patients with ESCC versus serum from patients who have benign diseases without systemic inflammation. Exosomal miR-21 was positively correlated with tumor progression and aggressiveness, suggesting that it may be a useful target for cancer therapy. Cancer 2013. © 2012 American Cancer Society.


Ceruloplasmin deficiency reduces levels of iron and BDNF in the cortex and striatum of young mice and increases their vulnerability to stroke.
Ceruloplasmin (Cp) is an essential ferroxidase that plays important roles in cellular iron trafficking. Previous findings suggest that the proper regulation and subcellular localization of iron are very important in brain cell function and viability. Brain iron dyshomeostasis is observed during normal aging, as well as in several neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, coincident with areas more susceptible to insults. Because of their high metabolic demand and electrical excitability, neurons are particularly vulnerable to ischemic injury and death. We therefore set out to look for abnormalities in the brain of young adult mice that lack Cp. We found that iron levels in the striatum and cerebral cortex of these young animals are significantly lower than wild-type (WT) controls. Also mRNA levels of the neurotrophin brain derived neurotrophic factor (BDNF), known for its role in maintenance of cell viability, were decreased in these brain areas. Chelator-mediated depletion of iron in cultured neural cells resulted in reduced BDNF expression by a posttranscriptional mechanism, suggesting a causal link between low brain iron levels and reduced BDNF expression. When the mice were subjected to middle cerebral artery occlusion, a model of focal ischemic stroke, we found increased brain damage in Cp-deficient mice compared to WT controls. Our data indicate that lack of Cp increases neuronal susceptibility to ischemic injury by a mechanism that may involve reduced levels of iron and BDNF.


Dermatophytes activate skin keratinocytes via mitogen-activated protein kinase signaling and induce immune responses.
Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte, Trichophyton equinum. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with Microsporum gypseum inducing the greatest level of damage and cytokine release. Using T. equinum as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected. T. equinum also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of T. equinum to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation.


Fatal bacterial septicemia in a bottlenose dolphin Tursiops truncatus caused by Streptococcus iniae.
A captive 8 yr old male bottlenose dolphin Tursiops truncatus succumbed to septicemia with multisystemic inflammation including suppurative enteritis, encephalitis, and pneumonia with chronic pancreatitis. A pure culture of beta-hemolytic, catalase- and oxidase-negative, Gram-positive cocci was isolated from the hilar lymph nodes and pancreas. The isolate was identified by 16S rDNA sequencing as Streptococcus iniae. Histological examination of the digestive system revealed a mixed infection of both bacteria and fungus. Recognized as a pathogen in fish, dolphins, and humans, this is the first report of S. iniae in a dolphin in mainland China. As the number of managed animals in oceanariums is increasing, so is the frequency of contact with fish used as food for marine mammals and humans, highlighting the importance of education and appropriate personal protective protocols to minimize the risk of transmission. An understanding of marine mammal infectious disease organisms is essential to ensuring the health of marine mammals and humans coming into contact with such animals and their food. This study illustrates a systematic clinical, microbiological, and pathological investigation into a septicemic bottlenose dolphin infected with S. iniae. Our findings provide useful information for those involved in the diagnosis and control of infectious diseases in marine mammals and offer insight into an important zoonotic pathogen.


Dietary fish oil n-3 fatty acids increase regulatory cytokine production and exert anti-inflammatory effects in two murine models of inflammation.
The higher incidence of inflammatory diseases in Western countries might be related, in part, to a high consumption of saturated fatty acids and n-6 polyunsaturated fatty acids (PUFA) and an insufficient intake of n-3 fatty acids. The purpose of this study was to examine the effects of dietary n-3 fatty acids on innate and specific immune response and their anti-inflammatory action in models of contact and atopic dermatitis. Balb/C mice were fed for 3 wk either n-6 or n-3 PUFA-fortified diets. After inducing a contact or an atopic dermatitis, immunological parameters were analyzed to evaluate the anti-inflammatory potential of these n-3 PUFA. n-3 PUFA reduced innate and specific immune responses through inhibition of TH1 and TH2 responses, increase of immunomodulatory cytokines such as IL-10, and regulation of gene expression. The inhibition of both kinds of responses was confirmed by the anti-inflammatory effect observed in contact and atopic dermatitis. Reduction in weight, edema, thickness, leukocyte infiltration, and enhancement of antioxidant defenses in the inflamed ears of mice from both models along with the prevention of delayed-type hypersensitivity induced in atopic dermatitis proved n-3 PUFA efficacy. Our data suggest that dietary fish oil-derived n-3 fatty acids have immunomodulatory effects and could be useful in inflammatory disorders.


