Cloning of P2Y6 cDNAs and identification of a pseudogene: comparison of P2Y receptor subtype expression in bone and brain tissues.
Cellular responses to ATP/UTP and analogs are mediated by G-protein coupled P2Y receptors and have been proposed to play a role in the regulation of bone metabolism. Using a degenerate PCR approach on MG-63 cell cDNA we found PCR fragments coding for human P2Y1 and a new receptor, P2Y6. cDNA cloning of the P2Y6 receptor identified three cDNA isoforms. Two contained the same contiguous ORFs but differed in their 5' UTRs and may therefore originate by alternative splicing whereas the third represents a pseudogene. Analysis of P2Y receptor subtype expression in human bone and the osteoblastic cell lines OHS-4 and MG-63 by RT-PCR showed that all known human P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y7) were expressed. In contrast, analysis of brain-derived cell lines suggests that a selective expression of P2Y receptor subtypes occurs in brain tissue.


Histology/cytology discrepancies in HIV-infected obstetric patients with normal pap smears.
To estimate the frequency of cervical cytologic/histologic discrepancies in a group of obstetric patients diagnosed as HIV infected by routine prenatal screening. Also, to determine if serum CD4 levels or sexually transmitted diseases (STDs) are associated with the occurrence of preinvasive cervical disease in these women. Thirty-two women who presented for routine prenatal care to Medical Center of Louisiana were diagnosed as HIV infected by ELISA and Western blot testing and had normal Pap smears. These patients then agreed to undergo the following: colposcopy with directed biopsies; chlamydia, gonorrhea, and syphilis screening; and serum CD4 level. No patients had AIDS-defining diagnoses other than CD4 < 200/mm3. Ten of 32 (31%) had cervical intraepithelial neoplasia (CIN) despite normal cytology. Six of 32 (19%) had STDs. One of 10 in the group with CIN had a STD. The mean CD4 level in those patients with CIN was 249/mm2 (range 1-524) vs 501/mm2 (range 210-979) in those without CIN. (P = 0.0118) Newly diagnosed HIV-infected pregnant women without clinical evidence of AIDS are noted to have CIN at a rate similar to nonpregnant HIV-infected women. The Pap smear appears to have a significant false-negative rate in this group. STDs, while common, were not directly associated with false-negative Pap smears. CIN is associated with immunosuppression, as measured by low CD4 counts.


Co-occurring gland angularity in localized subgraphs: predicting biochemical recurrence in intermediate-risk prostate cancer patients.
Quantitative histomorphometry (QH) refers to the application of advanced computational image analysis to reproducibly describe disease appearance on digitized histopathology images. QH thus could serve as an important complementary tool for pathologists in interrogating and interpreting cancer morphology and malignancy. In the US, annually, over 60,000 prostate cancer patients undergo radical prostatectomy treatment. Around 10,000 of these men experience biochemical recurrence within 5 years of surgery, a marker for local or distant disease recurrence. The ability to predict the risk of biochemical recurrence soon after surgery could allow for adjuvant therapies to be prescribed as necessary to improve long term treatment outcomes. The underlying hypothesis with our approach, co-occurring gland angularity (CGA), is that in benign or less aggressive prostate cancer, gland orientations within local neighborhoods are similar to each other but are more chaotically arranged in aggressive disease. By modeling the extent of the disorder, we can differentiate surgically removed prostate tissue sections from (a) benign and malignant regions and (b) more and less aggressive prostate cancer. For a cohort of 40 intermediate-risk (mostly Gleason sum 7) surgically cured prostate cancer patients where half suffered biochemical recurrence, the CGA features were able to predict biochemical recurrence with 73% accuracy. Additionally, for 80 regions of interest chosen from the 40 studies, corresponding to both normal and cancerous cases, the CGA features yielded a 99% accuracy. CGAs were shown to be statistically signicantly ([Formula: see text]) better at predicting BCR compared to state-of-the-art QH methods and postoperative prostate cancer nomograms.


Relevance of pharmacogenetics and pharmacogenomics in veterinary clinical practice: A review.
The recent advances in high-throughput next-generation sequencing technologies have heralded the arrival of the Big Data era. As a result, the use of pharmacogenetics in drug discovery and individualized drug therapy has transformed the field of precision medicine. This paradigm shift in drug development programs has effectively reshaped the old drug development practices, which were primarily concerned with the physiological status of patients for drug development. Pharmacogenomics bridges the gap between pharmacodynamics and pharmacokinetics, advancing current diagnostic and treatment strategies and enabling personalized and targeted drug therapy. The primary goals of pharmacogenetic studies are to improve drug efficacy and minimize toxicities, to identify novel drug targets, to estimate drug dosage for personalized medicine, and to incorporate it as a routine diagnostic for disease susceptibility. Although pharmacogenetics has numerous applications in individualized drug therapy and drug development, it is in its infancy in veterinary medicine. The objective of this review is to present an overview of historical landmarks, current developments in various animal species, challenges and future perspectives of genomics in drug development and dosage optimization for individualized medicine in veterinary subjects.


Lessons learned from developing a tailored print intervention: a guide for practitioners and researchers new to tailoring.
Although some "how-to" guides have been written on tailored messaging, we found no reports on lessons learned from the process of developing a tailored intervention. Such lessons may be useful for practitioners and researchers who are new to tailored intervention development. The authors describe lessons gleaned from the process of developing a repeat mammography tailored print intervention. Lessons learned include the following: Selection of determinants appropriate for tailoring should be based on a theoretic framework and refined through assessment of the target population; researchers should anticipate threats to fidelity of intervention delivery because of incomplete or illogical survey data; fingerprinting enables assessment of intervention dose and how it relates to effectiveness of the tailored intervention; and a systematic process for conducting a systems test is needed to check for inconsistencies and errors before final tailored letter production. These lessons are discussed in the context of challenges and possible solutions for tailored health communication.


Retrospective review of epidemic viral pneumonia cases in Turkey: A multicenter study.
Influenza A (H1N1) caused its first pandemic in 2009 in USA and Mexico. Since then, clinicians have exercised great care in order to make an early diagnosis of viral pneumonias. This is due in part to pandemic influenza A infection having greater impact on populations <65 years old than other viral strains, including seasonal influenza. Chest radiographies of those affected displayed a rapid progression of patchy infiltrates, and a large proportion of individuals required admission to intensive care units (ICU). Despite efforts, patients infected with the virus had a high mortality rate. The present multicenter study aimed to retrospectively evaluate the clinical, demographic and prognostic characteristics of patients diagnosed with epidemic viral pneumonia in Turkey. A total of 92 patients were included in the study. The Student's t-test and Chi-square tests were performed to analyze quantitative data, assuming a normal distribution, and to analyze qualitative data, respectively. Stepwise logistic regression was used to evaluate the effects of demographic variables and laboratory values on the virus mortality rate. The male/female ratio was 42/50 and the mean age was 48.74±16.65 years. A total of 69 (75%) patients were unvaccinated against influenza. The most common symptoms were cough (87%) and fever (63%). Chest computed tomography showed peripheral patchy areas of the lungs of ground glass density in 38 patients (41.3%). A total of 22 (59.4%) patients had H1N1, 5 (12.5%) patients had influenza B, and 38 (41.3%) patients met the criteria for admission to the ICU. Of these patients, 20 (52.63%) were monitored with a mechanical ventilator, with a noninvasive ventilator being adequate for 10 (26.32%) of patients. The length of stay in the ICU was 6.45±5.97 days and the duration of mechanical ventilation was 5.06±4.69 days. A total of 12 (13.04%) patients in the ICU succumbed. Logistic regression analysis revealed that among the parameters possibly associated with mortality, being an active smoker increased the risk of mortality 7.08-fold compared to other groups (P=0.005). In conclusion, viral pneumonia remains a significant health problem during the winter period. Considering the high number of ICU admissions and high rate of mortality for patients in the present study, earlier initiation of antiviral therapy is necessary. Active smoking increased mortality in viral pneumonia.


Comparison of hormone levels in nipple aspirate fluid of pre- and postmenopausal women: effect of oral contraceptives and hormone replacement.
The effects of ovarian suppression by oral contraceptives as well as hormone replacement therapy were studied on hormone levels and on products of hormone action in nipple aspirate fluid (NAF) from breasts of pre- and postmenopausal women. Multiple samples per subject revealed high consistency (intraclass correlation coefficients) for all products measured. Compared with premenopausal women, NAF progesterone was much lower in postmenopausal women, but NAF androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different. With oral contraceptive use, estradiol, estrone sulfate, and progesterone levels were similarly lower in serum and NAF. In postmenopausal women, NAF estradiol and estrone sulfate were not significantly less than those in premenopausal women, nor were epidermal growth factor or cathepsin D levels, but IL-6 was elevated. Despite corresponding changes in hormones in serum and NAF over time, correlations based on simultaneous sampling were not significant. It is concluded that: 1) potential precursors of estradiol remain at comparable levels in the breast after menopause; 2) local synthesis is important for maintenance of estradiol levels in NAF of postmenopausal women but less important for progesterone; and 3) changes in the serum parameters are accurately reflected in NAF, but only after a matter of days. These findings provide additional validation for the physiological relevance of NAF hormone levels as potential breast cancer risk markers.


Acquired stenosis of the upper airway in neonates. An increasing problem.
Thirty neonates with acquired airway stenosis were treated between 1975 and 1979 at the C. S. Mott Children's Hospital of the University of Michigan. Neonates surviving a period of ventilation are at risk of developing subglottic stenosis (8.3%). The stenosis is often severe. Children with respiratory distress syndrome and/or neurologic disorders were particularly prone to developing a stenosis (37%). Following treatment, 43% were successfully decannulated and decannulation occurred in a biphasic pattern. Thirty-seven percent were still tracheostomy-dependent but had a voice and were developing normal speech patterns. The mean decannulation time was 92.5 weeks, confirming that acquired subglottic stenosis in the neonate is a serious problem with long-term disability.


