Motivation and appraisal in perception of poorly specified speech.
Normal-hearing students (n = 72) performed sentence, consonant, and word identification in either A (auditory), V (visual), or AV (audiovisual) modality. The auditory signal had difficult speech-to-noise relations. Talker (human vs. synthetic), topic (no cue vs. cue-words), and emotion (no cue vs. facially displayed vs. cue-words) were varied within groups. After the first block, effects of modality, face, topic, and emotion on initial appraisal and motivation were assessed. After the entire session, effects of modality on longer-term appraisal and motivation were assessed. The results from both assessments showed that V identification was more positively appraised than A identification. Correlations were tentatively interpreted such that evaluation of self-rated performance possibly depends on subjective standard and is reflected on motivation (if below subjective standard, AV group), or on appraisal (if above subjective standard, A group). Suggestions for further research are presented.


Analysis of transmitting characteristics of high-transparency double-layer metallic meshes with submillimeter period using an analytical model.
The transmitting characteristics of high-transparency double-layer metallic meshes with submillimeter period were analyzed using an analytical model, which was established using angular spectrum propagation theory and verified through experiments. It was found through analysis that rotating misalignment has significant effect on the distribution of diffraction spot intensity. Large period and small linewidth can be used to obtain high transmittance and low levels of stray light. Substrate thickness has little effect on transmitting characteristics of mesh, and so it is a variable free to choose in optimizing shielding characteristics of mesh. We think, together with other ways and means of optimizing shielding characteristics of mesh, the model can also be used for the optimization of a high-pass mesh filter.


[Cine magnetic resonance imaging for evaluating flow dynamics in congenital heart diseases with left-to-right shunts].
Cine magnetic resonance imaging (cine MRI) was used to evaluate the cardiac structures and blood flow in congenital heart diseases with left-to-right shunts. Fifteen children with left-to-right shunts which were confirmed by echocardiography or angiography were investigated in the present study. Five children each had atrial septal defect, ventricular septal defect, and complete endocardial cushion defect. Their ages ranged from 4 months to 13 years (mean 5.5 years). Prior to cine MRI, the ECG-gated cardiac imaging using multi-slice acquisition was performed in all the children to localize the optimal slice for cine MRI. To select the optimal imaging planes for various cardiac structures, we used axial, coronal, sagittal and four-chamber views. Cine MRI was demonstrated by a fast low 30 degree flip angle imaging technique, with a 15 msec echo time, a 30-40 msec pulse repetition time, and a 256 x 256 or 128 x 128 acquisition matrix. Abnormalities of cardiac structures were defined extremely well in all the children using ECG-gated cardiac imaging. In 14 of the 15 children (93%), cine MRI clearly detected a left-to-right shunt flow, which was visualized as a low signal intensity area compared to the surrounding blood flow. Noninvasively, cine MRI provides accurate images of the anatomy of the cardiac structures, makes functional assessments of the cardiac chambers and walls, and flow relationships. It has no limitations of imaging planes imposed bones and lung, and is not associated with technical difficulties as required with echocardiography which has small cardiac window.(ABSTRACT TRUNCATED AT 250 WORDS)


Prefrontal-basal ganglia pathways are involved in the learning of arbitrary visuomotor associations: a PET study.
Primates can learn to associate sensory cues with particular movements according to arbitrary rules. We used positron emission tomography (PET) to study the neural network involved in learning such arbitrary associations by trial and error. Ten subjects were scanned at four different stages of learning a visuomotor conditional task (VC). The subjects were required to associate four different visual patterns, presented one at a time, with four different finger movements. Scan 1 was acquired during initial learning. Scans 2, 3 and 4 were performed after further interscan training periods of 1, 3 and 5 min. In order to control for non-specific time effects that could have confounded the learning-related rCBF changes, we also acquired four sensory-matched control scans, in which no movements were performed. In order to evaluate changes over time that were specific to learning the association of visual cues with movements, we acquired four scans during the learning of a motor sequence task. The statistical model tested with SPM considered both main effects of tasks and task x time interactions independently for each of the three experimental conditions. The right lingual gyrus and the left parahippocampal cortex increased their activity over scans in the VC task as compared to the sensory control. The right inferior frontal sulcus, the body of the caudate nucleus and a left cingulate motor area were specifically implicated in learning the VC task, showing task x time interactions with the motor sequence task. These findings suggest that the learning process involves a distributed network in the ventral extrastriate and prefrontal cortex, in association with the basal ganglia and the parahippocampal gyrus.


Accuracy of point-of-care serum creatinine devices for detecting patients at risk of contrast-induced nephropathy: a critical overview.
Contrast-induced nephropathy (CIN) is a common event in hospitals, with reported incidences ranging from 1 to 30%. Patients with underlying kidney disease have an increased risk of developing CIN. Point-of-care (POC) creatinine devices are handheld devices capable of providing quantitative data on a patient's kidney function that could be useful in stratifying preventive measures. This overview aims to synthesize the current evidence on diagnostic accuracy and clinical utility of POC creatinine devices in detecting patients at risk of CIN. Five databases were searched for diagnostic accuracy studies or clinical trials that evaluated the usefulness of POC devices in detecting patients at risk of CIN. Selected articles were critically appraised to assess their individual risk of bias by the use of standard criteria; 13 studies were found that addressed the diagnostic accuracy or clinical utility of POC creatinine devices. Most studies incurred a moderate to high risk of bias. Overall concordance between POC devices and reference standards (clinical laboratory procedures) was found to be moderate, with 95% limits of agreement often lying between -35.4 and +35.4 µmol/L (-0.4 and +0.4 mg/dL). Concordance was shown to decrease with worsening kidney function. Data on the clinical utility of these devices were limited, but a significant reduction in time to diagnosis was reported in two studies. Overall, POC creatinine devices showed a moderate concordance with standard clinical laboratory creatinine measurements. Several biases could have induced optimism in these estimations. Results obtained from these devices may be unreliable in cases of severe kidney failure. Randomized trials are needed to address the clinical utility of these devices.


No special treatment of independent object motion for heading perception.
How do we judge the direction of self-motion (i.e., heading) in the presence of independent object motion? Previous studies that examined this question confounded the effects of a moving object's speed and its position on heading judgments, and did not examine whether the visual system uses salient nonmotion visual cues (such as color contrast and binocular disparity) to segment a moving object from global optic flow prior to heading estimation. The current study addressed these issues with both behavioral testing and computational modeling. Our results show that the visual system does not treat independent object motion separately for the perception of heading during self-motion. This is surprising because we all can segment a moving object from global optic flow and perceive its scene-relative motion independent of self-motion. Our findings support the claim that the perception of self-motion with independent object motion and the perception of object motion during self-motion are performed by different neural mechanisms.


Dust deposition on the decks of the Mars Exploration Rovers: 10 years of dust dynamics on the Panoramic Camera calibration targets.
The Panoramic Cameras on NASA's Mars Exploration Rovers have each returned more than 17,000 images of their calibration targets. In order to make optimal use of this data set for reflectance calibration, a correction must be made for the presence of air fall dust. Here we present an improved dust correction procedure based on a two-layer scattering model, and we present a dust reflectance spectrum derived from long-term trends in the data set. The dust on the calibration targets appears brighter than dusty areas of the Martian surface. We derive detailed histories of dust deposition and removal revealing two distinct environments: At the Spirit landing site, half the year is dominated by dust deposition, the other half by dust removal, usually in brief, sharp events. At the Opportunity landing site the Martian year has a semiannual dust cycle with dust removal happening gradually throughout two removal seasons each year. The highest observed optical depth of settled dust on the calibration target is 1.5 on Spirit and 1.1 on Opportunity (at 601 nm). We derive a general prediction for dust deposition rates of 0.004 ± 0.001 in units of surface optical depth deposited per sol (Martian solar day) per unit atmospheric optical depth. We expect this procedure to lead to improved reflectance-calibration of the Panoramic Camera data set. In addition, it is easily adapted to similar data sets from other missions in order to deliver improved reflectance calibration as well as data on dust reflectance properties and deposition and removal history.


Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study.
Despite endorsement of digoxin in clinical practice guidelines, there exist limited data on its safety in atrial fibrillation/flutter (AF). The goal of this study was to evaluate the association of digoxin with mortality in AF. Using complete data of the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study from the U.S. Department of Veterans Affairs (VA) healthcare system, we identified patients with newly diagnosed, nonvalvular AF seen within 90 days in an outpatient setting between VA fiscal years 2004 and 2008. We used multivariate and propensity-matched Cox proportional hazards to evaluate the association of digoxin use with death. Residual confounding was assessed by sensitivity analysis. Of 122,465 patients with 353,168 person-years of follow-up (age 72.1 ± 10.3 years, 98.4% male), 28,679 (23.4%) patients received digoxin. Cumulative mortality rates were higher for digoxin-treated patients than for untreated patients (95 vs. 67 per 1,000 person-years; p < 0.001). Digoxin use was independently associated with mortality after multivariate adjustment (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.23 to 1.29, p < 0.001) and propensity matching (HR: 1.21, 95% CI: 1.17 to 1.25, p < 0.001), even after adjustment for drug adherence. The risk of death was not modified by age, sex, heart failure, kidney function, or concomitant use of beta-blockers, amiodarone, or warfarin. Digoxin was associated with increased risk of death in patients with newly diagnosed AF, independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies. These findings challenge current cardiovascular society recommendations on use of digoxin in AF.


