Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes.
Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication.Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes.Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively).Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Clin Cancer Res; 23(17); 5292-301. ©2017 AACR.


Pharmacoeconomics of long-acting atypical antipsychotics for acutely relapsed chronic schizophrenia in Finland.
Atypical long-acting injectable (LAI) antipsychotics are increasingly available for treating chronic schizophrenia in patients chronically non-adherent to prescribed regimens. Few economic studies have compared these products. To determine the cost-effectiveness of aripiprazole (ARI-LAI), paliperidone (PP-LAI), olanzapine (OLZ-LAI), and risperidone (RIS-LAI) in patients with chronic schizophrenia in Finland. A 1-year decision tree model was adapted with guidance from an expert panel. Patients started hospitalized in relapse; those who responded continued treatment, others were switched to secondary drugs, then clozapine in the event of 2nd line failure. Rates of adherence, stable disease, relapse, and hospitalization were taken from pivotal trials, and utilities from published research. Included were direct costs paid by the Finnish Ministry of Health, in 2015 euros. Outcomes included quality-adjusted life-years (QALYs), hospitalization rates, and rates of relapse not requiring hospitalization. Model robustness was assessed using a series of 1-way and multivariate sensitivity analyses. Expected costs were lowest for PP-LAI at 41,148€, followed by 41,543€ for ARI-LAI, 42,067€ for RIS-LAI and 45,406€ for OLZ-LAI. Respective QALYs were 0.683, 0.671, 0.666, and 0.672. Re-hospitalization rates and non-admitted relapses were 23.6% and 3.9% for PP-LAI, 28.5% and 4.1% for ARI-LAI, 28.8% and 5.0% for RIS-LAI, 28.3% and 5.2% for OLZ-LAI. PP-LAI treatment was associated with the most days with stable disease (132.0), followed by OLZ-LAI (125.5), ARI-LAI (122.6), and RIS-LAI (114.4). Sensitive inputs between PP-LAI and ARI-LAI included rates of adherence, dropouts, and relapses plus drug prices; dropout and relapse rates for RIS-LAI; OLZ-LAI results were insensitive. In probability sensitivity analyses, PP-LAI dominated ARI-LAI in 75.8% of the 10,000 iterations, RIS-LAI in 83.1% and OLZ-LAI in 95.7%. PP-LAI dominated the other atypicals. It appears to be the preferred option for treating chronic relapsing schizophrenia.


Review of the epidemiological evidence for physical activity and health from low- and middle-income countries.
Almost 80% of deaths from non-communicable diseases (NCDs) occur in low- and middle-income countries. Physical inactivity is a key risk factor for NCDs. Enhancing understanding of the scientific evidence linking physical activity and health in low- and middle-income countries is important for supporting national efforts to promote physical activity and reduce NCDs in these countries. A systematic review of three electronic databases was conducted in July 2013, including large population-based epidemiological studies with adult participants, conducted in low- and middle-income countries, and published in the past 30 years. Physical activity was consistently associated with a reduced risk of all-cause mortality, cardiovascular disease (CVD), diabetes and several types of cancer. Positive associations were also found between physical activity and body composition (including overweight and obesity), blood pressure, cholesterol, metabolic indices and bone mineral density. Overall, the results confirm that the epidemiological research into the health benefits of physical activity in low- and middle-income countries is consistent with previous research conducted in high-income countries. This summary of the available research can be used as an advocacy tool in low- and middle-income countries to support greater prominence of physical activity in NCD policies.


A randomized pilot study of the Engaging Moms Program for family drug court.
In response to the need for effective drug court interventions, the effectiveness of the Engaging Moms Program (EMP) versus Intensive Case Management Services (ICMS) on multiple outcomes for mothers enrolled in family drug court was investigated. In this intent-to-treat study, mothers (N = 62) were randomly assigned to either usual drug court care or the Engaging Moms drug court program. Mothers were assessed at intake and 3, 6, 12, and 18 months following intake. Results indicated that at 18 months post drug court enrollment, 77% of mothers assigned to EMP versus 55% of mothers assigned to ICMS had positive child welfare dispositions. There were statistically significant time effects for both intervention groups on multiple outcomes including substance use, mental health, parenting practices, and family functioning. EMP showed equal or better improvement than ICMS on all outcomes. The results suggest that EMP in family drug court is a viable and promising intervention approach to reduce maternal addiction and child maltreatment.