Saturating growth rate against phosphorus concentration explained by macromolecular allocation.
The Monod equation has been used to represent the relationship between growth rate and the environmental nutrient concentration under the limitation of this respective nutrient. This model often serves as a means to connect microorganisms to their environment, specifically in ecosystem and global models. Here, we use a simple model of a marine microorganism cell to illustrate the model's ability to capture the same relationship as Monod, while highlighting the additional physiological details our model provides. In this study, we focus on the relationship between growth rate and phosphorus concentration and find that RNA allocation largely contributes to the commonly observed trend. This work emphasizes the potential role our model could play in connecting microorganisms to the surrounding environment while using realistic physiological representations.


When conservation management becomes contraindicated: impact of food supplementation on health of endangered wildlife.
Understanding the conditions that force the implementation of management actions and their efficiency is crucial for conservation of endangered species. Wildlife managers are widely and increasingly using food supplementation for such species because the potentially immediate benefits may translate into rapid conservation improvements. Supplementary feeding can also pose risks eventually promoting undesired, unexpected, subtle, or indirect, and often unnoticed, effects that are generally poorly understood. For two decades, intensive food supplementation has been used in attempting to improve the breeding productivity of the Spanish Imperial Eagle, Aquila adalberti, one of the most endangered birds of prey in the world. Here, we examined the impact of this intensive management action on nestling health, including contamination, immunodepression, and acquisition of disease agents derived from supplementation techniques and provisioned food. Contrary to management expectations, we found that fed individuals were often inadvertently "medicated" with pharmaceuticals (antibiotics and antiparasitics) contained in supplementary food (domestic rabbits). Individuals fed with medicated rabbits showed a depressed immune system and a high prevalence and richness of pathogens compared with those with no or safe supplementary feeding using non-medicated wild rabbits. A higher presence of antibiotics (fluoroquinolones) was found in sick as opposed to healthy individuals among eaglets with supplementary feeding, which points directly toward a causal effect of these drugs in disease and other health impairments. This study represents a telling example of well-meaning management strategies not based on sound scientific evidence becoming a "contraindicated" action with detrimental repercussions undermining possible beneficial effects by increasing the impact of stochastic factors on extinction risk of endangered wildlife.


Efficient Removal of Cs+ and Sr2+ Ions by Granulous (Me2NH2)4/3(Me3NH)2/3Sn3S7·1.25H2O/Polyacrylonitrile Composite.
The need to effectively and selectively remove radioactive 137Cs and 90Sr from nuclear waste solutions persists to mitigate their environmental mobility and high radiotoxicity. Because it is difficult to effectively remove them from acidic environments that degrade most sorbents, new sorbent materials are highly desirable. Here, efficient removal of Cs+ and Sr2+ is achieved by the composite of layered tin sulfide (Me2NH2)4/3(Me3NH)2/3Sn3S7·1.25H2O (FJSM-SnS) and polyacrylonitrile (PAN) (FJSM-SnS/PAN). The granulous composite possesses regular particle morphology and good mechanical strength as an engineered form. It shows excellent acid-base and γ-irradiation resistance, high maximum adsorption capacities (qm) of 296.12 and 62.88 mg/g for Cs+ and Sr2+ ions, respectively, and high selectivity even in the presence of excess Na+ ions or using lake water. Impressively, qmCs of FJSM-SnS/PAN reaches 89.29 mg/g under even acidic conditions (pH = 2.5). The column loaded with FJSM-SnS/PAN granules exhibits high removal rates (R) toward low-concentration Cs+ and Sr2+ ions under both neutral and acidic conditions. Moreover, the composite can be recycled and reused with high RCs and RSr. This work highlights the great potential of metal sulfide ion-exchangers in engineered form for the efficient removal of Cs+ or Sr2+ ions, especially under acidic conditions, for radionuclide remediation.


Treatment of spinal stenosis and fixed sagittal imbalance.
Most commonly, sagittal imbalance associated with stenosis is seen with a hypolordotic fusion mass, junctional kyphosis, and junctional stenosis. If the deformity is flexible, it can be treated with anterior and posterior fusion with anterior structural grafting. If it is fixed, which it usually is, then a pedicle subtraction procedure with decompression and extension of the fusion usually is the most suitable operative approach.


NMR investigation of hydroxyethyl starch-induced aggregation of human erythrocytes.
Aggregation of human erythrocytes at physiological hematocrit by hydroxyethyl starch (HES) was investigated with a 1H nuclear magnetic resonance method which measures the erythrocyte mean water exchange time, tau a. A relationship that takes into account the effect of the aggregate as the water-exchanging unit was used to transform tau a values into the number of cells per aggregate, n. The procedure permits the determination of the time course of aggregation as well as its initial and equilibrium status. The values of n at equilibrium range from about 2 to 4 cells over the concentration of 1 to 5% HES in isotonic saline. The aggregation of erythrocytes in the presence of HES was found to follow first-order kinetics. The feasibility of this technique for application in the study of diseased states is indicated.


Variance components and genetic parameters for milk production and lactation pattern in an ethiopian multibreed dairy cattle population.
The objective of this study was to estimate variance components and genetic parameters for lactation milk yield (LY), lactation length (LL), average milk yield per day (YD), initial milk yield (IY), peak milk yield (PY), days to peak (DP) and parameters (ln(a) and c) of the modified incomplete gamma function (MIG) in an Ethiopian multibreed dairy cattle population. The dataset was composed of 5,507 lactation records collected from 1,639 cows in three locations (Bako, Debre Zeit and Holetta) in Ethiopia from 1977 to 2010. Parameters for MIG were obtained from regression analysis of monthly test-day milk data on days in milk. The cows were purebred (Bos indicus) Boran (B) and Horro (H) and their crosses with different fractions of Friesian (F), Jersey (J) and Simmental (S). There were 23 breed groups (B, H, and their crossbreds with F, J, and S) in the population. Fixed and mixed models were used to analyse the data. The fixed model considered herd-year-season, parity and breed group as fixed effects, and residual as random. The single and two-traits mixed animal repeatability models, considered the fixed effects of herd-year-season and parity subclasses, breed as a function of cow H, F, J, and S breed fractions and general heterosis as a function of heterozygosity, and the random additive animal, permanent environment, and residual effects. For the analysis of LY, LL was added as a fixed covariate to all models. Variance components and genetic parameters were estimated using average information restricted maximum likelihood procedures. The results indicated that all traits were affected (p<0.001) by the considered fixed effects. High grade B×F cows (3/16B 13/16F) had the highest least squares means (LSM) for LY (2,490±178.9 kg), IY (10.5±0.8 kg), PY (12.7±0.9 kg), YD (7.6±0.55 kg) and LL (361.4±31.2 d), while B cows had the lowest LSM values for these traits. The LSM of LY, IY, YD, and PY tended to increase from the first to the fifth parity. Single-trait analyses yielded low heritability (0.03±0.03 and 0.08±0.02) and repeatability (0.14±0.01 to 0.24±0.02) estimates for LL, DP and parameter c. Medium heritability (0.21±0.03 to 0.33±0.04) and repeatability (0.27±0.02 to 0.53±0.01) estimates were obtained for LY, IY, PY, YD and ln(a). Genetic correlations between LY, IY, PY, YD, ln(a), and LL ranged from 0.59 to 0.99. Spearman's rank correlations between sire estimated breeding values for LY, LL, IY, PY, YD, ln(a) and c were positive (0.67 to 0.99, p<0.001). These results suggested that selection for IY, PY, YD, or LY would genetically improve lactation milk yield in this Ethiopian dairy cattle population.


Total Internal Reflection Accounts for the Bright Color of the Saharan Silver Ant.
The Saharan silver ant Cataglyphis bombycina is one of the terrestrial living organisms best adapted to tolerate high temperatures. It has recently been shown that the hairs covering the ant's dorsal body part are responsible for its silvery appearance. The hairs have a triangular cross-section with two corrugated surfaces allowing a high optical reflection in the visible and near-infrared (NIR) range of the spectrum while maximizing heat emissivity in the mid-infrared (MIR). Those two effects account for remarkable thermoregulatory properties, enabling the ant to maintain a lower thermal steady state and to cope with the high temperature of its natural habitat. In this paper, we further investigate how geometrical optical and high reflection properties account for the bright silver color of C. bombycina. Using optical ray-tracing models and attenuated total reflection (ATR) experiments, we show that, for a large range of incidence angles, total internal reflection (TIR) conditions are satisfied on the basal face of each hair for light entering and exiting through its upper faces. The reflection properties of the hairs are further enhanced by the presence of the corrugated surface, giving them an almost total specular reflectance for most incidence angles. We also show that hairs provide an almost 10-fold increase in light reflection, and we confirm experimentally that they are responsible for a lower internal body temperature under incident sunlight. Overall, this study improves our understanding of the optical mechanisms responsible for the silver color of C. bombycina and the remarkable thermoregulatory properties of the hair coat covering the ant's body.


Chlorinated Paraffin Levels in Relation to Other Persistent Organic Pollutants Found in Pooled Human Milk Samples from Primiparous Mothers in 53 Countries.
The current production and use of chlorinated paraffins (CPs) at >1 million tons/y likely exceeds the lifetime production of polychlorinated biphenyls (PCBs). These persistent organic pollutants (POPs) are a concern to human health. The United Nations Environment Programme conducts global surveys of human milk samples from individual countries as a noninvasive method of investigating levels and trends in human exposures to POPs such as CPs. We measured CP concentrations and assessed their relation to other POPs in pooled samples collected during 2012-2019. We analyzed 57 official nationwide pooled milk samples from 53 countries on five continents (Africa, Central/South America, Asia, Europe, and Australia/Oceania). CP concentrations were further characterized by subgroups and compared with concentrations of 19 other POPs, including PCBs and a variety of pesticides. CPs were detected in pooled samples from all 53 countries, with concentrations of 23-700 ng/g lipid. CPs accounted for 18-46% of the total summed POPs in human milk, second only to dichlorodiphenyltrichloroethane (DDT). CP concentrations exceeded PCB concentrations in pooled samples from most countries. The presence of CPs in all samples, including samples from isolated locations (e.g., Pacific Island countries), emphasizes the ubiquitous presence of these compounds, whereas differences in subgroup ratios indicate a delay in the shift toward nonregulated medium-chain CPs (MCCPs) for these regions. The predominance of MCCPs in samples from many countries suggests a need for regulation and research on health effects. https://doi.org/10.1289/EHP7696.