NMR structure of a monomeric intermediate on the evolutionarily optimized assembly pathway of a small trimerization domain.
Efficient formation of specific intermolecular interactions is essential for self-assembly of biological structures. The foldon domain is an evolutionarily optimized trimerization module required for assembly of the large, trimeric structural protein fibritin from phage T4. Monomers consisting of the 27 amino acids comprising a single foldon domain subunit spontaneously form a natively folded trimer. During assembly of the foldon domain, a monomeric intermediate is formed on the submillisecond time scale, which provides the basis for two consecutive very fast association reactions. Mutation of an intermolecular salt bridge leads to a monomeric protein that resembles the kinetic intermediate in its spectroscopic properties. NMR spectroscopy revealed essentially native topology of the monomeric intermediate with defined hydrogen bonds and side-chain interactions but largely reduced stability compared to the native trimer. This structural preorganization leads to an asymmetric charge distribution on the surface that can direct rapid subunit recognition. The low stability of the intermediate allows a large free-energy gain upon trimerization, which serves as driving force for rapid assembly. These results indicate different free-energy landscapes for folding of small oligomeric proteins compared to monomeric proteins, which typically avoid the transient population of intermediates.


Pathways to psychosis in cannabis abuse.
Cannabis has been implicated as a risk factor for the development of schizophrenia, but the exact biological mechanisms remain unclear. In this review, we attempt to understand the neurobiological pathways that link cannabis use to schizophrenia. This has been an area of great debate; despite similarities between cannabis users and schizophrenia patients, the evidence is not sufficient to establish cause-and-effect. There have been advances in the understanding of the mechanisms of cannabis dependence as well as the role of the cannabinoid system in the development of psychosis and schizophrenia. The neurobiological mechanisms associated with the development of psychosis and effects from cannabis use may be similar but remain elusive. In order to better understand these associations, this paper will show common neurobiological and neuroanatomical changes as well as common cognitive dysfunction in cannabis users and patients of schizophrenia. We conclude that epidemiologic evidence highlights potential causal links; however, neurobiological evidence for causality remains weak.


Load factor control for implants in the posterior partially edentulous segment.
There are inherent biomechanical differences in the implant treatment of completely edentulous arches and posterior partially edentulous segments. The partial prosthesis does not benefit from cross-arch stabilization and is, therefore, more susceptible to bending loads. Because of the difference in mobility between teeth and implants, implants may carry a major share of load when mixed with teeth in the same quadrant. However, the frequency of implant overload in posterior partial restorations is low, and, with appropriate treatment planning, overload in these situations is almost always preventable. A checklist procedure is proposed to help the clinician enumerate and evaluate deleterious load factors. By screening patients for such factors in advance, the clinician may identify and avoid potential overload situations when conceiving and fabricating implant-supported posterior partial prostheses. A second checklist, for use at follow-up appointments, lists alarm factors that serve as an early warning of overload once the prosthesis is in place.


Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease.
Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.


Flexible alternatives to the Gompertz equation for describing growth with age in turkey hens.
A total of 49 profiles of growing turkey hens from commercial flocks were used in this study. Three flexible growth functions (von Bertalanffy, Richards, and Morgan) were evaluated with regard to their ability to describe the relationship between BW and age and were compared with the Gompertz equation with its fixed point of inflection, which might result in its overestimation. For each function, 4 ways of analysis were implemented. A basic model was fitted first, followed by implementation of a first-order autoregressive correlation structure. A model that considered only mature BW varied with year and another that considered only the rate coefficient varied with different years were applied. The results showed that the fixed point of inflection of the Gompertz equation can be a limitation and that the relationship between BW and age in turkeys was best described using flexible growth functions. However, the Richards equation failed to converge when fitted to the turkey growth data; therefore, it was not considered further. Inclusion of an autoregressive process of the first order rendered a substantially improved fit to data for the 3 growth functions. The Morgan equation provided the best fit to the data set and was used for characterizing mean growth curves for the 7 yr of production. It was estimated that the maximum growth rate occurred at 3.74, 3.65, 3.99, 4.18, 4.05, 4.01, and 3.77 kg BW for production years from 1997 to 2003, respectively. It is recommended that flexible growth functions should be considered as an alternative to the simpler functions (with a fixed point of inflection) for describing the relationship between BW and age in turkeys because they were easier to fit and very often gave a closer fit to data points because of their flexibility, and therefore a smaller residual MS value, than simpler models. It can also be recommended that studies should consider adding a first-order autoregressive process when analyzing repeated measures data with nonlinear models.


Chronic Myeloid Leukemia Associated Hypercalcemia: A Case Report and Literature Review.
BACKGROUND Hypercalcemia associated with chronic myeloid leukemia (CML) is an ominous sign. Although rare, several cases have been reported and multiple pathophysiologic mechanisms have been independently proposed. We present a patient case and a literature review of the clinical presentation and mechanisms of CML-associated hypercalcemia. CASE REPORT A 58-year-old male with a past medical history of CML diagnosed six years earlier, presented to the emergency department with one week of acute confusion, disorientation, polyuria, and polydipsia. On physical examination, we observed tachycardia, altered mental status, and dehydration. Blood analysis revealed leukocytosis, thrombocytosis, and marked hypercalcemia (18.6 mg/dL). His chest CT scan showed diffuse lytic lesions and bone destruction concerning for diffuse bone marrow involvement. The patient was diagnosed with hypercalcemia in the context of a CML blast phase. Treatment with hydration, calcitonin, and zoledronic acid lead to control of his symptoms and normalization of his serum calcium levels. After discharged, the patient was maintained on palliative treatment and zoledronic acid management without new episodes of hypercalcemia. However, eight months later, the patient died. CONCLUSIONS Evidence from the literature demonstrates a highly variable clinical presentation of CML-associated hypercalcemia, commonly occurring during an accelerated or a blast phase, and associated with poor survival. Multiple mechanisms could be involved and are not exclusive of each other. Better understanding of the pathophysiologic mechanisms involved in CML-associated hypercalcemia could lead to improvement in clinical and laboratory evaluation of these patients and be the foundation for the development of better management strategies and possibly target-directed therapy to positively improve prognosis.


Water exchange in lanthanide complexes for MRI applications. Lessons learned over the last 25 years.
The water exchange rates of water molecules coordinated to the metal ion in lanthanide complexes have been profusely investigated during the last 25 years, especially in the case of Gd3+ and Eu3+ complexes. This is mainly related to the important application of some Gd3+ complexes as contrast agents in magnetic resonance imaging (MRI), and the intensive investigation of Eu3+ complexes as contrast agent candidates providing contrast through the chemical exchange saturation transfer mechanism (CEST). Both applications require a fine tunning of the exchange rate of the coordinated water molecule to yield optimal response. Herein we review the progress made in this field to control water exchange in a rational way through ligand design, providing relationships between the observed trends, the structures of the complexes and the mechanisms responsible for the water exchange reaction.


The conceptual basis for interprofessional collaboration: core concepts and theoretical frameworks.
Interprofessional collaboration is a key factor in initiatives designed to increase the effectiveness of health services currently offered to the public. It is important that the concept of collaboration be well understood, because although the increasingly complex health problems faced by health professionals are creating more interdependencies among them, we still have limited knowledge of the complexity of interprofessional relationships. The goal of this literature review was to identify conceptual frameworks that could improve our understanding of this important aspect of health organizations. To this end, we have identified and taken into consideration: (A) the various definitions proposed in the literature and the various concepts associated with collaboration, and (B) the various theoretical frameworks of collaboration. Our results demonstrate that: (1) the concept of collaboration is commonly defined through five underlying concepts: sharing, partnership, power, interdependency and process; (2) the most complete models of collaboration seem to be those based on a strong theoretical background, either in organizational theory or in organizational sociology and on empirical data; (3) there is a significant amount of diversity in the way the various authors conceptualized collaboration and in the factors influencing collaboration; (4) these frameworks do not establish clear links between the elements in the models and the outputs; and (5) the literature does not provide a serious attempt to determine how patients could be integrated into the health care team, despite the fact that patients are recognized as the ultimate justification for providing collaborative care.


Minimal kinetic mechanism for misincorporation by DNA polymerase I (Klenow fragment).
The minimal kinetic mechanism for misincorporation of a single nucleotide (dATP) into a short DNA primer/template (9/20-mer) by the Klenow fragment of DNA polymerase I [KF(exo+)] has been previously published [Kuchta, R. D., Benkovic, P., & Benkovic, S.J. (1988) Biochemistry 27, 6716-6725]. In this paper are presented refinements to this mechanism. Pre-steady-state measurements of correct nucleotide incorporation (dTTP) in the presence of a single incorrect nucleotide (dATP) with excess KF-(exo+) demonstrated that dATP binds to the KF(exo+)-9/20-mer complex in two steps preceding chemistry. Substitution of (alpha S)dATP for dATP yielded identical two-step binding kinetics, removing nucleotide binding as a cause of the elemental effect on the rate of misincorporation. Pyrophosphate release from the ternary species [KF'(exo+)-9A/20-mer-PPi] was found to occur following a rate-limiting conformational change, with this species partitioning equally to either nucleotide via internal pyrophosphorolysis or to misincorporated product. The rate of 9A/20-mer dissociation from the central ternary complex (KF'-9A/20-mer-PPi) was shown to be negligible relative to exonucleolytic editing. Pyrophosphorolysis of the misincorporated DNA product (9A/20-mer), in conjunction with measurement of the rate of dATP misincorporation, permitted determination of the overall equilibrium constant for dATP misincorporation and provided a value similar to that measured for correct incorporation. A step by step comparison of the polymerization catalyzed by the Klenow fragment for correct and incorrect nucleotide incorporation emphasizes that the major source of the enzyme's replicative fidelity arises from discrimination in the actual chemical step and from increased exonuclease activity on the ternary misincorporated product complex owing to its slower passage through the turnover sequence.


Enhancing medical students' communication skills: development and evaluation of an undergraduate training program.
There is a relative lack of current research on the effects of specific communication training offered at the beginning of the medical degree program. The newly developed communication training "Basics and Practice in Communication Skills" was pilot tested in 2008 and expanded in the following year at the University Medical Centre Hamburg-Eppendorf in Germany. The goal was to promote and improve the communicative skills of participants and show the usefulness of an early offered intervention on patient-physician communication within the medical curriculum. The students participating in the project and a comparison group of students from the standard degree program were surveyed at the beginning and end of the courses. The survey consisted of a self-assessment of their skills as well as a standardised expert rating and an evaluation of the modules by means of a questionnaire. Students who attended the communication skills course exhibited a considerable increase of communication skills in this newly developed training. It was also observed that students in the intervention group had a greater degree of self-assessed competence following training than the medical students in the comparison group. This finding is also reflected in the results from a standardised objective measure. The empirical results of the study showed that the training enabled students to acquire specialised competence in communication through the course of a newly developed training program. These findings will be used to establish new communication training at the University Medical Centre Hamburg-Eppendorf.