Prediction of postoperative pulmonary complications on the basis of preoperative risk factors in patients who had undergone coronary artery bypass graft surgery.
Pulmonary complications are among the most frequently reported complications after coronary artery bypass graft (CABG) surgery. However, the risks of postoperative pulmonary complications (PPCs) are not equal for all patients. The aim of this study was to develop a model, based on preoperative factors, for classifying patients with high and low risks for PPCs in order to implement tailored interventions. Postoperative pulmonary complications were examined in 117 adult patients who had undergone elective CABG surgery at the University Medical Centre Utrecht, Utrecht, the Netherlands. The presence of preoperative risk factors (N=12) that have been described in the literature was noted for each patient. A risk model was developed by use of logistic regression analysis. Preoperative risk factors for developing PPCs were an age of (>/=70 years, productive cough, diabetes mellitus, and a history of cigarette smoking. Protective factors against the development of PPCs were a predicted inspiratory vital capacity of (>/=75% and a predicted maximal expiratory pressure of (>/=75%. These risk and protective factors were included in the model (sensitivity=87% and specificity=56%), and a sum score for its clinical use was generated. Six factors that can be determined easily before surgery, with need for only simple pulmonary testing, can provide a model for identifying patients at risk of developing PPCs after CABG surgery.


Aphid Sex Pheromone Compounds Interfere with Attraction of Common Green Lacewings to Floral Bait.
Common green lacewings (Chrysoperla carnea complex) form a group of generalist predators important for biological control. Several reports show attraction of these insects to plant volatiles, and a highly attractive ternary compound floral bait has been developed. With aphids being a preferred prey of larvae, one might expect these lacewings to be attracted to aphid semiochemicals, for instance, to aphid sex pheromones, as found for several other green lacewing species. However, in a previous study, we found that traps containing aphid sex pheromone compounds (1R,4aS,7S,7aR)-nepetalactol (NEPOH), (4aS,7S,7aR)-nepetalactone (NEPONE), and a ternary floral bait attracted fewer individuals than those containing the ternary floral bait alone. In the present study, possible causes for this effect of NEPOH and NEPONE on trap capture were studied. We established that C. carnea complex catches in traps with a ternary floral lure were not influenced by the presence of Chrysopa formosa individuals in traps (attracted by NEPOH and NEPONE) or by synthetic skatole (a characteristic component of Chrysopa defense secretion). A direct negative effect of NEPOH and NEPONE on attraction of C. carnea complex was found, suggesting active avoidance of these aphid sex pheromone components. This finding is surprising as the larvae of these lacewings prey preferentially on aphids. Possible mechanisms underlying this phenomenon are discussed.


Potential antimutagenic activity of berberine, a constituent of Mahonia aquifolium.
As part of a study aimed at developing new pharmaceutical products from natural resources, the purpose of this research was twofold: (1) to fractionate crude extracts from the bark of Mahonia aquifolium and (2) to evaluate the strength of the antimutagenic activity of the separate components against one of the common direct-acting chemical mutagens. The antimutagenic potency was evaluated against acridine orange (AO) by using Euglena gracilis as an eukaryotic test model, based on the ability of the test compound/fraction to prevent the mutagen-induced damage of chloroplast DNA. It was found that the antimutagenicity of the crude Mahonia extract resides in both bis-benzylisoquinoline (BBI) and protoberberine alkaloid fractions but only the protoberberine derivatives, jatrorrhizine and berberine, showed significant concentration-dependent inhibitory effect against the AO-induced chloroplast mutagenesis of E. gracilis. Especially berberine elicited, at a very low dose, remarkable suppression of the AO-induced mutagenicity, its antimutagenic potency being almost three orders of magnitude higher when compared to its close analogue, jatrorrhizine. Possible mechanisms of the antimutagenic action are discussed in terms of recent literature data. While the potent antimutagenic activity of the protoberberines most likely results from the inhibition of DNA topoisomerase I, the actual mechanism(s) for the BBI alkaloids is hard to be identified. Taken together, the results indicate that berberine possesses promising antimutagenic/anticarcinogenic potential that is worth to be investigated further.


Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys.
Horseshoe kidneys are a complex anatomic variant of fused kidneys, with a 20% reported incidence of associated calculi. Anatomic causes such as high insertion of the ureter on the renal pelvis and obstruction of the ureteropelvic junction are thought to contribute to stone formation via impaired drainage, with urinary stasis, and an increased incidence of infection. In this multi-institutional study, we evaluated whether metabolic factors contributed to stone development in patients with horseshoe kidneys. A retrospective review of 37 patients with horseshoe kidneys was performed to determine if these patients had metabolic derangements that might have contributed to calculus formation. Stone compositions as well as 24-hour urine collections were examined. Specific data points of interest were total urine volume; urine pH; urine concentrations of calcium, sodium, uric acid, oxalate, and citrate; and number of abnormalities per patient per 24-hour urine collection. These data were compared with those of a group of 13 patients with stones in caliceal diverticula as well as 24 age-, race-, and sex-matched controls with stones in anatomically normal kidneys. Eleven (9 men and 2 women) of the 37 patients (30%) with renal calculi in horseshoe kidneys had complete metabolic evaluations available for review. All patients were noted to have at least one abnormality, with an average of 2.68 abnormalities per 24-hour urine collection (range 1-4). One patient had primary hyperparathyroidism and underwent a parathyroidectomy. Low urine volumes were noted in eight patients on at least one of the two specimens (range 350-1640 mL/day). Hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia were noted in seven, three, six, and six patients, respectively. No patients were found to have gouty diathesis or developed cystine stones. Comparative metabolic analyses of patients with renal calculi in caliceal diverticula or normal kidneys revealed a distinct profile in patients with horseshoe kidneys, with a higher incidence of hypocitraturia. All patients with renal calculi in horseshoe kidneys were noted to have metabolic abnormalities predisposing to stone formation. In this initial series of 11 patients, hypovolemia, hypercalcuria and hypocitraturia were most common metabolic defects. These findings suggest that metabolic derangements play a role in stone formation in patients with a horseshoe kidney. Patients with calculi in anatomically abnormal kidneys should be considered for a metabolic evaluation to identify their stone-forming risk factors in order to initiate preventative selective medical therapy and reduce the risk of recurrent calculus formation.