Alzheimer's disease Aβ assemblies mediating rapid disruption of synaptic plasticity and memory.
Alzheimer's disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, pre-dementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-ß protein (Aβ) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Aβ, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Aβ aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxic amyloidogenic proteins including tau, α-synuclein and prion protein.


A gold nanoparticle-based lateral flow immunosensor for ultrasensitive detection of tetrodotoxin.
Tetrodotoxin (TTX) is a potent marine neurotoxin. Its frequent detection and widespread distribution pose a substantial health risk to consumers. The work presented herein describes the development of a lateral flow immunosensor based on a gold nanoparticle-labeled monoclonal antibody probe, which allows the affinity reaction of antigen-antibody and amplifies the reaction signal. The immunosensor assay was found to provide a visible limit of detection (vLOD) of 10 μg kg-1 in crucian and clam matrices without time-consuming pretreatment. Spiked samples were analyzed using the immunosensor and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The immunosensor gave average intra-assay recoveries of 84.0-103.9%, inter-assay recoveries of 76.1-105% for the crucian matrix and intra-assay recoveries of 78.5-93.0%, inter-assay recoveries of 74.8-85.7% for the clam matrix. The results obtained using the immunosensor and LC-MS/MS were in good agreement. The immunosensor test could be completed within 10 min, offering a convenient option or complementarity to the traditional methods of TTX detection.


Implementing a Need-Adapted Stepped-Care Model for Mental Health of Refugees: Preliminary Data of the State-Funded Project "RefuKey".
Introduction: Refugees have been shown to be a rather vulnerable population with increased psychiatric morbidity and lack of access to adequate mental health care. By expanding regional psychosocial and psychiatric-psychotherapeutic care structures and adapting psychiatric routine care to refugees' needs, the state-funded project "refuKey" based in Lower Saxony, Germany, pursues to ease access to mental health care and increase service quality for refugees. A stepped-care treatment model along with intercultural opening of mental health care services is proposed. Methods: The project is subject to a four-part evaluation study. The first part investigates the state of psychiatric routine care for refugees in Lower Saxony by requesting data from all psychiatric clinics, participating and non-participating ones, regarding the numbers of refugee patients, their diagnoses, settings of treatment, etc. The second part explores experiences and work satisfaction of mental health care professionals treating refugees in refuKey cooperation clinics. The third part consists of interviews and focus group discussions with experts regarding challenges in mental health care of refugees and expectations for improvement through refuKey. The fourth part compares mental health parameters like depression, anxiety, traumatization, somatization, psychoticism, quality of life, as well as "pathways-to-care" of refuKey-treated refugees before and after treatment and, in a follow-up, to a non-refuKey-treated refugee control group. Results: RefuKey-treated refugees reported many mental health problems and estimated their mental health burden as high. The symptoms decreased significantly over the course of treatment. Mental health in the refuKey sample was strongly linked to post-migration stressors. Discussion: The state of mental health care for refugees is discussed. Implications for the improvement and the need for adaptation of routine mental health care services are drawn.


Helping tomorrow's doctors to gain a population health perspective - good news for community stakeholders.
The modernising agenda of the NHS and recommendations of professional bodies demand that all doctors achieve a basic understanding of a population health perspective. The principle of integrated learning and the logistics of provision make it inappropriate for such learning to be delivered solely by public health specialists, and community-based learning has been promoted as the best setting in which to assist this objective. However, there is little evidence from practice as to whether non-specialist staff are willing or able to play a role in orienting tomorrow's doctors to the needs of communities. Semi-structured interviews, questionnaires and focus groups iterated the opinion of key stakeholders on their preferred contributions to community-oriented undergraduate medical education. Framework analysis was used to elicit key outcomes and process factors. There was consensus that community-based learning should be a core element of the medical curriculum as it can demonstrate the socioenvironmental context of care and the doctor's role in interagency working and preventive care. Effective academic/NHS partnerships were called for, with higher education leading the agenda on aims and objectives, creating collaborative structures, and reallocating resources to support new learning. Community-based stakeholders would offer the translation of theory into practice by demonstrating clinical and social diversity, models of teamworking, and a context for the application of prior learning. They also promoted recurrent contact with communities, and suggested an enhanced role in mentoring students through longer term relationships. Community-based personnel and NHS users are an under-used resource for medical education. Their proposed contributions strongly accord with the agenda for a population health perspective in basic training. Curriculum planners need to make long-term partnerships with community-based agencies, rather than using them as an intermittent provider of limited learning sessions with narrowly defined objectives.


Reinforced polypropylene composites: effects of chemical compositions and particle size.
In this work, the effects of wood species, particle sizes and hot-water treatment on some physical and mechanical properties of wood-plastic composites were studied. Composites of thermoplastic reinforced with oak (Quercus castaneifolia) and pine (Pinus eldarica) wood were prepared. Polypropylene (PP) and maleic anhydride grafted polypropylene (MAPP) were used as the polymer matrix and coupling agent, respectively. The results showed that pine fiber had significant effect on the mechanical properties considered in this study. This effect is explained by the higher fiber length and aspect ratio of pine compared to the oak fiber. The hot-water treated (extractive-free) samples, in both wood species, improved the tensile, flexural and impact properties, but increased the water absorption for 24h. This work clearly showed that lignocellulosic materials in both forms of fiber and flour could be effectively used as reinforcing elements in PP matrix. Furthermore, extractives have marked effects on the mechanical and physical properties.


Folliculotropic Metastatic Melanoma: A Case Report and Review of the Literature.
Folliculotropic metastasis of cutaneous melanoma is rare, with only 5 published case reports in the English language literature since it was first described in 2009. We report a 41-year-old man with a primary cutaneous melanoma of the right upper preauricular region with metastatic spread to the parotid gland and pulmonary lymph nodes. Excision of the primary lesion was performed and immunotherapy was initiated. Sixteen months later, the patient presented with 2 new lesions of the left forehead and left neck. Histopathological examination was consistent with folliculotropic dermal deposits of metastatic melanoma. Deeper sectioning into the blocks revealed only sparse perifollicular pigment deposition and rare dermal melanocytes-a potential diagnostic pitfall had this been seen in the initial sections. This case represents the sixth and youngest patient to date with folliculotropic metastatic melanoma. This entity often presents in patients with advanced disease, including increased Breslow thickness and/or multiple metastases to lymph nodes, internal organs, or both. The folliculotropic metastases tend to be small and are often multiple. The precise relationship between folliculotropic primary melanoma and folliculotropic metastasis is unclear. In one reported case and in our patient, the primary tumor was noted to have a "folliculocentric" pattern. Because of the latter finding, the differential diagnosis includes multiple primary folliculotropic melanomas. Thus, clinical correlation and knowledge concerning the evolution of disease in the patient are critical. This case highlights a rare and unusual pattern of metastatic melanoma and potential problems in differential diagnosis.


All-optical tunable delay line based on soliton self-frequency shift and filtering broadened spectrum due to self-phase modulation.
We propose a novel all-optical tunable delay line based on soliton self-frequency shift and filtering broadened spectrum due to self-phase modulation to compensate for the frequency shift. We experimentally demonstrate the proposed all-optical tunable delay line and achieve a continuous temporal shift up to 19.2 ps for 0.5 ps pulse, corresponding to a delay-to-pulse-width ratio of 38.4.


The transplacental passage of commonly used intrapartum antibiotics and its impact on the newborn management: A narrative review.
Neonates exposed to intra-amniotic infection are at increased risk of early-onset sepsis. Administration of antibiotics to the mother may offer some protection, however a comprehensive description of the determinants influencing their transplacental passage and delivery to the fetus has not been performed. While penicillin G, ampicillin, cefazolin and gentamicin reach therapeutic levels in the fetal serum rapidly following maternal administration, the transfer of second-line intrapartum antimicrobials, such as vancomycin and clindamycin, is slower and less predictable. Erythromycin, used in the context of preterm premature rupture of the membranes, has suboptimal influx into the fetal compartment. This evidence is predominantly drawn from term pregnancies and situations of low infectious risk; however, prematurity may negatively influence fetal exposure to intrapartum antibiotics. Optimal fetal antimicrobial concentrations to target are poorly defined and the extent to which our review findings apply to preterm early-onset neonatal sepsis prevention is unclear. Interpretation of blood cultures drawn in neonates with expected circulating levels of maternal antimicrobials above the minimal inhibitory concentration for Group B Streptococcus is challenging despite the use of contemporary optimized blood culture media.


Formation of (Aza)fulvenallene, Cyanocyclopentadiene, and (Aza)fluorenes in the Thermal Rearrangements of Indazoles, Azaindazoles, and Homoquinolinic Anhydride.
Flash vacuum pyrolysis (FVP) of pyrazoles and indazoles constitutes a valuable route to carbenes and nitrenes. In this study, we employed M062X and CCSD(T) calculations to provide a mechanistic rationale for the formation of fulvenallene and fluorenes from indazoles and the corresponding formation of azafulvenallene 15, cyanocyclopentadiene 19, and azafluorenes, e.g. 45, from azaindazoles, e.g. 12, and from homoquinolinic anhydride. The results reveal the importance of initial tautomerization in the pyrazole moiety of 7-azaindazole 12, which drives the mechanism toward 2-diazo-3-methylene-2,3-dihydropyridine 29 and hence 3-methylene-2,3-dihydropyridin-2-ylidene 26, followed by Wolff-type ring contraction to 1-azafulvenallene 15. This path has a calculated activation energy ∼10 kcal/mol lower than that for an alternate route involving ring opening to 3-diazomethylpyridine, dediazotization, and rearrangement of 3-pyridylcarbene to azacycloheptatetraene and phenylnitrene 24. FVP of 2,5-diphenyltetrazoles and phenyl(pyridyl)tetrazoles leads to nitrile imines, which cyclize to 3-phenylindazoles and -azaindazoles. Nitrogen elimination from these (aza) indazoles results in the formation of (aza) fluorenes, for which two alternate mechanisms are described: route A by rearrangement of (aza) indazoles to diazo(aza)cyclohexadienes and (aza)cyclohexadienylidenes and route B by rearrangement to diaryldiazomethanes and diarylcarbenes. Both paths are energetically feasible, but path A is preferred and corresponds to the azafluorenes obtained experimentally.