Evaluation of the effects of a 4.7-mg deslorelin acetate implant on egg laying in cockatiels (Nymphicus hollandicus).
OBJECTIVE To evaluate effects of administration of a 4.7-mg deslorelin acetate implant on egg laying in healthy cockatiels (Nymphicus hollandicus). ANIMALS 52 cockatiels. PROCEDURES 26 breeding pairs (a female and its respective male in each pair) were selected on the basis of their history of egg laying. Female birds were sedated and received a 4.7-mg deslorelin acetate implant (n = 13) or placebo implant (13) in the subcutaneous tissues between the scapulae. Male and female birds of each breeding pair were placed in separate but adjacent cages. Birds were exposed to 16 hours of light and 8 hours of darkness. A nest box was placed in cages of female birds to stimulate reproductive activity. Egg production and quality were monitored daily for 365 days. RESULTS Deslorelin acetate implants significantly suppressed egg laying in cockatiels, compared with effects for the placebo implants. Eleven of 13 placeboimplanted birds laid eggs between 12 and 42 days after implantation. None of the deslorelin-implanted birds laid eggs within 180 days after implantation, and only 5 of 13 deslorelin-implanted birds laid an egg during the study period (first egg laid between 192 and 230 days after implantation). No differences in egg quality or number of eggs per clutch were observed between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE Insertion of a 4.7-mg deslorelin acetate implant suppressed egg laying in healthy cockatiels for at least 180 days. Studies are necessary to evaluate effects of a deslorelin acetate implant in other avian species or in association with reproductive disorders.


The C-Terminal Fragment of Agrin (CAF), a Novel Marker of Renal Function, Is Filtered by the Kidney and Reabsorbed by the Proximal Tubule.
Agrin, a multidomain proteoglycan and neurotrypsin, a neuronal serine protease, are important for forming (neuromuscular) synapses. Proteolytical activity of neurotrypsin produces a C-terminal fragment of agrin, termed CAF, of approximately 22 kDA molecular size which also circulates in blood. The presence of CAF in urine suggests either glomerular filtration or secretion into urine. Blood levels of CAF have been identified as a potential novel marker of kidney function. Here we describe that several nephron segments in the mouse kidney express agrin and neutrotrypsin in addition to the localization of both protein in the glomerulum. Agrin mRNA and protein was detected in almost all nephron segments and mRNA abundance was highest in the inner medullary collecting duct. Neurotrypsin mRNA was mostly detected in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the inner medullary collecting duct. Moreover, we show that the proximal tubule absorbs injected recombinant CAF by a process shared with receptor-mediated and fluid phase endocytosis. Co-injection of CAF with recombinant human transferrin, a substrate of the receptor-mediated endocytic pathway as well as with FITC-labelled dextran (10 kDa), a marker of fluid phase endocytosis, showed partial colocalization of CAF with both markers. Further colocalization of CAF with the lysosomal marker cathepsin B suggested degradation of CAF by the lysosome in the proximal tubule. Thus, the murine kidney expresses agrin and neurotrypsin in nephron segments beyond the glomerulum. CAF is filtered by the glomerulum and is reabsorbed by endocytosis by the proximal tubule. Thus, impaired kidney function could impair glomerular clearance of CAF and thereby increase circulating CAF levels.


Systematic Review of Care Coordination Interventions Linking Health and Social Services for High-Utilizing Patient Populations.
Recognizing that social factors influence patient health outcomes and utilization, health systems have developed interventions to address patients' social needs. Care coordination across the health care and social service sectors is a distinct and important strategy to address social determinants of health, but limited information exists about how care coordination operates in this context. To address this gap, the authors conducted a systematic review of peer-reviewed publications that document the coordination of health care and social services in the United States. After a structured elimination process, 25 publications of 19 programs were synthesized to identify patterns in care coordination implementation. Results indicate that patient needs assessment, in-person patient contact, and standardized care coordination protocols are common across programs that bridge health care and social services. Publications discussing these programs often provide limited detail on other key elements of care coordination, especially the nature of referrals and care coordinator caseload. Additional research is needed to document critical elements of program implementation and to evaluate program impacts.


A Chirality-Based Quantum Leap.
There is increasing interest in the study of chiral degrees of freedom occurring in matter and in electromagnetic fields. Opportunities in quantum sciences will likely exploit two main areas that are the focus of this Review: (1) recent observations of the chiral-induced spin selectivity (CISS) effect in chiral molecules and engineered nanomaterials and (2) rapidly evolving nanophotonic strategies designed to amplify chiral light-matter interactions. On the one hand, the CISS effect underpins the observation that charge transport through nanoscopic chiral structures favors a particular electronic spin orientation, resulting in large room-temperature spin polarizations. Observations of the CISS effect suggest opportunities for spin control and for the design and fabrication of room-temperature quantum devices from the bottom up, with atomic-scale precision and molecular modularity. On the other hand, chiral-optical effects that depend on both spin- and orbital-angular momentum of photons could offer key advantages in all-optical and quantum information technologies. In particular, amplification of these chiral light-matter interactions using rationally designed plasmonic and dielectric nanomaterials provide approaches to manipulate light intensity, polarization, and phase in confined nanoscale geometries. Any technology that relies on optimal charge transport, or optical control and readout, including quantum devices for logic, sensing, and storage, may benefit from chiral quantum properties. These properties can be theoretically and experimentally investigated from a quantum information perspective, which has not yet been fully developed. There are uncharted implications for the quantum sciences once chiral couplings can be engineered to control the storage, transduction, and manipulation of quantum information. This forward-looking Review provides a survey of the experimental and theoretical fundamentals of chiral-influenced quantum effects and presents a vision for their possible future roles in enabling room-temperature quantum technologies.


Field efficacy evaluation and post-treatment contamination risk assessment of an ultraviolet disinfection and safe storage system.
Inconsistent use of household water treatment and safe storage (HWTS) systems reduces their potential health benefits. Ultraviolet (UV) disinfection is more convenient than some existing HWTS systems, but it does not provide post-treatment residual disinfectant, which could leave drinking water vulnerable to recontamination. In this paper, using as-treated analyses, we report on the field efficacy of a UV disinfection system at improving household drinking water quality in rural Mexico. We further assess the risk of post-treatment contamination from the UV system, and develop a process-based model to better understand household risk factors for recontamination. This study was part of a larger cluster-randomized stepped wedge trial, and the results complement previously published population-level results of the intervention on diarrheal prevalence and water quality. Based on the presence of Escherichia coli (proportion of households with ≥ 1 E. coli/100 mL), we estimated a risk difference of -28.0% (95% confidence interval (CI): -33.9%, -22.1%) when comparing intervention to control households; -38.6% (CI: -48.9%, -28.2%) when comparing post- and pre-intervention results; and -37.1% (CI: -45.2%, -28.9%) when comparing UV disinfected water to alternatives within the household. We found substantial increases in post-treatment E. coli contamination when comparing samples from the UV system effluent (5.0%) to samples taken from the storage container (21.1%) and drinking glasses (26.0%). We found that improved household infrastructure, additional extractions from the storage container, additional time from when the storage container was filled, and increased experience of the UV system operator were associated with reductions in post-treatment contamination. Our results suggest that the UV system is efficacious at improving household water quality when used as intended. Promoting safe storage habits is essential for an effective UV system dissemination. The drinking glass appears to represent a small but significant source of recontamination that is likely to impact all HWTS systems.


A facile hydrothermal synthesis of carbon dots modified g-C3N4 for enhanced photocatalytic H2-evolution performance.
Carbon dots (CDs)/g-C3N4 is a promising photocatalyst to split water for H2 production; however, the synthesis of CDs/g-C3N4 is usually rigorous and involves multiple steps, which limits its practical application. In this study, a facile hydrothermal approach was developed to prepare CDs/g-C3N4 photocatalysts using l-ascorbic acid and g-C3N4 as the precursors. Upon in situ thermal polymerization of l-ascorbic acid on the g-C3N4 surface, the carbon dots were homogeneously and solidly modified on the g-C3N4 surface. The CDs/g-C3N4 photocatalysts showed higher photocatalytic performance for H2 production than g-C3N4 under UV light irradiation using lactic acid as the sacrificial agent. The improved photocatalytic performance of CDs/g-C3N4 was mainly attributed to rapid interfacial charge transfer. After a Pt co-catalyst was loaded, the Pt-CDs/g-C3N4 catalyst formed exhibited a further improved photocatalytic performance for H2 production and could even split pure water to produce H2. Considering our present economic and facile synthetic approach for the modification of carbon dots on the surface of g-C3N4 photocatalysts, the as-prepared CDs/g-C3N4 photocatalysts will be promising for practical use in water splitting.


Recurrent antimicrobial exposure and acute psychosis.
There is an increased prevalence of recent antimicrobial exposure in patients with acute psychosis. We previously found recurrent urinary tract infections (UTIs) in some patients with psychosis. We evaluated the prevalence of recurrent antimicrobial exposure in acutely ill inpatients with psychosis. We performed a retrospective chart review of 85 patients age 18 to 65 with multiple hospitalizations for acute psychosis. Antimicrobial exposure was defined as occurring within 3 days of each psychiatric hospitalization. Recurrent infections were defined as antimicrobial exposure during ≥2 separate hospitalizations for acute psychosis. The prevalence of recurrent antimicrobial exposure was 26% (22/85), including 25% (13/51) in patients with schizophrenia and 26% (9/34) in patients with psychotic mood disorders. Patients with schizophrenia and recurrent antimicrobial exposure were significantly more likely to have visual hallucinations in admissions with infection vs without (31% vs 14%, respectively, P = .04). We found that a subset of patients with schizophrenia and psychotic mood disorders has recurrent infections at the time of hospitalization for acute psychosis. Findings replicate an association between recurrent UTIs and acute psychosis. Although the mechanism of this association remains unclear, findings provide additional evidence that infections may be relevant to illness relapse in some patients with psychosis.