The prediction of neck extensor force using surface electromyography.
The relationship between muscular force and electromyography (EMG) has been investigated by numerous researchers. EMG has not previously been used as a means of estimating force in the cervical erector spinae (CES). Use EMG of the CES musculature to indirectly predict neck extension force. Isometric contractions of the CES muscles were studied at increasing levels of contractile force across all participants (n= 12) to produce an individualised force-EMG relationship. The method of least squares was used to determine the linear regression trend line for the force-EMG relationship. The validity of these individual `correlation curves' was demonstrated through further, blinded, investigation. A linear relationship was identified for the individualised correlation curves that gained in strength for < 50% maximum voluntary contraction (MVC; R2> 0.8 for 80% of trials). The prediction of muscle force from the correlation curves was found to be statistically similar to the equivalent experimental data (p> 0.05). Given the tendency of EMG to slightly overestimate force in most cases, an adjustment coefficient was calculated to reduce the error in the predicted force data. This study reports a validated method using EMG to indirectly acquire CES muscular force, which has application for clinicians and research scientists working in fields including sport and rehabilitation.


Toxoplasmosis in dasyurid marsupials.
During a histopathologic survey of 240 dasyurid marsupials a high prevalence of infection of Toxoplasma gondii was found in eight of thenine species examined. Amongst the infected species, endemic infection in field animals was proved in Dasyuroides byrnei, but there was also good evidence of laboratory infection probably derived from raw sheep tissues in their diet. Infection was never demonstrated in animals less than six months of age. The 21 Antechinus stuartii examined remained free from infection despited a lengthy stay in the laboratory and a similar diet. This freedom from infection may indicate a particular resistance to Toxoplasma infection by this species.


Stage-specific suppression of basal defense discriminates barley plants containing fast- and delayed-acting Mla powdery mildew resistance alleles.
Nonspecific recognition of pathogen-derived general elicitors triggers the first line of plant basal defense, which in turn, preconditions the host towards resistance or susceptibility. To elucidate how basal defense responses influence the onset of Mla (mildew resistance locus a)-specified resistance, we performed a meta-analysis of GeneChip mRNA expression for 155 basal defense-related genes of barley (Hordeum vulgare) challenged with Blumeria graminis f. sp. hordei, the causal agent of powdery mildew disease. In plants containing the fast-acting Mla1, Mla6, or Mla13 alleles, transcripts hyper-accumulated from 0 to 16 h after inoculation (hai) in both compatible and incompatible interactions. Suppression of basal defense-related transcripts was observed after 16 hai only in compatible interactions, whereas these transcripts were sustained or increased in incompatible interactions. By contrast, in plants containing wild-type and mutants of the delayed-acting Mla12 allele, an early hyper-induction of transcripts from 0 to 8 hai was observed, but the expression of many of these genes is markedly suppressed from 8 to 16 hai. These results suggest that the inhibition of basal defense facilitates the development of haustoria by the pathogen, consequently delaying the onset of host resistance responses. Thus, we hypothesize that the regulation of basal defense influences host-cell accessibility to the fungal pathogen and drives allelic diversification of gene-specific resistance phenotypes.


Separation of function between the domains of toxic shock syndrome toxin-1.
Toxic shock syndrome toxin-1 (TSST1) is a superantigenic exotoxin produced by certain strains of Staphylococcus aureus Structurally, TSST1 is composed of two domains: residues determined by crystallography to directly interact with MHC II molecules reside within the N-terminal domain, while TSST1 residues critical for superantigenicity are within the C-terminal domain. In this study, we expressed the individual N- and C-terminal domains of TSST1 in Escherichia coli and studied their biologic activities. The TSST1 N-terminal domain (TSST(1-87)) did not induce proliferation of human PBLs or release of TNF-beta, but did induce TNF-alpha release. However, TSST1-elicited proliferation and release of both TNF isoforms were inhibited by a molar excess of TSST(1-87). The TSST1 C-terminal domain (TSST(88-194)) did not bind MHC II molecules, yet it elicited production of TNF-alpha and TNF-beta, and induced TCR Vbeta-specific proliferation similarly to intact TSST1. When covalently cross-linked to tumor cells, TSST(88-194) elicited a local in vivo antitumor response indistinguishable from TSST1. Although intact TSST1 causes lethal shock in vivo, the individual domains of this molecule may have therapeutic potential: the N-terminal domain to antagonize lymphocyte activation and TNF release during acute TSST1-precipitated toxic shock syndrome, and the C-terminal domain to stimulate antitumor responses without MHC II binding.