Perspectives on the COVID-19 pandemic impact on cardio-oncology: results from the COVID-19 International Collaborative Network survey.
Re-allocation of resources during the COVID-19 pandemic has resulted in delays in care delivery to patients with cardiovascular disease and cancer. The ability of health care providers to provide optimal care in this setting has not been formally evaluated. To assess the impact of COVID-19 resource re-allocation on scheduling, testing, elective procedures, telemedicine access, use of new COVID-19 therapies, and providers' opinions on healthcare policies among oncology and cardiology practitioners. An electronic survey was conducted by a cardio-oncology collaborative network through regional and state chapters of the American College of Cardiology, American Society of Clinical Oncology, and the International Cardio-Oncology Society. Descriptive statistics were reported by frequency and proportion for analyses, and stratified categorically by geographic region and specialty. One thousand four hundred fifteen providers (43 countries) participated: 986 cardiologists, 306 oncologists, and 118 trainees/internal medicine. 63% (195/306) of oncologists vs 92% (896/976) of cardiologists reported cancellations of treatments/elective procedures (p = 0.01). 46% (442/970) of cardiologists and 25% (76/303) of oncologists modified the scope of their practice (p = < 0.001). Academic physicians (74.5%) felt better supplied with personal protective equipment (PPE) vs non-academic (74.5% vs 67.2%; p = 0.018). Telemedicine was less common in Europe 81% (74/91), and Latin America 64% (101/158), than the United States, 88% (950/1097) (p = < 0.001). 95% of all groups supported more active leadership from medical professional societies. These results support initiatives to promote expanded coverage for telemedicine, increased access to PPE, better testing availability and involvement of medical professional societies to help with preparedness for future health care crisis.


Renal replacement therapy for acute kidney injury in Australian and New Zealand intensive care units: a practice survey.
There are few published data on the practice of renal replacement therapy (RRT) in Australian and New Zealand intensive care units. These data are essential for designing trials to compare new treatment approaches with "standard care". A prospective survey of RRT practice in ICUs interested in participating in the Australian and New Zealand Randomised Evaluation of Normal vs. Augmented Level (RENAL) Replacement Therapy in ICU Trial. 34 ICUs in Australia and New Zealand. Information on choice of therapeutic modality, technique, dose prescription, dose adjustment, technology, and replacement fluid composition before the initiation of the trial. All ICUs used continuous veno-venous RRT (CRRT) as the therapy of first choice. The most common technique, continuous veno-venous (CVV) haemodiafiltration, was used in 62% (21/34) of ICUs, followed by CVV haemofiltration in 35%, (12/34) and CVV haemodialysis in 3% (1/34). Replacement fluid was given prefilter (pre-dilution) in most cases (94%). Lactate-based replacement fluid or dialysate accounted for 55% of all commercial fluid supplied by pharmacies to participating ICUs, bicarbonate-based fluid for 43% and citrate-based fluid for 2%. In all ICUs, CRRT was prescribed by critical care physicians alone, according to unit policy. The effluent dose varied from 1.5 L/h to 4 L/h, and was not adjusted to body weight in any of the ICUs surveyed. The median (and mode) effluent dose was a fixed regimen of 2 L/h. The most commonly used machine was the Gambro Prisma (38%), followed by the Gambro AK 10 blood module combined with volumetric fluid infusion pumps (29%), and the Kimal Hygieia (18%). The median (and mode) blood flow was 200mL/min. Given the information supplied on pre-dilution rates, the median blood flow, and estimates of haematocrit and body weight based on previous surveys, the "typical" prescribed CRRT urea clearance dose ("standard") before the RENAL trial was estimated to be approximately 25 mL/kg/h. These findings provide insight into RRT practice in ICUs in Australia and New Zealand, as well as useful data to assess whether the control group in the RENAL trial receives "standard" therapy as delivered in Australian and New Zealand trial centres at the time.


Dual microcoil NMR probe coupled to cyclic ce for continuous separation and analyte isolation.
Capillary electrophoresis (CE)-nuclear magnetic resonance (NMR) spectroscopy combines the separation efficiency of CE and the information-rich detection capabilities of NMR. However, the temporally narrow CE peaks reduce NMR sensitivity and prevent on-line multidimensional NMR acquisitions. In this work, cyclic CE with multicoil NMR instrumentation is developed to perform CE in multiple closed loops. As a proof of concept, a two-loop five-junction capillary configuration creates two connected yet independently operable fluidic loops. With appropriate voltage switching, analytes can be directed as desired around or between the loops, and a particular analyte band can be parked in one NMR detector coil while CE continues in the second loop and monitored with a second NMR detector coil. The separation of a mixture of amino acids (Ala, Val, Thr) is achieved in two cycles. After one CE cycle, Ala is separated and COSY data are recorded in one loop while Val and Thr are separated in the second loop. At the end of the second cycle, both Val and Thr are separated and multidimensional NMR spectra acquired. With this instrumentation and appropriate protocols, two-dimensional NMR data acquisition and CE separation are achieved simultaneously.


Expression of varicella-zoster virus immediate-early regulatory protein IE63 in neurons of latently infected human sensory ganglia.
Varicella-zoster virus (VZV) causes varicella and establishes latency in sensory nerve ganglia, but the characteristics of VZV latency are not well defined. Immunohistochemical detection of the VZV immediate-early 63 (IE63) protein in ganglion neurons has been described, but there are significant discrepancies in estimates of the frequency of IE63-positive neurons, varying from a rare event to abundant expression. We examined IE63 expression in cadaver ganglia using a high-potency rabbit anti-IE63 antibody and corresponding preimmune serum. Using standard immunohistochemical techniques, we evaluated 10 ganglia that contained VZV DNA from seven individuals. These experiments showed that neuronal pigments were a confounding variable; however, by examining sections coded to prevent investigator bias and applying statistical analysis, we determined that IE63 protein, if present, is in a very small proportion of neurons (<2.8%). To refine estimates of IE63 protein abundance, we modified our protocol by incorporating a biological stain to exclude the pigment signal and evaluated 27 ganglia from 18 individuals. We identified IE63 protein in neurons within only one ganglion, in which VZV glycoprotein E and an immune cell infiltrate were also demonstrated. Antigen preservation was shown by detection of neuronal synaptophysin. These data provide evidence that the expression of IE63 protein, which has been referred to as a latency-associated protein, is rare. Refining estimates of VZV protein expression in neurons is important for developing a hypothesis about the mechanisms by which VZV latency may be maintained.


Relation between dust exposure and lung function in miners and ex-miners.
A sample of men working in the British coal industry in the 1950s has been followed up and examined 22 years later. The relations between lung function and individual cumulative exposure to respirable dust have been studied in 1867 men who were still working in the industry at the time of follow up and 2192 men who had left. Levels of forced expired volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio at follow up were found to be inversely related to exposure to respirable dust after allowing for other factors, even in men without pneumoconiosis. The magnitude of this estimated effect was equivalent to a loss of 228 ml FEV1 in response to an exposure of 300 gh/m3, a moderately high exposure for this group. Ex-miners aged under 65 had worse lung function than miners on average, suggesting that ill health had encouraged some of these men to leave the industry. Whereas a more severe response to dust exposure among ex-miners under 65 was suggested, this difference could easily have arisen by chance. The presence of symptoms of chronic bronchitis was associated with reduced levels of lung function, however, and, additionally, ex-miners under 65 with chronic bronchitis showed a more severe response of the FVC to dust exposure than miners without these symptoms. Among these ex-miners with chronic bronchitis a small group of men who had taken other jobs showed a much more severe effect of dust exposure on their lung function than the average, likely in heavily exposed men to contribute importantly to disability. Men in this group who had given up smoking showed and even more severe effect of dust exposure, equivalent to a loss of 940 ml FEV1 in response to an exposure of 300 gh/m3. These results indicate that exposure to respirable dust can occasionally cause severe respiratory impairment in the absence of progressive massive fibrosis. Dust exposure was related to a parallel reduction of FEV1 and FVC, implying that the pathology of dust induced lung damage differs form that induced by smoking. This pattern of abnormality was shown by some non-smokers, whereas smokers and ex-smokers apparently severely affected by dust showed a classic obstructive pattern of abnormality with pronounced reduction of the FEV1/FVC ratio.


Implications of anti-Ro/Sjögren's syndrome A antigen autoantibody in normal sera for autoimmunity.
We have applied a sensitive assay to analyze lupus and Sjögren's syndrome autoantibodies in 40 normal sera. Seven of these bound Ro/Sjögren's syndrome A antigen (SSA). Although this binding was 1,000-fold lower than the highest anti-Ro/SSA level measured from patients, it was inhibited by human Ro/SSA. Positive normal serum-bound Ro/SSA in Western immunoblots and binding activity was demonstrated in the F(ab')2 fragment of IgG. Affinity purification of normal anti-Ro/SSA IgG increased the specific anti-Ro/SSA binding by greater than 17-fold. This purified antibody formed a Ro/SSA precipitin and had a relative affinity for Ro/SSA identical to that of Ro/SSA precipitin-positive patients. These data demonstrate that the anti-Ro/SSA present in healthy normal donors is true autoantibody. Anti-La/Sjögren's syndrome B antigen (SSB) autoantibodies were found in 3 of the 40 normal sera, while none bound nuclear ribonucleoprotein (Sm). Finding low levels of anti-Ro/SSA and anti-La/SSB among normals may indicate that anti-Ro/SSA and anti-La/SSB occur in disease by enhancement of a preexisting immune response.