Fetal ventriculomegaly: Pregnancy outcomes and follow-ups in ten years.
The aim of this study is to evaluate the pregnancy outcomes and prognoses for fetuses with ventriculomegaly. Two hundred and forty-one cases of fetuses with ventriculomegaly were included in this study. The subjects were divided into three groups according to their lateral ventricular width: "Mild Ventriculomegaly" (10 ‒ < 12 mm), "Moderate Ventriculomegaly" (12 ‒ < 15 mm) and "Severe Ventriculomegaly" (≥ 15 mm). Pediatric examination records and telephone interviews were conducted to track the outcomes of children until the age of 9 years. Eight-two cases were Isolated Ventriculomegaly (34.0%), while Non-Isolated Ventriculomegaly was found in 159 cases (66.0%). The pregnancy was terminated in 91 cases, and a higher abortion ratio was found in the NIVM (Non-Isolated Ventriculomegaly) group compared with the IVM (Isolated Ventriculomegaly) group. The fetuses were delivered in 150 cases, and four infants suffered deaths with NIVM. Of the surviving fetuses, 7 with IVM and 9 with NIVM showed significant abnormalities. The Mild and Moderate VM groups had more favorable prognoses compared with the Severe VM group. Regarding the outcomes and progression of lateral ventricular width, 1 out of 42 cases in the regressed group and 19 out of 108 cases in the stable group showed significant abnormalities. This study suggests that the degree and the progression of ventricular dilatation are main factors that affect pregnancy outcomes and prognoses.


Dual transgene expression in murine cerebellar Purkinje neurons by viral transduction in vivo.
Viral-vector mediated gene transfer to cerebellar Purkinje neurons in vivo is a promising avenue for gene therapy of cerebellar ataxias and for genetic manipulation in functional studies of animal models of cerebellar disease. Here, we report the results of experiments designed to identify efficient methods for viral transduction of adult murine Purkinje neurons in vivo. For these analyses, several lentiviral and an adeno-associated virus (AAV), serotype 1, vector with various promoter combinations were generated and compared for in situ transduction efficiency, assayed by fluorescent reporter protein expression in Purkinje neurons. Additional experiments were also conducted to identify the optimal experimental strategy for co-expression of two proteins in individual Purkinje neurons. Of the viruses tested, AAV1 with a CAG promoter exhibited the highest specificity for Purkinje neurons. To deliver two proteins to the same Purkinje neuron, several methods were tested, including: an internal ribosome entry site (IRES), a 2A sequence, a dual promoter vector, and co-injection of two viruses. Efficient expression of both proteins in the same Purkinje neuron was only achieved by co-injecting two AAV1-CAG viruses. We found that use of an AAV1-CAG virus outperformed similar lentivirus vectors and that co-injection of two AAV1-CAG viruses could be used to efficiently deliver two proteins to the same Purkinje neuron in adult mice. AAV1 with a CAG promoter is highly efficient and selective at transducing adult cerebellar Purkinje neurons and two AAV-CAG viruses can be used to efficiently express two proteins in the same neuron in vivo.


Emergency cricothyroidotomy performed by inexperienced clinicians--surgical technique versus indicator-guided puncture technique.
To improve the ease and safety of cricothyroidotomy especially in the hand of the inexperienced, new instruments have been developed. In this study, we compared a new indicator-guided puncture technique (PCK) with standard surgical technique (ST) regarding success rate, performance time and complications. Cricothyroidotomy in 30 human cadavers performed by 30 first year anaesthesia residents. The set chosen for use was randomised: PCK-technique (n=15) and ST (n=15). Success rates, insertion times and complications were compared. Traumatic lesions were anatomically confirmed after dissection. The ST-group had a higher success rate (100% vs 67%; p=0.04). There was no difference in time taken to complete the procedure (PCK 82 s. vs ST 95 s.; p=0.89). There was a higher complication rate in the PCK-group (67% vs 13%; p=0.04). Most frequent complication in the PCK-group was injury to the posterior tracheal wall (n=8), penetration to the oesophageal lumen (n=4) and injury to the thyroid and/or cricoid cartilage (n=5). In the ST-group in only 2 cases minor complications were observed (small vessel injury). In this human cadaver study the PCK technique produced more major complications and more failures than the ST. In the hand of the inexperienced operator the standard surgical approach seems to be a safe procedure, which can successfully be performed within an adequate time. The PCK technique cannot be recommended for inexperienced operators.


Serum zonulin and claudin-5 levels in children with obsessive-compulsive disorder.
Background: Obsessive-compulsive disorder (OCD), a chronically debilitating neuropsychiatric disorder, is characterized by distinctive and recurrent obsessions and/or compulsions. An increasing number of evidence indicates that sophisticated interactions between different neurobiological factors play a part in OCD etiology, but the certain underlying mechanisms are still mainly unknown. The present research aimed to explore whether the concentrations of serum zonulin and claudin-5 vary between OCD patients and healthy controls. The present research also intended to explore whether there is an association between zonulin and claudin-5 concentrations and OCD severity.Methods: Twenty-four (13 boys and 11 girls) OCD patients and 24 (13 boys and 11 girls) healthy controls were included in this study. The clinical severity of the OCD symptoms was evaluated by the Children's Yale-Brown Obsessive-Compulsive Scale and the Maudsley Obsessive-Compulsive Inventory. Participants also filled out the Revised Child Anxiety and Depression Scales-Child Version to determine the anxiety and depression levels of the children. Venous blood samples were collected, and serum zonulin and claudin-5 levels were measured.Results: Serum claudin-5 levels were found to be significantly higher in OCD patient whereas serum zonulin levels were not significantly different between the groups.Conclusions: Taken together with our results, our study suggests that dysregulation of the blood-brain barrier, especially claudin-5, may be involved in the etiology of OCD.


Process Mapping in a Pediatric Emergency Department to Minimize Missed Urinary Tract Infections.
Urinary tract infections (UTIs) are common in young children and are seen in emergency departments (EDs) frequently. Left untreated, UTIs can lead to more severe conditions. Our goal was to undertake a quality improvement (QI) initiative to help minimize the number of children with missed UTIs in a newly established tertiary care pediatric emergency department (PED). A retrospective chart review was undertaken to identify missed UTIs in children < 3 years old who presented to a children's hospital's ED with positive urine cultures. It was found that there was no treatment or follow-up in 12% of positive urine cultures, indicating a missed or possible missed UTI in a significant number of children. Key stakeholders were then gathered and process mapping (PM) was completed, where gaps and barriers were identified and interventions were subsequently implemented. A follow-up chart review was completed to assess the impact of PM in reducing the number of missed UTIs. Following PM and its implementation within the ED, there was no treatment or follow-up in only 1% of cases. Based on our results, the number of potentially missed UTIs in the ED decreased dramatically, indicating that PM can be a successful QI tool in an acute care pediatric setting.


[Hypernatremia caused by treatment with GHB obtained via a doctor's prescription].
In the last few years, gamma hydroxybutyric acid (GHB) has been used increasingly as a party drug; this has led to a marked increase in the number of requests for professional help with the treatment of GHB addiction. Pharmaceutical GHB (sodium oxybate, the sodium-salt of GHB), registered for cataplexia in narcolepsy patients, is used off-label to treat the withdrawal symptoms associated with GHB addiction. Pharmaceutical GHB has a high sodium load. In this report we present the cases of two patients who developed symptomatic hypernatremia following treatment with pharmaceutical GHB and who thereafter needed intensive care for the severe withdrawal symptoms that they experienced.


Peripheral nerve entrapment and injury in the upper extremity.
Peripheral nerve injury of the upper extremity commonly occurs in patients who participate in recreational (e.g., sports) and occupational activities. Nerve injury should be considered when a patient experiences pain, weakness, or paresthesias in the absence of a known bone, soft tissue, or vascular injury. The onset of symptoms may be acute or insidious. Nerve injury may mimic other common musculoskeletal disorders. For example, aching lateral elbow pain may be a symptom of lateral epicondylitis or radial tunnel syndrome; patients who have shoulder pain and weakness with overhead elevation may have a rotator cuff tear or a suprascapular nerve injury; and pain in the forearm that worsens with repetitive pronation activities may be from carpal tunnel syndrome or pronator syndrome. Specific history features are important, such as the type of activity that aggravates symptoms and the temporal relation of symptoms to activity (e.g., is there pain in the shoulder and neck every time the patient is hammering a nail, or just when hammering nails overhead?). Plain radiography and magnetic resonance imaging are usually not necessary for initial evaluation of a suspected nerve injury. When pain or weakness is refractory to conservative therapy, further evaluation (e.g., magnetic resonance imaging, electrodiagnostic testing) or surgical referral should be considered. Recovery of nerve function is more likely with a mild injury and a shorter duration of compression. Recovery is faster if the repetitive activities that exacerbate the injury can be decreased or ceased. Initial treatment for many nerve injuries is nonsurgical.


Lin28 proteins are required for germ layer specification in Xenopus.
Lin28 family proteins share a unique structure, with both zinc knuckle and cold shock RNA-binding domains, and were originally identified as regulators of developmental timing in Caenorhabditis elegans. They have since been implicated as regulators of pluripotency in mammalian stem cells in culture. Using Xenopus tropicalis, we have undertaken the first analysis of the effects on the early development of a vertebrate embryo resulting from global inhibition of the Lin28 family. The Xenopus genome contains two Lin28-related genes, lin28a and lin28b. lin28a is expressed zygotically, whereas lin28b is expressed both zygotically and maternally. Both lin28a and lin28b are expressed in pluripotent cells of the Xenopus embryo and are enriched in cells that respond to mesoderm-inducing signals. The development of axial and paraxial mesoderm is severely abnormal in lin28 knockdown (morphant) embryos. In culture, the ability of pluripotent cells from the embryo to respond to the FGF and activin/nodal-like mesoderm-inducing pathways is compromised following inhibition of lin28 function. Furthermore, there are complex effects on the temporal regulation of, and the responses to, mesoderm-inducing signals in lin28 morphant embryos. We provide evidence that Xenopus lin28 proteins play a key role in choreographing the responses of pluripotent cells in the early embryo to the signals that regulate germ layer specification, and that this early function is probably independent of the recognised role of Lin28 proteins in negatively regulating let-7 miRNA biogenesis.