Motor system activation reveals infants' on-line prediction of others' goals.
Despite much research demonstrating infants' abilities to attribute goals to others' actions, it is unclear whether infants can generate on-line predictions about action outcomes, an ability crucial for the human propensity to cooperate and collaborate with others. This lack of evidence is mainly due to methodological limitations restricting the interpretation of behavioral data. Here, we exploited the fact that observers' motor systems are recruited during the observation of goal-directed actions. We presented 9-month-old infants with part of an action. For this action to be interpreted as goal directed, the infants would need to predict an outcome for the action. Measuring the attenuation of the sensorimotor alpha signal during observation of action, we found that infants exhibited evidence of motor activation only if the observed action permitted them to infer a likely outcome. This result provides evidence for on-line goal prediction in infancy, and our method offers a new way to explore infants' cognitive abilities.


Genetic Association in the Maintenance of the Mitochondrial Microenvironment and Sperm Capacity.
Sperm motility is one of the major determinants of male fertility. Since sperm need a great deal of energy to support their fast movement by active metabolism, they are thus extremely vulnerable to oxidative damage by the reactive oxygen species (ROS) and other free radicals generated as byproducts in the electron transport chain. The present study is aimed at understanding the impact of a mitochondrial oxidizing/reducing microenvironment in the etiopathology of male infertility. We detected the mitochondrial DNA (mtDNA) 4,977 bp deletion in human sperm. We examined the gene mutation of ATP synthase 6 (ATPase6 m.T8993G) in ATP generation, the gene polymorphisms of uncoupling protein 2 (UCP2, G-866A) in the uncoupling of oxidative phosphorylation, the role of genes such as manganese superoxide dismutase (MnSOD, C47T) and catalase (CAT, C-262T) in the scavenging system in neutralizing reactive oxygen species, and the role of human 8-oxoguanine DNA glycosylase (hOGG1, C1245G) in 8-hydroxy-2'-deoxyguanosine (8-OHdG) repair. We found that the sperm with higher motility were found to have a higher mitochondrial membrane potential and mitochondrial bioenergetics. The genotype frequencies of UCP2 G-866A, MnSOD C47T, and CAT C-262T were found to be significantly different among the fertile subjects, the infertile subjects with more than 50% motility, and the infertile subjects with less than 50% motility. A higher prevalence of the mtDNA 4,977 bp deletion was found in the subjects with impaired sperm motility and fertility. Furthermore, we found that there were significant differences between the occurrences of the mtDNA 4,977 bp deletion and MnSOD (C47T) and hOGG1 (C1245G). In conclusion, the maintenance of the mitochondrial redox microenvironment and genome integrity is an important issue in sperm motility and fertility.


Cytopathic effects of Mycoplasma pulmonis in vivo and in vitro.
This study was performed to evaluate the cytopathic features resulting from Mycoplasma pulmonis infection of tracheal organ cultures compared to with those seen in in vivo infection and to use this system to determine possible differences in cytopathic effects in two M. pulmonis variants found to cause different diseases in vivo. The attachment of M. pulmonis to respiratory epithelium was similar in vivo and in vitro. Cytopathic effects seen in both systems were also similar in loss of tight junctions between cells and exfoliation of respiratory cells, resulting in exposure of the subepithelial layer. These similarities indicate that the observed tissue damage is initiated by the mycoplasmas rather than by immunologic host responses but does not exclude the possibility that host responses may subsequently contribute to the cytopathological events. Comparison of the effects of the two variants (one known to cause death in vivo) did not reveal differences in vitro. This suggests that host factors (not present in vitro) may account for differences in virulence. Detailed in vitro studies allowed the identification of the time frame corresponding to the in vivo infection and also revealed the limitations of the in vitro system.