Smartphone and Mobile Health Apps for Tinnitus: Systematic Identification, Analysis, and Assessment.
Modern smartphones contain sophisticated high-end hardware features, offering high computational capabilities at extremely manageable costs and have undoubtedly become an integral part in users' daily life. Additionally, smartphones offer a well-established ecosystem that is easily discoverable and accessible via the marketplaces of differing mobile platforms, thus encouraging the development of many smartphone apps. Such apps are not exclusively used for entertainment purposes but are also commonplace in health care and medical use. A variety of those health and medical apps exist within the context of tinnitus, a phantom sound perception in the absence of any physical external source. In this paper, we shed light on existing smartphone apps addressing tinnitus by providing an up-to-date overview. Based on PRISMA guidelines, we systematically searched and identified existing smartphone apps on the most prominent app markets, namely Google Play Store and Apple App Store. In addition, we applied the Mobile App Rating Scale (MARS) to evaluate and assess the apps in terms of their general quality and in-depth user experience. Our systematic search and screening of smartphone apps yielded a total of 34 apps (34 Android apps, 26 iOS apps). The mean MARS scores (out of 5) ranged between 2.65-4.60. The Tinnitus Peace smartphone app had the lowest score (mean 2.65, SD 0.20), and Sanvello-Stress and Anxiety Help had the highest MARS score (mean 4.60, SD 0.10). The interrater agreement was substantial (Fleiss κ=0.74), the internal consistency was excellent (Cronbach α=.95), and the interrater reliability was found to be both high and excellent-Guttman λ6=0.94 and intraclass correlation, ICC(2,k) 0.94 (95% CI 0.91-0.97), respectively. This work demonstrated that there exists a plethora of smartphone apps for tinnitus. All of the apps received MARS scores higher than 2, suggesting that they all have some technical functional value. However, nearly all identified apps were lacking in terms of scientific evidence, suggesting the need for stringent clinical validation of smartphone apps in future. To the best of our knowledge, this work is the first to systematically identify and evaluate smartphone apps within the context of tinnitus.


[Analysis of evolution of the size of decompression gas bubbles in diver tissues during schedules of medical recompression].
The mathematical model of gas bubble dynamics in body tissues was used for the analysis of evolution of their size during the treatment of decompression sickness in divers by means of recompression in accordance with RN table 72 and USN table 6A. It was shown that the duration of the process of bubble dissolution depends on the compression - decompression profile, as well on the initial size of a bubble, the oxygen content in the breathing mixture and the rate of nitrogen diffusion between a bubble and the surrounding tissue. The results of this study give the grounds to assume that the effect of recompression regimes used in the UK, USA and Russia promotes the treatment of DCS as a result of complete dissolution or significant reduction in the bubble sizes as well as due to therapeutic action of moderately hyperoxic breathing mixture on the tissues affected by bubbles.


Pharmacodynamic Models of Indirect Effects and Irreversible Inactivation with Turnover: Applicability to Mechanism-Based Modeling of Gene Silencing and Targeted Protein Degradation.
Indirect response (IDR) and turnover with inactivation (TI) comprise two arrays of mechanism-based pharmacodynamic (PD) models widely used to describe delayed drug effects. IDR Model-IV (stimulation of response loss) and TI (irreversible loss) have been described with discerning "signature" profiles; classical IDR-IV response-time profiles display slow declines where peak response shifts later with increasing dose, whereas TI profiles feature steep response declines with earlier-shifting nadirs. Herein, we demonstrate mathematical convergence of IDR-IV and TI models upon implementation with identical linear versus nonlinear pharmacologic effect terms. Time of peak response in IDR-IV can in fact shift earlier or later depending on PK or PD parameters (e.g., kel, Smax) and effect type. A generalized dynamic model linking mRNA and protein turnover is proposed. Applicability of IDR-IV and TI, with either linear or nonlinear terms acting on degradation/catabolism/loss of response, is demonstrated through model-fitting PK-PD effects of three proteolysis-targeting chimeras (PROTACs) and two ligand-conjugated small interfering RNAs (siRNA). This work clarifies mathematical properties, convergence, and expected responses of IDR-IV and TI, demonstrates their applicability for targeted gene-silencing and protein-degrading agents, and illustrates how well-designed in vivo studies covering broad dose ranges with richly sampled time-points can influence PK-PD model structure and parameter resolution.


[Recanalization of urethral strictures using a temporary curved biocompatible new generation metal endoprosthesis]].
The male urethral stricture treatment is actual clinical issue with its resolution being increasingly frequently based on application of minimum invasive therapeutic interventional uroradiology methods. Since the methodology is applied over the last two decades, the most reasonable therapeutic algorithm has not been defined yet with respect to the correlation with the contemporary surgical treatment. The results of application of the temporary covered self-expandable nitinol Allium stents, which have been applied for the first time ever at our Institution in October 2003. Over the last 3 years, the method was applied in 40 males, averagely aged 54 years with urethral strictures previously treated by urological methods. In four cases, stent placement was performed after endourethral incision. The most common etiology of the stricture was the posttraumatic (55%), post-inflammatory (32%) and iatrogenic (10%). In all the cases, stents were removed 12-14 months after their insertions. The results are evaluated using uroflowmetry and urethrocystography, revealing in 85% of the cases permanent recanalization free of dysuric complaints. Development of a stricture on the anterior stent end was evidenced in 15% of the cases.


Epilepsy, sex hormones and antiepileptic drugs in female patients.
Women with epilepsy have a higher incidence of reproductive endocrine disorders than the general female population. These alterations include polycystic ovary syndrome, hyperandrogenemia, infertility, hypothalamic amenorrhea and hyperprolactinemia. Reproductive dysfunction is attributed both to epilepsy itself and to antiepileptic drugs (AEDs). Focal epileptic discharges from the temporal lobe may have a direct influence on the function of the hypothalamic-pituitary axis, thus altering the release of sex steroid hormones, including the production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone and prolactin. AEDs may modulate hormone release from the hypothalamic-pituitary-gonadal axis and they may alter the metabolism of sex hormones and their binding proteins. Hepatic enzyme-inducing AEDs, such as carbamazepine and phenytoin, may be most clearly linked to altered metabolism of sex steroid hormones, but valproic acid, an enzyme inhibitor, has also been associated with a frequent occurrence of polycystic ovary syndrome and hyperandrogenism in women with epilepsy. Therefore, treatment of epilepsy and selection of AEDs are important for reproductive health in female patients. The aim of the present review is to critically evaluate the recently published data concerning the interactions between sex hormones, epilepsy and AEDs.


Molecular cloning and expression of a purine-specific N-ribohydrolase from Trypanosoma brucei brucei. Sequence, expression, and molecular analysis.
N-Ribohydrolases, including the inosine-adenosine-guanosine-preferring (IAG) nucleoside hydrolase, have been proposed to be involved in the nucleoside salvage pathway of protozoan parasites and may constitute rational therapeutic targets for the treatment of these diseases. Reported is the complete sequence of the Trypanosoma brucei brucei iagnh gene, which encodes IAG-nucleoside hydrolase. The 1.4-kilobase iagnh cDNA contains an open reading frame of 981 base pairs, corresponding to 327 amino acids. The iagnh gene is present as one copy/haploid genome and is located on the size-polymorphic pair of chromosome III or IV in the genome of T. b. brucei. In Southern blot analysis, the iagnh probe hybridized strongly with Trypanosoma brucei gambiense, Trypanosoma brucei rhodesiense, Trypanosoma evansi, Trypanosoma congolense, and Trypanosoma vivax and, to a lesser extent, with Trypanosoma cruzi genomic DNA. The iagnh gene is expressed in blood-stream forms and procyclic (insect) life-cycle stages of T. b. brucei. There are no close amino acid homologues of IAG-nucleoside hydrolase outside bacterial, yeast, or parasitic organisms. Low amino acid sequence similarity is seen with the inosine-uridine-preferring nucleoside hydrolase isozyme from Crithidia fasciculata. The T. b. brucei iagnh open reading frame was cloned into Escherichia coli BL21 (DE3), and a soluble recombinant IAG-nucleoside hydrolase was expressed and purified to > 97% homogeneity. The molecular weights of the recombinant IAG-nucleoside hydrolase, based on the amino acid sequence and observed mass, were 35,735 and 35,737, respectively. The kinetic parameters of the recombinant IAG-nucleoside hydrolase are experimentally identical to the native IAG-nucleoside hydrolase.


Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes.
When a patient taking an antipsychotic is not experiencing symptomatic remission, or is experiencing adverse effects (AEs) that are intolerable or damaging to his or her physical health, a change in medication may be the best path to a good outcome. However, many clinicians are reluctant to switch medications in all but the clearest cases of failure. This reluctance is intensified by the occurrence of AEs caused by transitioning patients too rapidly between agents with different receptor-binding profiles. Emergent antipsychotic-switching syndromes include the "withdrawal triad," comprised of cholinergic rebound, supersensitivity psychosis, and emergent withdrawal dyskinesias (and other motor syndromes). More recently, another element has been observed consistent with an activation syndrome. This activation syndrome may occur as a consequence of switching from highly sedative agents or as a consequence of initial prodopaminergic drive. All of these effects can be minimized by careful planning of gradual switch procedures and judicious use of adjunctive medications.