Catalytic cysteine of thymidylate synthase is activated upon substrate binding.
The role of Ser 167 of Escherichia coli thymidylate synthase (TS) in catalysis has been characterized by kinetic and crystallographic studies. Position 167 variants including S167A, S167N, S167D, S167C, S167G, S167L, S167T, and S167V were generated by site-directed mutagenesis. Only S167A, S167G, S167T, and S167C complemented the growth of thymidine auxotrophs of E. coli in medium lacking thymidine. Steady-state kinetic analysis revealed that mutant enzymes exhibited k(cat) values 1.1-95-fold lower than that of the wild-type enzyme. Relative to wild-type TS, K(m) values of the mutant enzymes for 2'-deoxyuridylate (dUMP) were 5-90 times higher, while K(m) values for 5,10-methylenetetrahydrofolate (CH(2)H(4)folate) were 1.5-16-fold higher. The rate of dehalogenation of 5-bromo-2'-deoxyuridine 5'-monophosphate (BrdUMP), a reaction catalyzed by TS that does not require CH(2)H(4)folate as cosubstrate, by mutant TSs was analyzed and showed that only S167A and S167G catalyzed the dehalogenation reaction and values of k(cat)/K(m) for the mutant enzymes were decreased by 10- and 3000-fold, respectively. Analysis of pre-steady-state kinetics of ternary complex formation revealed that the productive binding of CH(2)H(4)folate is weaker to mutant TSs than to the wild-type enzyme. Chemical transformation constants (k(chem)) for the mutant enzymes were lower by 1.1-6.0-fold relative to the wild-type enzyme. S167A, S167T, and S167C crystallized in the I2(1)3 space group and scattered X-rays to either 1.7 A (S167A and S167T) or 2.6 A (S167C). The high-resolution data sets were refined to a R(crys) of 19.9%. In the crystals some cysteine residues were derivatized with 2-mercaptoethanol to form S,S-(2-hydroxyethyl)thiocysteine. The pattern of derivatization indicates that in the absence of bound substrate the catalytic cysteine is not more reactive than other cysteines. It is proposed that the catalytic cysteine is activated by substrate binding by a proton-transfer mechanism in which the phosphate group of the nucleotide neutralizes the charge of Arg 126', facilitating the transfer of a proton from the catalytic cysteine to a His 207-Asp 205 diad via a system of ordered water molecules.


The Impact of Low-Level Iron Supplements on the Faecal Microbiota of Irritable Bowel Syndrome and Healthy Donors Using In Vitro Batch Cultures.
Ferrous iron supplementation has been reported to adversely alter the gut microbiota in infants. To date, the impact of iron on the adult microbiota is limited, particularly at low supplementary concentrations. The aim of this research was to explore the impact of low-level iron supplementation on the gut microbiota of healthy and Irritable Bowel Syndrome (IBS) volunteers. Anaerobic, pH-controlled in vitro batch cultures were inoculated with faeces from healthy or IBS donors along with iron (ferrous sulphate, nanoparticulate iron and pea ferritin (50 μmol-1 iron)). The microbiota were explored by fluorescence in situ hybridisation coupled with flow cytometry. Furthermore, metabolite production was assessed by gas chromatography. IBS volunteers had different starting microbial profiles to healthy controls. The sources of iron did not negatively impact the microbial population, with results of pea ferritin supplementation being similar to nanoparticulate iron, whilst ferrous sulphate led to enhanced Bacteroides spp. The metabolite data suggested no shift to potentially negative proteolysis. The results indicate that low doses of iron from the three sources were not detrimental to the gut microbiota. This is the first time that pea ferritin fermentation has been tested and indicates that low dose supplementation of iron is unlikely to be detrimental to the gut microbiota.


A systemic cell cycle block impacts stage-specific histone modification profiles during Xenopus embryogenesis.
Forming an embryo from a zygote poses an apparent conflict for epigenetic regulation. On the one hand, the de novo induction of cell fate identities requires the establishment and subsequent maintenance of epigenetic information to harness developmental gene expression. On the other hand, the embryo depends on cell proliferation, and every round of DNA replication dilutes preexisting histone modifications by incorporation of new unmodified histones into chromatin. Here, we investigated the possible relationship between the propagation of epigenetic information and the developmental cell proliferation during Xenopus embryogenesis. We systemically inhibited cell proliferation during the G1/S transition in gastrula embryos and followed their development until the tadpole stage. Comparing wild-type and cell cycle-arrested embryos, we show that the inhibition of cell proliferation is principally compatible with embryo survival and cellular differentiation. In parallel, we quantified by mass spectrometry the abundance of a large set of histone modification states, which reflects the developmental maturation of the embryonic epigenome. The arrested embryos developed abnormal stage-specific histone modification profiles (HMPs), in which transcriptionally repressive histone marks were overrepresented. Embryos released from the cell cycle block during neurulation reverted toward normality on morphological, molecular, and epigenetic levels. These results suggest that the cell cycle block by HUA alters stage-specific HMPs. We propose that this influence is strong enough to control developmental decisions, specifically in cell populations that switch between resting and proliferating states such as stem cells.


Negative and positive affect as predictors of inflammation: Timing matters.
Very little research has assessed how measures of negative and positive affect (NA and PA) derived from assessments at multiple time points per day (e.g., via ecological momentary assessment [EMA]), as opposed to questionnaires that rely on recall over a longer period, are related to levels of peripheral inflammation. We examined how different indicators of NA and PA predicted concentrations of C-reactive protein (CRP) and seven peripheral inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-8, IL-4, IL-10, and IFN-γ) that were examined in the form of an inflammatory composite. A community-based sample of 220 adults (62% Black/African-American and 25% Hispanic/Latino; aged 25-65; 65% female) completed questionnaires at baseline (including recalled affect "over the past month") and then provided EMA reports 5x/day for 14 days. Blood was drawn from each participant after completion of EMA and used to determine plasma levels of CRP and cytokines. Analyses examined if indicators of affect predicted inflammation, controlling for age, gender, body mass index, education, health conditions, and statin use. Neither recalled NA or PA nor momentary NA or PA (aggregated across the 14 days of EMA) were significantly associated with the cytokine composite or CRP. Negative mood more proximal to the blood draw (i.e., aggregated momentary NA in week 2 of EMA) was associated with the cytokine composite but not CRP. Exploratory moderation analyses revealed that the cytokine composite was also associated with PA in week 2 for men only, and with recalled NA for those with lower education. Exploratory analyses around temporal dynamics suggested that the timing of NA measurement relative to the blood draw mattered: Specifically, there were stronger trends of association between momentary NA and inflammatory cytokines when NA was assessed closer in time to blood collection. Future investigation of the relevance of temporal proximity and other measurement details may improve understanding of how affect relates to inflammation.


Dynamic Nuclear Polarization and other magnetic ideas at EPFL.
Although nuclear magnetic resonance (NMR) can provide a wealth of information, it often suffers from a lack of sensitivity. Dynamic Nuclear Polarization (DNP) provides a way to increase the polarization and hence the signal intensities in NMR spectra by transferring the favourable electron spin polarization of paramagnetic centres to the surrounding nuclear spins through appropriate microwave irradiation. In our group at EPFL, two complementary DNP techniques are under investigation: the combination of DNP with magic angle spinning at temperatures near 100 K ('MAS-DNP'), and the combination of DNP at 1.2 K with rapid heating followed by the transfer of the sample to a high-resolution magnet ('dissolution DNP'). Recent applications of MAS-DNP to surfaces, as well as new developments of magnetization transfer of (1)H to (13)C at 1.2 K prior to dissolution will illustrate the work performed in our group. A second part of the paper will give an overview of some 'non-enhanced' activities of our laboratory in liquid- and solid-state NMR.


In situ electrochemical electron paramagnetic resonance spectroscopy as a tool to probe electrical double layer capacitance.
Electron paramagnetic resonance (EPR) spectroscopy is applied in situ to monitor the electrochemical capacitance of activated carbon in aqueous solutions, thereby revealing aspects of the charge storage mechanism. The EPR signal of activated carbon increases during the charging process and returns reversibly when discharged. Simulation of the spectral lineshape and its temperature dependence indicate that two kinds of spins exist: spin at defects giving rise to a narrow signal, and spins associated with surface-bound aromatic moieties causing a broad signal. A potential-dependent response of the narrow feature is seen in each of the electrolyte solutions used, while changes of the broad feature occur only at higher electrolyte concentrations. The results suggest that the observed increase of unpaired electron density on activated carbon is due to the formation of radical species due to reduction of functional groups. The potential dependence of the broad feature at higher electrolyte concentrations may be related to the further adsorption of ions into the deep porous structure of activated carbon.