Character of cellulase activity in the guts of flagellate-free termites with different feeding habits.
Cellulose digestion in termites (Isoptera) is highly important for ecological reasons and applications in biofuel conversion. The speciose Termitidae family has lost flagellates in the hindgut and developed diverse feeding habits. To address the response of cellulase activity to the differentiation of feeding habits, a comparative study of the activity and distribution of composite cellulases, endo-β-1,4-glucanase, and β-glucosidase was performed in seven common flagellate-free termites with three feeding habits: the humus-feeding termites Sinocapritermes mushae (Oshima et Maki), Malaysiocapritermes zhangfengensis Zhu, Yang et Huang and Pericapritermes jiangtsekiangensis (Kemner); the fungus-growing termites Macrotermes barneyi Light and Odontotermes formosanus (Shiraki); and the wood-feeding termites Nasutitermes parvonasutus (Shiraki) and Havilanditermes orthonasus (Tsai et Chen). The results showed that in diverse feeding groups, the wood-feeding group had the highest total composite cellulase and endo-β-1,4-glucanase activities, while the fungus-growing group had the highest β-glucosidase activity. In terms of the distribution of cellulase activity in the alimentary canals, the cellulase activities in wood-feeding termites were concentrated in the midgut, but there was no significant difference between all gut segments in humus-feeding termites. As for the fungus-growing termites, the main site of composite cellulase activity was in the midgut. The endo-β-1,4-glucanase activity was restricted to the midgut, but the primary site of β-glucosidase activity was in the foregut and the midgut (Mac. barneyi). The functions of the gut segments apparently differentiated between feeding groups. The results suggest that the differentiation of feeding habits in flagellate-free termites was characterized by the distribution of cellulases in the gut rather than by variations in cellulase activity.


Syndecan-1 and Free Indoxyl Sulfate Levels Are Associated with miR-126 in Chronic Kidney Disease.
Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically cel-miR-39. The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD.


Dasatinib Changes Immune Cell Profiles Concomitant with Reduced Tumor Growth in Several Murine Solid Tumor Models.
Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8+ T cells in PB, together with a higher amount of tumor-infiltrating CD8+ T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4+ and CD8+ T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials. Cancer Immunol Res; 5(2); 157-69. ©2017 AACR.


A randomized, double-blind, placebo-controlled trial to assess the bacterial anti-adhesion effects of cranberry extract beverages.
In this study, we examined the ex vivo urinary anti-adhesion activity of low-calorie cranberry extract beverages in both a pilot study (n = 10) and a randomized, double-blind, placebo controlled clinical trial (n = 59). In the pilot study, subjects consumed a cranberry extract beverage (CEB) or a cranberry extract and juice beverage (CEJB), compared to placebo. Both cranberry beverages utilized a standardized cranberry extract powder at a level equivalent to low-calorie cranberry juice cocktail (LCJC) on a PAC content basis. Clean-catch urine samples collected at baseline and post intervention were tested for anti-adhesion activity utilizing a mannose-resistant human red blood cell hemagglutination assay specific for P-fimbriated E. coli. Results from the pilot study indicated that ex vivo anti-adhesion activity for both cranberry treatments were higher (p < 0.05) than placebo. In the clinical trial, we compared CEJB to LCJC and a placebo beverage. Post-consumption urine from both cranberry treatment groups showed significantly higher (p < 0.05) anti-adhesion activity compared to placebo. There were no differences observed in anti-adhesion activity between CJEB and LCJC, indicating similar bioactivity. Therefore, acute beverage consumption of cranberry extract and/or juice provides ex vivo anti-adhesion activity, which may help to improve urinary tract health.


Pest trade-offs in technology: reduced damage by caterpillars in Bt cotton benefits aphids.
The rapid adoption of genetically engineered (GE) plants that express insecticidal Cry proteins derived from Bacillus thuringiensis (Bt) has raised concerns about their potential impact on non-target organisms. This includes the possibility that non-target herbivores develop into pests. Although studies have now reported increased populations of non-target herbivores in Bt cotton, the underlying mechanisms are not fully understood. We propose that lack of herbivore-induced secondary metabolites in Bt cotton represents a mechanism that benefits non-target herbivores. We show that, because of effective suppression of Bt-sensitive lepidopteran herbivores, Bt cotton contains reduced levels of induced terpenoids. We also show that changes in the overall level of these defensive secondary metabolites are associated with improved performance of a Bt-insensitive herbivore, the cotton aphid, under glasshouse conditions. These effects, however, were not as clearly evident under field conditions as aphid populations were not correlated with the amount of terpenoids measured in the plants. Nevertheless, increased aphid numbers were visible in Bt cotton compared with non-Bt cotton on some sampling dates. Identification of this mechanism increases our understanding of how insect-resistant crops impact herbivore communities and helps underpin the sustainable use of GE varieties.