Abiogenic formation of alkanes in the Earth's crust as a minor source for global hydrocarbon reservoirs.
Natural hydrocarbons are largely formed by the thermal decomposition of organic matter (thermogenesis) or by microbial processes (bacteriogenesis). But the discovery of methane at an East Pacific Rise hydrothermal vent and in other crustal fluids supports the occurrence of an abiogenic source of hydrocarbons. These abiogenic hydrocarbons are generally formed by the reduction of carbon dioxide, a process which is thought to occur during magma cooling and-more commonly-in hydrothermal systems during water-rock interactions, for example involving Fischer-Tropsch reactions and the serpentinization of ultramafic rocks. Suggestions that abiogenic hydrocarbons make a significant contribution to economic hydrocarbon reservoirs have been difficult to resolve, in part owing to uncertainty in the carbon isotopic signatures for abiogenic versus thermogenic hydrocarbons. Here, using carbon and hydrogen isotope analyses of abiogenic methane and higher hydrocarbons in crystalline rocks of the Canadian shield, we show a clear distinction between abiogenic and thermogenic hydrocarbons. The progressive isotopic trends for the series of C1-C4 alkanes indicate that hydrocarbon formation occurs by way of polymerization of methane precursors. Given that these trends are not observed in the isotopic signatures of economic gas reservoirs, we can now rule out the presence of a globally significant abiogenic source of hydrocarbons.


Prebrushing rinse with water on plaque removal: a split-mouth design.
The aim was to evaluate whether there is an additional beneficial effect on dental plaque removal of rinsing the oral cavity with water before toothbrushing. In total, 48 non-dental, systemically healthy participants ≥18 years were included in this randomized controlled clinical trial using a split-mouth design. The participants were requested to refrain from any form of oral hygiene for 48 h. First dental plaque scores (PI) were assessed full mouth. Two randomly assigned contra-lateral quadrants were brushed. Next the participant rinsed for 1 min with 15 ml water. Subsequently, the opposite two contra-lateral quadrants were brushed. Brushing was performed without toothpaste. Subsequently the second full-mouth PI assessment was performed. The brushing and rinsing procedure was performed under supervision and brushing time was tracked by a timer, each quadrant was brushed for 30 s. For the buccal, lingual, and approximal surfaces and tooth type, a subanalysis was performed. At baseline there was no statistically significantly difference between the two sets of contra-lateral quadrants. When a water rinse was used before toothbrushing the PI-score was reduced by 58%. If water rinse was used post-brushing the PI-score reduced by 57%. The difference of 0.04 in mean plaque index score reduction between the two brushing regimens was not significant(P = 0.162). When a 2 min brushing exercise was performed, on average more than 55% dental plaque was removed. Prerinsing with water did not contribute significantly to toothbrush efficacy.


Role of coronary artery calcium score in the primary prevention of cardiovascular disease.
First developed in 1990, the Agatston coronary artery calcium (CAC) score is an international guideline-endorsed decision aid for further risk assessment and personalized management in the primary prevention of atherosclerotic cardiovascular disease. This review discusses key international studies that have informed this 30 year journey, from an initial coronary plaque screening paradigm to its current role informing personalized shared decision making. Special attention is paid to the prognostic value of a CAC score of zero (the so called "power of zero"), which, in a context of low estimated risk thresholds for the consideration of preventive therapy with statins in current guidelines, may be used to de-risk individuals and thereby inform the safe delay or avoidance of certain preventive therapies. We also evaluate current recommendations for CAC scoring in clinical practice guidelines around the world, and past and prevailing barriers for its use in routine patient care. Finally, we discuss emerging approaches in this field, with a focus on the potential role of CAC informing not only the personalized allocation of statins and aspirin in the general population, but also of other risk-reduction therapies in special populations, such as individuals with diabetes and people with severe hypercholesterolemia.


Strategies for prevention and operative treatment of aortic lesions related to spinal interventions.
A retrospective analysis of a case series was performed. To give recommendations for the prevention and operative treatment of thoracic and thoracoabdominal aortic lesions in association with spinal interventions. Aortic lesions after spinal interventions for traumatic vertebral fractures, segmental spondylodiscitis, or vertebral metastasis are fortunately rare, but associated with a high perioperative mortality rate and absolute numbers are unknown. Therefore, preventive strategies to avoid perioperative major vessel injuries and recommendations for the operative treatment of aortic lesions related to spinal surgery are required. The clinical course of 10 patients with an acute aortic hemorrhage or an increased intraoperative risk for aortic injuries in association with primary or secondary spinal interventions is reported. All patients were evaluated before surgery by orthopedic trauma surgeons, vascular surgeons, and diagnostic radiologists. Five patients had preventive vascular interventions to avoid major aortic injuries during spinal reinterventions, and 5 patients were treated as an emergency for acute intraoperative hemorrhage related to spinal interventions. The operative treatment was performed by direct aortic sutures (n = 3), segmental alloplastic reconstructions (n = 2), or endovascular stent graft implantations (n = 3). Prophylactic banding of the thoracic aorta during thoracotomy or a femoral access for possible aortic balloon blockade was performed in patients with an estimated lower risk for an aortic laceration caused by malpositioned pedicle screws. No perioperative mortality was observed in patients treated by this interdisciplinary concept, but 1 patient treated under emergency condition for spondylodiscitis with an initially unrecognized aortic lesion died. In patients with complex spinal trauma, spondylodiscitis or difficult vertebral reinterventions, and an increased risk of major vessel injury, a preoperative interdisciplinary evaluation is recommended, even under emergency conditions. Endovascular stent graft technique is an additional option for prevention and treatment of suspected or acute aortic injuries of thoracic and infrarenal aortic lesions, whereas injuries to the visceral aortic segment still require advanced vascular reconstructions.


Bond lengths in organic and metal-organic compounds revisited: X-H bond lengths from neutron diffraction data.
The number of structures in the Cambridge Structural Database (CSD) has increased by an order of magnitude since the preparation of two major compilations of standard bond lengths in mid-1985. It is now of interest to examine whether this huge increase in data availability has implications for the mean bond-length values published in the late 1980s. Those compilations reported mean X-H bond lengths derived from rather sparse information and for rather few chemical environments. During the intervening years, the number of neutron studies has also increased, although only by a factor of around 2.25, permitting a new analysis of X-H bond-length distributions for (a) organic X = C, N, O, B, and (b) a variety of terminal and homometallic bridging transition metal hydrides. New mean values are reported here and are compared with earlier results. These new overall means are also complemented by an analysis of X-H distances at lower temperatures (T < or = 140 K), which indicates the general level of librational effects in X-H systems. The study also extends the range of chemical environments for which statistically acceptable mean X-H bond lengths can be obtained, although values from individual structures are also collated to further extend the chemical range of this compilation. Updated default 'neutron-normalization' distances for use in hydrogen-bond and deformation-density studies are also proposed for C-H, N-H and O-H, and the low-temperature analysis provides specific values for certain chemical environments and hybridization states of X.


Development of inward currents in chick sensory and autonomic neuronal precursor cells in culture.
The development of ionic inward currents was studied in cultured neuronal precursors from chick sensory dorsal root ganglia (DRG) and compared with neuronal precursors from the cholinergic ciliary ganglia (CG) using whole cell patch-clamp recording. Neuronal precursors devoid of neuron-specific surface markers were isolated during the period of neuronal birth, i.e., at embryonic day (E) 6 from DRG and at E4.5 from CG. All neuronal precursor cells from DRG, as well as CG, showed outward K+ currents directly after they had attached to the substrate. During the first 5 hr in culture, half of the DRG cells had no inward currents at all, whereas the other half displayed a rapidly and fully inactivating Ca2+ current, which was activated with small depolarizing pulses from a holding potential of -80 mV to a -50 mV membrane potential (low-voltage-activated current, LVA). At these early stages, no other inward currents were resolved. TTX-blockable Na+ currents and slowly inactivating classical Ca2+ currents, which were activated with larger depolarizing pulses to a -20 mV membrane potential (high-voltage-activated currents, HVA) appeared concurrently after 15-20 hr in culture. In contrast, more than half of the CG cells showed LVA currents, as well as Na+ currents, as early as during the first 5 hr in culture. The HVA Ca2+ currents from the majority of the cells could be recorded only after 10-15 hr in culture. In both types of precursor-derived neurons, the LVA Ca2+ current preceded the classical HVA Ca2+ current. However, the temporal relation of the first Na+ currents to the first HVA Ca2+ currents seemed to be different in the 2 preparations. In DRG cells, Na+ and HVA Ca2+ currents appeared at the same time, whereas in CG cells, the HVA Ca2+ current showed a time lag with respect to the Na+ current. In addition, the relative amplitudes of the currents differed in the CG and DRG cells. This shows that as early as E4-6, shortly after their terminal mitosis, neurons from distinct peripheral ganglia in chick vary in the development of their basic ionic currents.


All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to ponatinib.
The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients.


The relationship perceived between the real body and the mirror image.
We analyse here people's perception of their reflections in mirrors placed in different positions. In two experiments, participants looked at their mirror image, in a third experiment they looked at another person's image. In both cases they were asked to answer a series of questions about how the virtual body appeared relative to the real body, focusing on different aspects. In experiment 1, they were asked to decide whether the reflections were identical, similar, different, or opposite in terms of the global relationship, orientation, and lateralisation (left right arm). In experiment 2 they were instructed to make simple gestures and to evaluate if the gestures in the reflection were identical, opposite, similar, or different from theirs. Results show that 'identity' was preferred when the mirror was in front, and 'opposition' was preferred when the mirror was below. When opposition was experienced, it was attributed mainly to the exocentric frame of reference. Egocentric left-right reversal was not a common experience, although it was reported more frequently when the mirror was in front. The different roles of the exocentric and egocentric frames of reference were further tested in experiment 3, in which the condition of an observer looking at another person's reflection was studied. Contrary to the emphasis on the egocentric frame of reference in the literature on the 'mirror question', results presented in this paper demonstrate the importance of the exocentric frame of reference in influencing how observers react to their reflections.


On the measured current in needle- and needleless electrospinning.
The electric current was measured during needle-, rod- and roller electrospinning. The influence of the needle diameter, flow rate, protrusion needle length, and relative humidity on the current was studied using various polymer solutions. The results of Bhattacharjee et al. were confirmed in the experiments with polyethylene oxide solutions. Electrospinning from a droplet of a polymer solution placed on a steel rod confirmed the expected direct proportionality between the number of jets and the current. By measuring the current and the polymer throughput during roller electrospinning while simultaneously recording the process on a camera, the following process characteristics were found: the number of jets per spinning surface area, throughput per jet, total current, current per jet, and distance between Taylor cones on the surface of the spinning roller.