Dissociable contributions of the prefrontal cortex to hippocampus- and caudate nucleus-dependent virtual navigation strategies.
The hippocampus and the caudate nucleus are critical to spatial- and stimulus-response-based navigation strategies, respectively. The hippocampus and caudate nucleus are also known to be anatomically connected to various areas of the prefrontal cortex. However, little is known about the involvement of the prefrontal cortex in these processes. In the current study, we sought to identify the prefrontal areas involved in spatial and response learning. We used functional magnetic resonance imaging (fMRI) and voxel-based morphometry to compare the neural activity and grey matter density of spatial and response strategy users. Twenty-three healthy young adults were scanned in a 1.5 T MRI scanner while they engaged in the Concurrent Spatial Discrimination Learning Task, a virtual navigation task in which either a spatial or response strategy can be used. In addition to increased BOLD activity in the hippocampus, spatial strategy users showed increased BOLD activity and grey matter density in the ventral area of the medial prefrontal cortex, especially in the orbitofrontal cortex. On the other hand, response strategy users exhibited increased BOLD activity and grey matter density in the dorsal area of the medial prefrontal cortex. Given the prefrontal cortex's role in reward-guided decision-making, we discuss the possibility that the ventromedial prefrontal cortex, including the orbitofrontal cortex, supports spatial learning by encoding stimulus-reward associations, while the dorsomedial prefrontal cortex supports response learning by encoding action-reward associations.


A proposed stepwise screening framework for the selection of polycyclic aromatic hydrocarbon (PAH)-degrading white rot fungi.
This study suggests a simple three-step screening protocol for the selection of white rot fungi (WRF) capable of degrading polycyclic aromatic hydrocarbons (PAHs), which combines easily applicable bioassay techniques, and verifies that protocol by evaluating the PAH degradation activity, ligninolytic enzyme secretion, and relevant gene expressions of the selected PAH-degraders. Using 120 fungal strains, a sequence of bioassay techniques was applied: Bavendamm's reaction (Step 1), remazol brilliant blue R (RBBR) decolorization (Step 2); assays for tolerance to four mixed PAHs-phenanthrene, anthracene, fluoranthene, and pyrene (Step 3). This stepwise protocol selected 14 PAH-degrading WRF, including Microporus vernicipes, Peniophora incarnata, Perenniporia subacida, Phanerochaete sordida, Phlebia acerina, and Phlebia radiata. Of these, P. incarnata exhibited the highest PAH degradative activity, ranging from 40 to > 90%, which was related to the time-variable secretions of three extracellular ligninolytic enzymes: laccase, manganese-dependent peroxidase (MnP) and lignin peroxidase (LiP). Laccase and MnP production by P. incarnata tended to be greater in the early stages of PAH degradation, whereas its LiP production became intensified with decreasing laccase and MnP production. Pilc1 and pimp1 genes encoding laccase and MnP were expressed, indicating the occurrence of extracellular enzyme-driven biodegradation of PAH by the fungal strains.


Comparison of calcaneus joint internal and external fractures in open surgery and minimal invasive methods in patients.
Surgical management of calcaneal fractures has various complications. In recent years, minimally invasive surgeries have been utilized for a wide range of surgical procedures on different body parts significantly declining complications. This paper compares surgical outcomes of calcaneal fracture management between the open reduction and internal fixation technique (ORIF) and the MIS technique. In this randomized clinical trial forty patients with calcaneus fractures were randomly assigned to two equal groups; ORIF group and MIS group. Patients were followed for 1 year post-operatively. Gissane and Bohler's angles, AOFAS questionnaire, pain intensity, ability to conduct previous activities and various complications like wound healing complications and irritation with shoe wear were assessed in the final post-operative visit. Eventually data obtained from the two groups were compared. All patients obtained fracture union. Bohler's and Gissane angles significantly increased and decreased, respectively, after the operation in both groups (p˂0.05), however, no significant difference was found between the two research groups. AOFAS scores and pain intensity was similar in both groups, however, surgical duration in the MIS group was significantly less than the ORIF group (P=0.021). Only one patient from the ORIF group was not able to resume his previous occupation. 12 patients from the ORIF group and five patients from the MIS group experienced irritation from shoe wear (p=0.025). In the ORIF group, 4 patients suffered from wound healing complications, however, none of the patients of the MIS group had wound complications (p=0.035). In conclusion, based on the results, it can be concluded that the MIS technique demonstrated better functional and radiographic outcomes as well as a more favorable complication profile, thus, it is recommended for the management of calcaneus fractures.


A Simple, Low-Cost Platform for Real-Time Isothermal Nucleic Acid Amplification.
Advances in microfluidics and the introduction of isothermal nucleic acid amplification assays have resulted in a range of solutions for nucleic acid amplification tests suited for point of care and field use. However, miniaturisation of instrumentation for such assays has not seen such rapid advances and fluorescence based assays still depend on complex, bulky and expensive optics such as fluorescence microscopes, photomultiplier tubes and sensitive lens assemblies. In this work we demonstrate a robust, low cost platform for isothermal nucleic acid amplification on a microfluidic device. Using easily obtainable materials and commercial off-the-shelf components, we show real time fluorescence detection using a low cost photodiode and operational amplifier without need for lenses. Temperature regulation on the device is achieved using a heater fabricated with standard printed circuit board fabrication methods. These facile construction methods allow fabrications at a cost compatible with widespread deployment to resource poor settings.


Denoising and spatial resolution enhancement of 4D flow MRI using proper orthogonal decomposition and lasso regularization.
4D-Flow MRI has emerged as a powerful tool to non-invasively image blood velocity profiles in the human cardio-vascular system. However, it is plagued by issues such as velocity aliasing, phase offsets, acquisition noise, and low spatial and temporal resolution. In imaging small blood vessel malformations such as intra-cranial aneurysms, the spatial resolution of 4D-Flow is often inadequate to resolve fine flow features. In this paper, we address the problem of low spatial resolution and noise by combining 4D-Flow MRI and patient specific computational fluid dynamics using Least Absolute Shrinkage and Selection Operator. Extensive experiments using numerical phantoms of two actual intra-cranial aneurysms geometries show the applicability of the proposed method in recovering the flow profile. Comparisons with the state-of-the-art denoising methods for 4D-Flow show lower error metrics. This method can enable more accurate computation of flow derived patho-physiological parameters such as wall shear stresses, pressure gradients, and viscous dissipation.


The PPCD1 mouse: characterization of a mouse model for posterior polymorphous corneal dystrophy and identification of a candidate gene.
The PPCD1 mouse, a spontaneous mutant that arose in our mouse colony, is characterized by an enlarged anterior chamber resulting from metaplasia of the corneal endothelium and blockage of the iridocorneal angle by epithelialized corneal endothelial cells. The presence of stratified multilayered corneal endothelial cells with abnormal patterns of cytokeratin expression are remarkably similar to those observed in human posterior polymorphous corneal dystrophy (PPCD) and the sporadic condition, iridocorneal endothelial syndrome. Affected eyes exhibit epithelialized corneal endothelial cells, with inappropriate cytokeratin expression and proliferation over the iridocorneal angle and posterior cornea. We have termed this the "mouse PPCD1" phenotype and mapped the mouse locus for this phenotype, designated "Ppcd1", to a 6.1 Mbp interval on Chromosome 2, which is syntenic to the human Chromosome 20 PPCD1 interval. Inheritance of the mouse PPCD1 phenotype is autosomal dominant, with complete penetrance on the sensitive DBA/2J background and decreased penetrance on the C57BL/6J background. Comparative genome hybridization has identified a hemizygous 78 Kbp duplication in the mapped interval. The endpoints of the duplication are located in positions that disrupt the genes Csrp2bp and 6330439K17Rik and lead to duplication of the pseudogene LOC100043552. Quantitative reverse transcriptase-PCR indicates that expression levels of Csrp2bp and 6330439K17Rik are decreased in eyes of PPCD1 mice. Based on the observations of decreased gene expression levels, association with ZEB1-related pathways, and the report of corneal opacities in Csrp2bp(tm1a(KOMP)Wtsi) heterozygotes and embryonic lethality in nulls, we postulate that duplication of the 78 Kbp segment leading to haploinsufficiency of Csrp2bp is responsible for the mouse PPCD1 phenotype. Similarly, CSRP2BP haploinsufficiency may lead to human PPCD.


WNT regulation of embryonic development likely involves pathways independent of nuclear CTNNB1.
The bovine was used to examine the potential for WNT signaling to affect the preimplantation embryo. Expression of seven key genes involved in canonical WNT signaling declined to a nadir at the morula or blastocyst stage. Expression of 80 genes associated with WNT signaling in the morula and inner cell mass (ICM) and trophectoderm (TE) of the blastocyst was also evaluated. Many genes associated with WNT signaling were characterized by low transcript abundance. Seven genes were different between ICM and TE, and all of them were overexpressed in TE as compared to ICM, including WNT6, FZD1, FZD7, LRP6, PORCN, APC and SFRP1 Immunoreactive CTNNB1 was localized primarily to the plasma membrane at all stages examined from the 2-cell to blastocyst stages of development. Strikingly, neither CTNNB1 nor non-phospho (i.e., active) CTNNB1 was observed in the nucleus of blastomeres at any stage of development even after the addition of WNT activators to culture. In contrast, CTNNB1 associated with the plasma membrane was increased by activators of WNT signaling. The planar cell polarity pathway (PCP) could be activated in the embryo as indicated by an experiment demonstrating an increase in phospho-JNK in the nucleus of blastocysts treated with the non-canonical WNT11. Furthermore, WNT11 improved development to the blastocyst stage. In conclusion, canonical WNT signaling is attenuated in the preimplantation bovine embryo but WNT can activate the PCP component JNK. Thus, regulation of embryonic development by WNT is likely to involve activation of pathways independent of nuclear actions of CTNNB1.


Transepidermal elimination in exogenous ochronosis. A report of two cases.
Exogenous ochronosis is caused by the long-term application of skin-lightening creams containing hydroquinone. This irreversible disfiguring cosmetic problem assumes epidemic proportions in South African blacks. Mild ochronosis is characterized clinically by coarsening and darkening of the skin; severe ochronosis, by coalescing, caviar-like black papules and atrophy. Histology shows ochronotic collagen fibers with eventual formation of ochronotic colloid milium. A variable cellular infiltrate, which may be granulomatous, is present. We describe two patients with severe exogenous ochronosis who developed superimposed papular lesions. Histology in both cases showed transfollicular elimination of ochronotic fibers. In one patient, gross epidermal hyperplasia, a dense lichenoid infiltrate, and partial destruction of ochronotic fibers accompanied the process of elimination (cell-rich type). In the other, concomitant epidermal hyperplasia and a cellular infiltrate were absent (cell-poor type). Further studies are needed to prove or disprove the existence of such a proposed subdivision. Transepidermal elimination in exogenous ochronosis has been mentioned in a previous report, but to our knowledge this is the first detailed documentation of this phenomenon. The clinical and histopathological spectrum of exogenous ochronosis is thus expanded.