The mechanics of embodiment: a dialog on embodiment and computational modeling.
Embodied theories are increasingly challenging traditional views of cognition by arguing that conceptual representations that constitute our knowledge are grounded in sensory and motor experiences, and processed at this sensorimotor level, rather than being represented and processed abstractly in an amodal conceptual system. Given the established empirical foundation, and the relatively underspecified theories to date, many researchers are extremely interested in embodied cognition but are clamoring for more mechanistic implementations. What is needed at this stage is a push toward explicit computational models that implement sensorimotor grounding as intrinsic to cognitive processes. In this article, six authors from varying backgrounds and approaches address issues concerning the construction of embodied computational models, and illustrate what they view as the critical current and next steps toward mechanistic theories of embodiment. The first part has the form of a dialog between two fictional characters: Ernest, the "experimenter," and Mary, the "computational modeler." The dialog consists of an interactive sequence of questions, requests for clarification, challenges, and (tentative) answers, and touches the most important aspects of grounded theories that should inform computational modeling and, conversely, the impact that computational modeling could have on embodied theories. The second part of the article discusses the most important open challenges for embodied computational modeling.


Acute pulmonary toxicity of particulate matter filter extracts in rats: coherence with epidemiologic studies in Utah Valley residents.
Epidemiologic reports by C.A. Pope III et. al. demonstrated that in the Utah Valley, closure of an open-hearth steel mill over the winter of 1987 was associated with reductions in respiratory disease and related hospital admissions in valley residents. To better examine the relationship between plant-associated changes in ambient particulate matter (PM) and respiratory health effects, we obtained total suspended particulate filters originally collected near the steel mill during the winter of 1986 (before closure), 1987 (during closure), and 1988 (after plant reopening). PM subcomponents were water-extracted from these filters and Sprague-Dawley rats were intratracheally instilled with equivalent masses of extract. Data indicated that 24 hr later, rats exposed to 1986 or 1988 extracts developed significant pulmonary injury and neutrophilic inflammation. Additionally, 50% of rats exposed to 1986 or 1988 extracts had increased airway responsiveness to acetylcholine, compared to 17 and 25% of rats exposed to saline or the 1987 extract, respectively. By 96 hr, these effects were largely resolved except for increases in lung lavage fluid neutrophils and lymphocytes in 1986 extract-exposed rats. Analogous effects were observed with lung histologic assessment. Extract analysis using inductively coupled plasma-mass spectroscopy demonstrated in all three extracts nearly 70% of the mass appeared to be sodium-based salts derived from the glass filter matrix. Interestingly, relative to the 1987 extract, the 1986/1988 extracts contained more sulfate, cationic salts (i.e., calcium, potassium, magnesium), and certain metals (i.e., copper, zinc, iron, lead, strontium, arsenic, manganese, nickel). Although total metal content was (3/4) 1% of the extracts by mass, the greater quantity detected in the 1986 and 1988 extracts suggests metals may be important determinants of the pulmonary toxicity observed. In conclusion, the pulmonary effects induced by exposure of rats to water-based extracts of local ambient PM filters were in good accord with the cross-sectional epidemiologic reports of adverse respiratory health effects in Utah Valley residents.


Transcription mapping of the 5q- syndrome critical region: cloning of two novel genes and sequencing, expression, and mapping of a further six novel cDNAs.
The 5q- syndrome is a myelodysplastic syndrome with the 5q deletion ¿del(5q) as the sole karyotypic abnormality. We are using the expressed sequence tag (EST) resource as our primary approach to identifying novel candidate genes for the 5q- syndrome. Seventeen ESTs were identified from the Human Gene Map at the National Center for Biotechnology Information that had no significant homology to any known genes and were assigned between DNA markers D5S413 and D5S487, flanking the critical region of the 5q- syndrome at 5q31-q32. Eleven of the 17 cDNAs from which the ESTs were derived (65%) were shown to map to the critical region of the 5q- syndrome by gene dosage analysis and were then sublocalized by PCR screening to a YAC contig encompassing the critical region. Eight of the 11 cDNA clones, upon full sequencing, had no significant homology to any known genes. Each of the 8 cDNA clones was shown to be expressed in human bone marrow. The complete coding sequence was obtained for 2 of the novel genes, termed C5orf3 and C5orf4. The 2.6-kb transcript of C5orf3 encodes a putative 505-amino-acid protein and contains an ATP/GTP-binding site motif A (P loop), suggesting that this novel gene encodes an ATP- or a GTP-binding protein. The novel gene C5orf4 has a transcript of 3.1 kb, encoding a putative 144-amino-acid protein. We describe the cloning of 2 novel human genes and the sequencing, expression patterns, and mapping to the critical region of the 5q- syndrome of a further 6 novel cDNA clones. Genomic localization and expression patterns would suggest that the 8 novel cDNAs described in this report represent potential candidate genes for the 5q- syndrome.