The Association Between Neighborhood Socioeconomic Disadvantage and Readmissions for Patients Hospitalized With Sepsis.
To evaluate associations between a readily availvable composite measurement of neighborhood socioeconomic disadvantage (the area deprivation index) and 30-day readmissions for patients who were previously hospitalized with sepsis. A retrospective study. An urban, academic medical institution. The authors conducted a manual audit for adult patients (18 yr old or older) discharged with an International Classification of Diseases, 10th edition code of sepsis during the 2017 fiscal year to confirm that they met SEP-3 criteria. None. The area deprivation index is a publicly available composite score constructed from socioeconomic components (e.g., income, poverty, education, housing characteristics) based on census block level, where higher scores are associated with more disadvantaged areas (range, 1-100). Using discharge data from the hospital population health database, residential addresses were geocoded and linked to their respective area deprivation index. Patient characteristics, contextual-level variables, and readmissions were compared by t tests for continuous variables and Fisher exact test for categorical variables. The associations between readmissions and area deprivation index were explored using logistic regression models. A total of 647 patients had an International Classification of Diseases, 10th edition diagnosis code of sepsis. Of these 647, 116 (17.9%) either died in hospital or were discharged to hospice and were excluded from our analysis. Of the remaining 531 patients, the mean age was 61.0 years (± 17.6 yr), 281 were females (52.9%), and 164 (30.9%) were active smokers. The mean length of stay was 6.9 days (± 5.6 d) with the mean Sequential Organ Failure Assessment score 4.9 (± 2.5). The mean area deprivation index was 54.2 (± 23.8). The mean area deprivation index of patients who were readmitted was 62.5 (± 27.4), which was significantly larger than the area deprivation index of patients not readmitted (51.8 [± 22.2]) (p < 0.001). In adjusted logistic regression models, a greater area deprivation index was significantly associated with readmissions (β, 0.03; p < 0.001). Patients who reside in more disadvantaged neighborhoods have a significantly higher risk for 30-day readmission following a hospitalization for sepsis. The insight provided by neighborhood disadvantage scores, such as the area deprivation index, may help to better understand how contextual-level socioeconomic status affects the burden of sepsis-related morbidity.


Targeting vascular structure for the treatment of sexual dysfunction.
Erectile dysfunction (ED) and cardiovascular disease often coexist and have many common risk factors. In hypertension, the structure of blood vessels is modified such that there is an increase in medial wall thickness relative to lumen size. Certain antihypertensive agents have been found to induce a regression of vascular structure such that a "hypertensive" vessel appears phenotypically more like that from a normotensive. To provide an update on the findings to date on the impact of vascular remodeling on erectile function. Review of peer reviewed literature related to vascular remodeling induced by antihypertensive agents and the potential impact on sexual function. A literature review was performed on clinical and experimental evidence regarding the association between cardiovascular disease and ED, the impact of vascular remodeling on these conditions, the impact of antihypertensive therapy on ED, and the mechanisms of antihypertensive drug-induced remodeling. There is increasing evidence that ED may be an early marker for progressing cardiovascular disease. Certain antihypertensive agents have beneficial effects on both vascular structure and erectile function. The major site of resistance in the penile vasculature occurs at the level of the pudendal artery. Although structural remodeling has not yet been investigated in this vessel specifically, antihypertensive drugs have been shown to induce remodeling of the pudendal-penile vasculature and cavernosal arteries. Antihypertensive drug-induced vascular remodeling can be characterized by a decrease in the ratio of wall thickness to lumen diameter, and may result from vascular smooth muscle cell apoptosis, rearrangement of cells around a smaller lumen, and/or changes in the extracellular matrix composition depending on the vessel type. Determining the mechanisms involved in antihypertensive drug-induced vascular remodeling in the pudendal vasculature may provide novel targets for the treatment of ED.


Geoprocessing via google maps for assessing obesogenic built environments related to physical activity and chronic noncommunicable diseases: validity and reliability.
This study analyzes the reliability and validity of obesogenic built environments related to physical activity and chronic noncommunicable diseases through Google Maps in a heterogeneous urban area (i.e., residential and commercial, very poor and very rich) in São Paulo (SP), Brazil. There are no important differences when comparing virtual measures with street audit. Based on Kappa statistic, respectively for validity and reliability, 78% and 80% of outcomes were classified as nearly perfect agreement or substantial agreement. Virtual measures of geoprocessing via Google Maps provided high validity and reliability for assessing built environments.


Novel hybrid structure silica/CdTe/molecularly imprinted polymer: synthesis, specific recognition, and quantitative fluorescence detection of bovine hemoglobin.
This work presented a novel strategy for the synthesis of the hybrid structure silica/CdTe/molecularly imprinted polymer (Si-NP/CdTe/MIP) to recognize and detect the template bovine hemoglobin (BHb). First, amino-functionalized silica nanoparticles (Si-NP) and carboxyl-terminated CdTe quantum dots (QDs) were assembled into composite nanoparticles (Si-NP/CdTe) using the EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) chemistry. Next, Si-NP/CdTe/MIP was synthesized by anchoring molecularly imprinted polymer (MIP) layer on the surface of Si-NP/CdTe through the sol-gel technique and surface imprinting technique. The hybrid structure possessed the selectivity of molecular imprinting technique and the sensitivity of CdTe QDs as well as well-defined morphology. The binding experiment and fluorescence method demonstrated its special recognition performance toward the template BHb. Under the optimized conditions, the fluorescence intensity of the Si-NP/CdTe/MIP decreased linearly with the increase of BHb in the concentration range 0.02-2.1 μM, and the detection limit was 9.4 nM. Moreover, the reusability and reproducibility and the successful applications in practical samples indicated the synthesis of Si-NP/CdTe/MIP provided an alternative solution for special recognition and determination of protein from real samples.


Predictors of complementary therapy use among asthma patients: results of a primary care survey.
Patients with chronic conditions are increasingly using complementary therapies. Asthma is the most common chronic disease in the UK. Qualitative research has suggested reasons why asthma patients use complementary therapies. However, there is little reliable quantitative evidence regarding the prevalence of complementary therapy use among asthma patients and predictors of use. A postal survey of complementary therapy use among asthma patients was therefore conducted via 27 general practices across seven Primary Care Trusts within the South West Strategic Health Authority (England), during August 2005 to May 2006. A total of 14,833 asthma patients were identified. A 1-in-4 random sample generated 3693 potential respondents, of whom 1320 (36%) returned questionnaires. Taking full account of the survey design, 14.5% (190/1308; 95% confidence interval 12.5% to 16.6%) had used complementary therapies for asthma; 54% of these patients had not disclosed their complementary therapy use to a health professional. The three therapies most commonly used were homeopathy, herbal medicine and relaxation. Just over half of those using complementary therapies for asthma reported that they usually or always helped; the most common reported benefits were symptom reduction, calming breathing and reducing panic. Multivariable analyses indicated an inverted U-shaped relationship between complementary therapy use for asthma and age, and increased likelihood of use among women, those with educational qualifications, those not usually helped by asthma medication, and those who have difficulty sleeping because of asthma symptoms. Dissatisfaction with conventional care was not associated with complementary therapy use for asthma. Asthma patients may use complementary therapies with or without the knowledge of their healthcare providers. Open communication between professionals and patients about complementary therapies may be valuable to give patients enhanced opportunities to discuss the impact of asthma on their quality of life and the effectiveness of their conventional treatment.


Testosterone, identity and the body: Exploring cultural definitions of disorder.
Medically-sanctioned testosterone administration has seen increasingly widespread application in the treatment of gender dysphoria (GD). Yet, by comparison, this approach is not medically accepted for those who are experiencing muscle dysmorphia (MD), a specifier of body dysmorphic disorder (BDD), despite both conditions reflecting incongruences between self-perception, identity and phenotype, and both currently being classified as mental health disorders. Rather, by stark contrast, those with MD are largely treated with psychological intervention to accept themselves as they physically are and the illicit use of testosterone for muscle-related body perception purposes is generally subject to criminal justice enforcement actions. In this commentary, we examine attempts to distinguish between the use of testosterone for gender-affirming hormone therapy in the case of GD and for aesthetic (muscle enhancement) use in the case of MD, as well as explore the implications of this disparity. Moreover, we consider how such disparity in policy and practice may be understood, in part, as an example of a bias reflecting the selective pathologizing of anabolic-androgenic steroid (AAS) use, socio-cultural evolutions in gender identity and expression and, more broadly, the manner in which culture defines disorder and its appropriate response.


False memory and level of processing effect: an event-related potential study.
Event-related potentials (ERPs) were used to determine the effects of level of processing on true and false memory, using the Deese-Roediger-McDermott (DRM) paradigm. In the DRM paradigm, lists of words highly associated to a single nonpresented word (the 'critical lure') are studied and, in a subsequent memory test, critical lures are often falsely remembered. Lists with three critical lures per list were auditorily presented here to participants who studied them with either a shallow (saying whether the word contained the letter 'o') or a deep (creating a mental image of the word) processing task. Visual presentation modality was used on a final recognition test. True recognition of studied words was significantly higher after deep encoding, whereas false recognition of nonpresented critical lures was similar in both experimental groups. At the ERP level, true and false recognition showed similar patterns: no FN400 effect was found, whereas comparable left parietal and late right frontal old/new effects were found for true and false recognition in both experimental conditions. Items studied under shallow encoding conditions elicited more positive ERP than items studied under deep encoding conditions at a 1000-1500 ms interval. These ERP results suggest that true and false recognition share some common underlying processes. Differential effects of level of processing on true and false memory were found only at the behavioral level but not at the ERP level.