Learning Disentangled Semantic Representation for Domain Adaptation.
Domain adaptation is an important but challenging task. Most of the existing domain adaptation methods struggle to extract the domain-invariant representation on the feature space with entangling domain information and semantic information. Different from previous efforts on the entangled feature space, we aim to extract the domain invariant semantic information in the latent disentangled semantic representation (DSR) of the data. In DSR, we assume the data generation process is controlled by two independent sets of variables, i.e., the semantic latent variables and the domain latent variables. Under the above assumption, we employ a variational auto-encoder to reconstruct the semantic latent variables and domain latent variables behind the data. We further devise a dual adversarial network to disentangle these two sets of reconstructed latent variables. The disentangled semantic latent variables are finally adapted across the domains. Experimental studies testify that our model yields state-of-the-art performance on several domain adaptation benchmark datasets.


Biodegradable, Drug-Loaded Nanovectors via Direct Hydration as a New Platform for Cancer Therapeutics.
The stabilization and transport of low-solubility drugs, by encapsulation in nanoscopic delivery vectors (nanovectors), is a key paradigm in nanomedicine. However, the problems of carrier toxicity, specificity, and producibility create a bottleneck in the development of new nanomedical technologies. Copolymeric nanoparticles are an excellent platform for nanovector engineering due to their structural versatility; however, conventional fabrication processes rely upon harmful chemicals that necessitate purification. In engineering a more robust (copolymeric) nanovector platform, it is necessary to reconsider the entire process from copolymer synthesis through self-assembly and functionalization. To this end, a process is developed whereby biodegradable copolymers of poly(ethylene glycol)-block-poly(trimethylene carbonate), synthesized via organocatalyzed ring-opening polymerization, undergo assembly into highly uniform, drug-loaded micelles without the use of harmful solvents or the need for purification. The direct hydration methodology, employing oligo(ethylene glycol) as a nontoxic dispersant, facilitates rapid preparation of pristine, drug-loaded nanovectors that require no further processing. This method is robust, fast, and scalable. Utilizing parthenolide, an exciting candidate for treatment of acute lymphoblastic leukemia (ALL), discrete nanovectors are generated that show strikingly low carrier toxicity and high levels of specific therapeutic efficacy against primary ALL cells (as compared to normal hematopoietic cells).


Metrics for the Human Proteome Project 2015: Progress on the Human Proteome and Guidelines for High-Confidence Protein Identification.
Remarkable progress continues on the annotation of the proteins identified in the Human Proteome and on finding credible proteomic evidence for the expression of "missing proteins". Missing proteins are those with no previous protein-level evidence or insufficient evidence to make a confident identification upon reanalysis in PeptideAtlas and curation in neXtProt. Enhanced with several major new data sets published in 2014, the human proteome presented as neXtProt, version 2014-09-19, has 16,491 unique confident proteins (PE level 1), up from 13,664 at 2012-12 and 15,646 at 2013-09. That leaves 2948 missing proteins from genes classified having protein existence level PE 2, 3, or 4, as well as 616 dubious proteins at PE 5. Here, we document the progress of the HPP and discuss the importance of assessing the quality of evidence, confirming automated findings and considering alternative protein matches for spectra and peptides. We provide guidelines for proteomics investigators to apply in reporting newly identified proteins.


Relative Cost Effectiveness of In-Person and Internet Interventions for Relationship Distress.
While the efficacy of couple therapy has been repeatedly demonstrated, most distressed couples do not seek treatment. To improve reach and overcome barriers to therapy, Integrative Behavioral Couple Therapy (IBCT) was translated into a web-based program, OurRelationship (OR). While both IBCT and OR have been shown to improve relationship and individual functioning, the goal of the present study was to compare the relative cost effectiveness of these two treatment modalities. In IBCT, 74% of couples experienced reliable improvement, compared to 55% of couples in OR. Within-group Cohen's d effect sizes during treatment for relationship satisfaction were d = 0.87 for IBCT and d = 0.96 for OR. Relative cost effectiveness analyses revealed that even at the highest expense estimates for OR and the lowest expense estimates for IBCT, OR was more cost effective in creating reliable improvement once at least 229 couples were served and was more cost effective in creating large-size effects once at least 153 couples were served. Cost-effectiveness increases for both IBCT and OR as more couples are served; however, this cost savings occurs at a much more rapid rate for OR. These findings demonstrate that despite higher initial development costs, Internet programs are a cost-effective option for dissemination either as a stand-alone service or as an initial intervention in a stepped care model with more intensive in-person services.


Salivary metabolomics with alternative decision tree-based machine learning methods for breast cancer discrimination.
The aim of this study is to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls. Saliva samples were collected after 9 h fasting and were immediately stored at - 80 °C. Capillary electrophoresis and liquid chromatography with mass spectrometry were used to quantify hundreds of hydrophilic metabolites. Conventional statistical analyses and artificial intelligence-based methods were used to assess the discrimination abilities of the quantified metabolites. A multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning method were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods. One hundred sixty-six unstimulated saliva samples were collected from 101 patients with invasive carcinoma of the breast (IC), 23 patients with ductal carcinoma in situ (DCIS), and 42 healthy controls (C). Of the 260 quantified metabolites, polyamines were significantly elevated in the saliva of patients with breast cancer. Spermine showed the highest area under the receiver operating characteristic curves [0.766; 95% confidence interval (CI) 0.671-0.840, P < 0.0001] to discriminate IC from C. In addition to spermine, polyamines and their acetylated forms were elevated in IC only. Two hundred each of two-fold, five-fold, and ten-fold cross-validation using different random values were conducted and the MLR model had slightly better accuracy. The ADTree with an ensemble approach showed higher accuracy (0.912; 95% CI 0.838-0.961, P < 0.0001). These prediction models also included spermine as a predictive factor. These data indicated that combinations of salivary metabolomics with the ADTree-based machine learning methods show potential for non-invasive screening of breast cancer.


Effects of levosimendan on ventriculo-arterial coupling and cardiac efficiency in paediatric patients with single-ventricle physiology after surgical palliation: retrospective study.
The use of levosimendan for paediatric patients with low cardiac output after congenital heart surgery has been recently described. We sought to evaluate ventriculo-arterial coupling (VAC) and other ventricular energetic parameters before and after 72 h from levosimendan start in infants with single-ventricle physiology and cardiac failure after palliation with Norwood or hybrid procedures. In this single-centre retrospective study, 9 consecutive patients affected by hypoplastic left heart syndrome-like anatomy were retrospectively analysed. Systolic elastance, diastolic elastance, arterial elastance, VAC and cardiac mechanical efficiency were calculated by measuring, through 2-dimensional echocardiography, end-systolic volume and end-diastolic volume and by recording mean arterial pressure and central venous pressure. The median (range) weight and age were 2.8 (2.3-6) kg and 16.5 (6-116) days, respectively. After 72 h from levosimendan start, end-systolic volume significantly decreased (-1 ml, -3.2 to -0.1, P = 0.007), whereas mean arterial pressure and end-diastolic volume remained stable. Heart rate showed a significant decrease (-28 beats/min, -41 to 22, P = 0.008). Systolic elastance (2.9 mmHg/ml, 0.4-5.4, P = 0.008), arterial elastance (-5.9, -24 to -0.5, P = 0.038), VAC (-0.86, -1.5 to -0.16, P = 0.009) and cardiac mechanical efficiency (0.18, 0.03-0.22, P = 0.008) differences also showed significant modifications. In a small case series of patients with single-ventricle physiology, levosimendan showed to improve contractility and optimize VAC, with a reduction of heart rate. Monitoring of VAC and ventricular energetics can be an interesting aspect to improve the management of heart failure in infants with univentricular anatomy.


Transgenic mouse models of corneal neovascularization: new perspectives for angiogenesis research.
Corneal neovascularization (NV) refers to the growth of blood vessels and/or lymphatics into the physiologically avascular cornea, which occurs in several pathological processes. In mouse models, corneal NV can be artificially induced to investigate mechanisms of corneal pathologies. However, mouse models of corneal NV are not restricted to cornea-specific research, but also are widely used to investigate general mechanisms of angiogenesis. Because the cornea is transparent and easily accessible, corneal NV models are among the most useful in vivo models in angiogenesis research. The three different approaches that are used to study corneal NV in mice are based on direct application of proangiogenic or antiangiogenic transmitters, external injury to the cornea, or genetically engineered mice, which spontaneously develop corneal NV. The aim of this review is to compare the scope and limitations of the different approaches for corneal NV in mice. Our main focus is to highlight the potential of transgenic spontaneous models of corneal NV. Transgenic models do not require any experimental interference and make it possible to investigate different interconnected proangiogenic signaling cascades. As a result, transgenic models are highly useful for disease-centered angiogenesis research. In summary, transgenic models of corneal NV will complement and advance existing ocular NV assays, and help to discover new angiogenesis-related treatment strategies for ocular and extraocular diseases.


Epitope mapping via selection of anti-FVIII antibody-specific phage-presented peptide ligands that mimic the antibody binding sites.
The most serious complication in today's treatment of congenital haemophilia A is the development of neutralising antibodies (inhibitors) against factor VIII (FVIII). Although FVIII inhibitors can be eliminated by immune tolerance induction (ITI) based on repeated administration of high doses of FVIII, 20-30% of patients fail to become tolerant. Persistence of FVIII inhibitors is associated with increased morbidity and mortality. Data from recent studies provide evidence for a potential association between ITI outcome and epitope specificity of FVIII inhibitors. Nevertheless the determination of epitopes and their clinical relevance has not yet been established. In this study a general strategy for the identification of anti-FVIII antibody epitopes in haemophilia A patient plasma was to be demonstrated. Phage-displayed peptide libraries were screened against anti-FVIII antibodies to isolate specific peptides. Peptide specificity was confirmed by FVIII-sensitive ELISA binding. Peptide residues essential for antibody binding were identified by mutational analysis and epitopes were predicted via FVIII homology search. The proposed mapping strategy was validated for the monoclonal murine antibody (mAb) 2-76. Binding studies with FVIII variants confirmed the location of the predicted epitope at the level of individual amino acids. In addition, anti-FVIII antibody-specific peptide ligands were selected for 10 haemophilia A patients with FVIII inhibitors. Detailed epitope mapping for three of them showed binding sites on the A2, A3 and C2 domains. Precise epitope mapping of anti-FVIII antibodies using antibody-specific peptide ligands can be a useful approach to identify antigenic sites on FVIII.


Mitochondrial plasticity of the hippocampus in a genetic rat model of depression after antidepressant treatment.
Depressive disorders and the treatment thereof have been associated with a number of neuroplastic events, such as neurogenesis and synaptic remodeling in discrete areas of the brain. The associations of these events in changes regarding the energy supply have not been investigated. Here, we investigated the changes in mitochondrial plasticity and its correlation to morphological alterations of neuroplasticity in the hippocampus, both associated with a depressive phenotype, and after treatment, with antidepressant imipramine. Design-based stereological methods were used to estimate the number and volume of mitochondria in CA1 of the hippocampus in two different strains of rats, the Sprague-Dawley (SD) and Flinders rats, which display a genetic susceptibility to depressive behavior, the Flinders-sensitive line (FSL) and their corresponding controls, the Flinders-resistant line (FRL). Results showed a significantly reduced number of mitochondria in CA1, which was significantly smaller in the untreated FSL saline group compared to the FRL group. However, the mean volume of mitochondria was significantly larger in the FSL saline group compared to the FRL saline group. Following treatment, the FSL imipramine group showed a significant increase in the number of mitochondria compared to the FSL saline group. Treatment with imipramine in the SD rats did not induce significant differences in the number of mitochondria. Our results indicate that depression may be related to impairments of mitochondrial plasticity in the hippocampus and antidepressant treatment may counteract with the structural impairments. Moreover, the changes in mitochondrial morphology and number are a consistent feature of neuroplasticity.


Learning About Dying and Living: An Applied Approach to End-of-Life Communication.
The purpose of this article is to expand on prior research in end-of-life communication and death and dying communication apprehension, by developing a unique course that utilizes a hospice setting and an applied, service-learning approach. Therefore, this essay describes and discusses both students' and my experiences over a 7-year period from 2008 through 2014. The courses taught during this time frame provided an opportunity to analyze students' responses, experiences, and discoveries across semesters/years and cocultures. This unique, 3-credit, 14-week, service-learning, end-of-life communication course was developed to provide an opportunity for students to learn the theories related to this field of study and to apply that knowledge through volunteer experiences via interactions with dying patients and their families. The 7 years of author's notes, plus the 91 students' electronically submitted three reflection essays each (273 total documents) across four courses/years, served as the data for this study. According to the students, verbally in class discussions and in numerous writing assignments, this course helped lower their death and dying communication apprehension and increased their willingness to interact with hospice patients and their families. Furthermore, the students' final research papers clearly demonstrated how utilizing a service-learning approach allowed them to apply classroom learnings and interactions with dying patients and their families at the hospice, to their analyses of end-of-life communication theories and behaviors. The results of these classes suggest that other, difficult topic courses (e.g., domestic violence, addiction, etc.) might benefit from a similar pedagogical approach.


The creation of a measurable contusion injury in skeletal muscle.
The effect that compressed air massage (CAM) has on skeletal muscle has been ascertained by the morphological and morphometric evaluation of healthy vervet monkey and rabbit skeletal muscle. How CAM may influence the process of healing following a contusion injury is not known. To determine how CAM or other physiotherapeutic modalities may influence healing, it is necessary to create a minor injury that is both reproducible and quantifiable at the termination of a pre-determined healing period. An earlier study described changes in the morphology of skeletal muscle following a reproducible contusion injury. This study extended that work in that it attempted to quantify the 'severity' of such an injury. A 201 g, elongated oval-shaped weight was dropped seven times through a 1 m tube onto the left vastus lateralis muscle of four New Zealand white rabbits. Biopsies were obtained 6 days after injury from the left healing juxta-bone and sub-dermal muscle and uninjured (control) right vastus lateralis of each animal. The tissue was fixed in formal saline, embedded in wax, cut and stained with haematoxylin and phosphotungstic haematoxylin. The muscle was examined by light microscopy and quantification of the severity of injury made using a modified, 'in-house' morphological index and by the comparative morphometric measurement of the cross-sectioned epimysium and myofibres in injured and control muscle. The results showed that a single contusion causes multiple, quantifiable degrees of injury from skin to bone - observations of particular importance to others wishing to investigate contusion injury in human or animal models.


Reduced reticulization of palatine tonsils with IgA nephropathy.
Tonsillar abnormalities have been observed in patients with IgA nephropathy (IgAN). In addition, it has been suggested that the reticulization of tonsillar crypt epithelium is important in tonsillar immunity. Therefore, we investigated reticulization of this area in patients with IgAN (10 cases) and compared results with those of control patients who exhibited recurrent tonsillitis or tonsillar hypertrophy (12 cases). Immunohistochemical staining of anti-keratin antibody PKK1 was employed to visualize reticulization. Tonsils of controls showed well developed reticular crypt epithelia with lymphoepithelial symbiosis, and the non-reticulated area was less than 7% (mean 1.9%, range 0-6.3%) of the total crypt epithelia per overall section. In IgAN tonsils, however, non-reticulated crypt epithelium was frequently observed and, in the advanced stage of IgAN, exceeded 50% (mean 62%, range 50-69%) of total crypt epithelia. The extent of glomerular damage in IgAN patients correlated significantly with the percentage of the area of non-reticulated crypt epithelia in palatine tonsils with a correlation coefficient of 0.91. Considering together with our finding that PKK1-positive epithelial reticular cells strongly expressed HLA-DR antigens in normal tonsils, the low level of reticulization in IgAN patients may induce the unusual immunity responsible for the pathogenesis of IgAN.


A single point mutation responsible for c-mos polymorphism in cancer patients.
A rare EcoRI restriction fragment length polymorphism (RFLP) in the 3' end of the human c-mos locus has been identified in DNA from patients with breast tumors, esophageal carcinomas and leukemias. Until now, this RFLP has not been found in normal populations, suggesting that its presence may reflect some cancer susceptibility. To characterize this RFLP, we have isolated both alleles of the c-mos locus from DNA of a breast cancer patient and determined the nucleotide sequence of the polymorphic region. Our results show that this RFLP is due to a single nucleotide substitution (T instead of C), resulting in the disappearance of EcoRI site.


The regulated secretory pathway in CD4(+) T cells contributes to human immunodeficiency virus type-1 cell-to-cell spread at the virological synapse.
Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1) at the virological synapse (VS) is an efficient mode of dissemination between CD4(+) T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4(+) T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS). Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC) and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL) and we show that the HIV-1 envelope glycoprotein (Env) localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4(+) T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4(+) T cells to enhance its dissemination.


Inhibition of tumor necrosis factor by curcumin, a phytochemical.
Curcumin, contained in the rhizome of the plant Curcuma longa Linn, is a naturally occurring phytochemical that has been used widely in India and Indonesia for the treatment of inflammation. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) induces the production of interleukin-1 beta (IL-1), and, together, they play significant roles in many acute and chronic inflammatory diseases. They have been implicated in the pathogenesis of intracellular parasitic infections, atherosclerosis, AIDS and autoimmune disorders. This report shows that, in vitro, curcumin, at 5 microM, inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-1 by a human monocytic macrophage cell line, Mono Mac 6. In addition, it demonstrates that curcumin, at the corresponding concentration, inhibited LPS-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in L929 fibroblast lytic assay.


The complete genome sequence of the nitrile biocatalyst Rhodocccus rhodochrous ATCC BAA-870.
Rhodococci are industrially important soil-dwelling Gram-positive bacteria that are well known for both nitrile hydrolysis and oxidative metabolism of aromatics. Rhodococcus rhodochrous ATCC BAA-870 is capable of metabolising a wide range of aliphatic and aromatic nitriles and amides. The genome of the organism was sequenced and analysed in order to better understand this whole cell biocatalyst. The genome of R. rhodochrous ATCC BAA-870 is the first Rhodococcus genome fully sequenced using Nanopore sequencing. The circular genome contains 5.9 megabase pairs (Mbp) and includes a 0.53 Mbp linear plasmid, that together encode 7548 predicted protein sequences according to BASys annotation, and 5535 predicted protein sequences according to RAST annotation. The genome contains numerous oxidoreductases, 15 identified antibiotic and secondary metabolite gene clusters, several terpene and nonribosomal peptide synthetase clusters, as well as 6 putative clusters of unknown type. The 0.53 Mbp plasmid encodes 677 predicted genes and contains the nitrile converting gene cluster, including a nitrilase, a low molecular weight nitrile hydratase, and an enantioselective amidase. Although there are fewer biotechnologically relevant enzymes compared to those found in rhodococci with larger genomes, such as the well-known Rhodococcus jostii RHA1, the abundance of transporters in combination with the myriad of enzymes found in strain BAA-870 might make it more suitable for use in industrially relevant processes than other rhodococci. The sequence and comprehensive description of the R. rhodochrous ATCC BAA-870 genome will facilitate the additional exploitation of rhodococci for biotechnological applications, as well as enable further characterisation of this model organism. The genome encodes a wide range of enzymes, many with unknown substrate specificities supporting potential applications in biotechnology, including nitrilases, nitrile hydratase, monooxygenases, cytochrome P450s, reductases, proteases, lipases, and transaminases.