Role of Rho in chemoattractant-activated leukocyte adhesion through integrins.
Heterotrimeric guanine nucleotide binding protein (G protein)-linked receptors of the chemoattractant subfamily can trigger adhesion through leukocyte integrins, and in this role they are thought to regulate immune cell-cell interactions and trafficking. In lymphoid cells transfected with formyl peptide or interleukin-8 receptors, agonist stimulation activated nucleotide exchange on the small guanosine triphosphate-binding protein RhoA in seconds. Inactivation of Rho by C3 transferase exoenzyme blocked agonist-induced lymphocyte alpha4beta1 adhesion to vascular cell adhesion molecule-1 and neutrophil beta2 integrin adhesion to fibrinogen. These findings suggest that Rho participates in signaling from chemoattractant receptors to trigger rapid adhesion in leukocytes.


Pyruvate kinase activators for treatment of pyruvate kinase deficiency.
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia with wide-ranging clinical symptoms and complications associated with significant morbidity and reduced health-related quality of life in both children and adults. The management of patients with PK deficiency has been historically challenging due to difficulties in the diagnostic evaluation, heterogeneity of clinical manifestations, and treatment options limited to supportive care with transfusions and splenectomy. An oral allosteric PK activator, mitapivat, is now a clinically available disease-modifying treatment for adults with PK deficiency. Phase 2 and 3 clinical trials of mitapivat have demonstrated sustained improvements in hemolytic anemia, hematopoiesis, and quality of life in many adults with PK deficiency and a generally reassuring safety profile with continued dosing. Additional long-term benefits include rapid and ongoing reduction in iron overload and potential stabilization of bone health. Clinical trials of treatment with mitapivat in children with PK deficiency are ongoing. In addition to disease-modifying treatment with PK activators, gene therapy is a potentially curative treatment currently under evaluation in clinical trials. With the availability of disease-targeted therapies, accurately diagnosing PK deficiency in patients with chronic hemolytic anemia is critical. PK activation and gene therapy have the potential to change the natural history of PK deficiency by improving clinical manifestations and patient quality of life and decreasing the risk of long-term complications.


Auxin transport at cellular level: new insights supported by mathematical modelling.
The molecular basis of cellular auxin transport is still not fully understood. Although a number of carriers have been identified and proved to be involved in auxin transport, their regulation and possible activity of as yet unknown transporters remain unclear. Nevertheless, using single-cell-based systems it is possible to track the course of auxin accumulation inside cells and to specify and quantify some auxin transport parameters. The synthetic auxins 2,4-dichlorophenoxyacetic acid (2,4-D) and naphthalene-1-acetic acid (NAA) are generally considered to be suitable tools for auxin transport studies because they are transported specifically via either auxin influx or efflux carriers, respectively. Our results indicate that NAA can be metabolized rapidly in tobacco BY-2 cells. The predominant metabolite has been identified as NAA glucosyl ester and it is shown that all NAA metabolites were retained inside the cells. This implies that the transport efficiency of auxin efflux transporters is higher than previously assumed. By contrast, the metabolism of 2,4-D remained fairly weak. Moreover, using data on the accumulation of 2,4-D measured in the presence of auxin transport inhibitors, it is shown that 2,4-D is also transported by efflux carriers. These results suggest that 2,4-D is a promising tool for determining both auxin influx and efflux activities. Based on the accumulation data, a mathematical model of 2,4-D transport at a single-cell level is proposed. Optimization of the model provides estimates of crucial transport parameters and, together with its validation by successfully predicting the course of 2,4-D accumulation, it confirms the consistency of the present concept of cellular auxin transport.


Performance of activities of daily living in multiple sclerosis.
To assess the performance of activities of daily living (ADL) in individuals with moderate to severe multiple sclerosis (MS). A total of 12 men and 32 women with MS (Expanded Disability Status Scale, EDSS, 6.0-8.5) were studied. The performance of personal ADL (P-ADL) and instrumental ADL (I-ADL) was assessed with the Functional Independence Measure (FIM) and the Assessment of Motor and Process Skills (AMPS). Twenty-four of the 44 individuals were rated dependent in P-ADL by the FIM motor score, mainly due to limitations in some areas of self-care and in transfers and locomotion. Only three individuals were rated dependent by the FIM cognitive score, indicating no or little cognitive disability. Two thirds of the individuals who were rated independent/modified independent in P-ADL by the FIM were rated dependent in I-ADL by the AMPS. Only the FIM motor score was significantly related to the EDSS score, indicating that ADL performance and disease severity is weakly related. Moderate to severe MS reduces the ability to perform both P-ADL and I-ADL. An individual with MS can be independent in P-ADL but still unable to perform I-ADL satisfactorily. Assessments of both P-ADL and I-ADL are advocated to evaluate ADL performance in order to implement appropriate management strategies for individuals with MS.


Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes.
Myelin basic protein (MBP) may be an important autoantigen in multiple sclerosis (MS), with the MBP(82-100) region being immunodominant for T cells and autoantibodies. The structural requirements for autoantibody recognition were compared to those previously defined for MBP-specific T cell clones. MBP autoantibodies were affinity-purified from central nervous system lesions of 11/12 postmortem cases studied. The MBP(83-97) peptide was immunodominant in all 11 cases since it inhibited autoantibody binding to MBP > 95%. Residues contributing to autoantibody binding were located in a 10-amino acid segment (V86-T95) that also contained the MHC/T cell receptor contact residues of the T cell epitope. In the epitope center, the same residues were important for antibody binding and T cell recognition. Based on the antibody-binding motif, microbial peptides were identified that were bound by purified autoantibodies. Autoantibody binding of microbial peptides required sequence identity at four or five contiguous residues in the epitope center. Microbial peptides previously found to activate T cell clones did not have such obvious homology to MBP since sequence identity was not required at MHC contacts. The similar fine specificity of B cells and T cells may be useful for tolerance induction to MBP in MS.


Glycosaminoglycans bind factor Xa in a Ca2+-dependent fashion and modulate its catalytic activity.
Recent studies have demonstrated the existence of a Ca(2+)-dependent heparin-binding site on factor Xa. To characterize this heparin-binding site, the extrinsic fluorescence of fluorescein-labeled, active site-blocked factor Xa was monitored as it was titrated with glycosaminoglycans of various sulfate content and chain length. The binding of glycosaminoglycans to factor Xa appears to be charge-dependent because affinity is correlated with degree of glycosaminoglycan sulfation. All glycosaminoglycans bind factor Xa with higher affinity in the presence of Ca(2+) than in its absence. In contrast, when Gla-domainless factor Xa was substituted for factor Xa, glycosaminoglycans bound with similar affinities in the absence and presence of Ca(2+). These results support the hypothesis that the anionic Gla domain impairs glycosaminoglycan binding in the absence of Ca(2+). The changes in fluorescence intensity of factor Xa when titrated with glycosaminoglycans suggest that glycosaminoglycans induce conformational changes in the active site environment of factor Xa. To explore the consequences of these conformational changes, the effect of glycosaminoglycans on the catalytic activity of factor Xa was examined. Glycosaminoglycans influenced the ability of factor Xa to cleave chromogenic substrates and attenuated the capacity of factor Xa to activate factor VII. The potency of glycosaminoglycans in these assays reflected their affinity for factor Xa. These studies suggest that glycosaminoglycan binding perturbs exosites on the surface of factor Xa, potentially modifying interactions with cofactors or substrates.


Incremental planning in sequence production.
People produce long sequences such as speech and music with incremental planning: mental preparation of a subset of sequence events. The authors model in music performance the sequence events that can be retrieved and prepared during production. Events are encoded in terms of their serial order and timing relative to other events in a planning increment, a contextually determined distribution of event activations. Planning is facilitated by events' metrical similarity and serial/temporal proximity and by developmental changes in short-term memory. The model's predictions of larger planning increments as production rate decreases and as producers' age-experience increases are confirmed in serial-ordering errors produced by adults and children. Incremental planning is considered as a general retrieval constraint in serially ordered behaviors.


Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain.
Chronic renal fibrosis is the final common pathway of end stage renal disease caused by glomerular or tubular pathologies. Genetic background has a strong influence on the progression of chronic renal fibrosis. We recently found that Rowett black hooded rats were resistant to renal fibrosis. We aimed to investigate the role of sustained inflammation and oxidative/nitrative stress in renal fibrosis progression using this new model. Our previous data suggested the involvement of podocytes, thus we investigated renal fibrosis initiated by doxorubicin-induced (5 mg/kg) podocyte damage. Doxorubicin induced progressive glomerular sclerosis followed by increasing proteinuria and reduced bodyweight gain in fibrosis-sensitive, Charles Dawley rats during an 8-week long observation period. In comparison, the fibrosis-resistant, Rowett black hooded rats had longer survival, milder proteinuria and reduced tubular damage as assessed by neutrophil gelatinase-associated lipocalin (NGAL) excretion, reduced loss of the slit diaphragm protein, nephrin, less glomerulosclerosis, tubulointerstitial fibrosis and matrix deposition assessed by periodic acid-Schiff, Picro-Sirius-red staining and fibronectin immunostaining. Less fibrosis was associated with reduced profibrotic transforming growth factor-beta, (TGF-β1) connective tissue growth factor (CTGF), and collagen type I alpha 1 (COL-1a1) mRNA levels. Milder inflammation demonstrated by histology was confirmed by less monocyte chemotactic protein 1 (MCP-1) mRNA. As a consequence of less inflammation, less oxidative and nitrative stress was obvious by less neutrophil cytosolic factor 1 (p47phox) and NADPH oxidase-2 (p91phox) mRNA. Reduced oxidative enzyme expression was accompanied by less lipid peroxidation as demonstrated by 4-hydroxynonenal (HNE) and less protein nitrosylation demonstrated by nitrotyrosine (NT) immunohistochemistry and quantified by Western blot. Our results demonstrate that mediators of fibrosis, inflammation and oxidative/nitrative stress were suppressed in doxorubicin nephropathy in fibrosis-resistant Rowett black hooded rats underlying the importance of these pathomechanisms in the progression of renal fibrosis initiated by glomerular podocyte damage.