Direct reaction of iodine-activated lanthanoid metals with 2,6-diisopropylphenol.
Rare earth metals activated with ca. 2% iodine react directly with 2,6-diisopropylphenol (HOdip) in tetrahydrofuran (thf), 1,2-dimethoxyethane (dme), and dig-dme (dig = di(2-methoxyethyl) ether) to give solvated phenolate complexes [Ln(Odip)(3)(thf)(n)] (Ln = La, Nd, n = 3; Ln = Sm, Dy, Y, Yb, n = 2), [Eu(Odip)(μ-Odip)(thf)(2)](2), [Ln(Odip)(3)(dme)(2)] (Ln = La, Yb) and [La(Odip)(3)(dig)] in good yield for Ln = La, Nd, Eu but modest yield for smaller Ln metals under comparable conditions. However, increasing the excess of metal greatly increased the yield for Ln = Y. The synthetic method has general potential, at least for lanthanoid phenolates. Comparison redox transmetallation/protolysis (RTP) reactions between Ln metals, Hg(C(6)F(5))(2) and the phenol gave higher yields in shorter time and, for Eu, gave [Eu(Odip)(3)(thf)(3)] in contrast to an Eu(II) complex from Eu(I(2)). New [Ln(Odip)(3)(thf)(3)] complexes have fac-octahedral structures and [Ln(Odip)(3)(thf)(2)] monomeric five coordinate distorted trigonal bipyramidal structures with apical thf ligands. [Eu(Odip)(μ-Odip)(thf)(2)](2) is an unsymmetrical dimer with two bridging Odip ligands. One five coordinate Eu atom has distorted trigonal bipyramidal stereochemistry and the other is distorted square pyramidal. Whilst [La(Odip)(3)(dme)(2)] has irregular seven coordination with mer-Odip and chelating dme ligands, [Ln(Odip)(3)(dme)(2)] (Ln = Dy, Y (prepared by ligand exchange), Yb) are monomeric six coordinate with one chelating and one unidentate dme. A six coordinate fac-octahedral arrangement is observed in [La(Odip)(3)(dig)].


Pilot study of mobile phone technology in allergic rhinitis in European countries: the MASK-rhinitis study.
The use of Apps running on smartphones and tablets profoundly affects medicine. The MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) App (Allergy Diary) assesses allergic rhinitis symptoms, disease control and impact on patients' lives. It is freely available in 20 countries (iOS and Android platforms). To assess in a pilot study whether (i) Allergy Diary users were able to properly provide baseline characteristics (ii) simple phenotypic characteristics based upon data captured by the Allergy Diary could be identified and (iii) information gathered by this study could suggest novel research questions. The Allergy Diary users were classified into six groups according to the baseline data that they entered into the App: (i) asymptomatic; (ii) nasal symptoms excluding rhinorrhea; (iii) rhinorrhea; (iv) rhinorrhea plus 1-2 nasal/ocular symptoms; (v) rhinorrhea plus ≥3 nasal/ocular symptoms; and (vi) rhinorrhea plus all nasal/ocular symptoms. By 1 June 2016, 3260 users had registered with the Allergy Diary and 2710 had completed the baseline questionnaire. Troublesome symptoms were found mainly in the users with the most symptoms. Around 50% of users with troublesome rhinitis and/or ocular symptoms suffered work impairment. Sleep was impaired by troublesome symptoms and nasal obstruction. This is the first App (iOS and Android) to have tested for allergic rhinitis and conjunctivitis. A simple questionnaire administered by cell phones enables the identification of phenotypic differences between a priori defined rhinitis groups. The results suggest novel concepts and research questions in allergic rhinitis that may not be identified using classical methods.


Reconceptualising risk-benefit analyses: the case of HIV cure research.
Modern antiretroviral therapies (ART) are capable of suppressing HIV in the bloodstream to undetectable levels. Nonetheless, people living with HIV must maintain lifelong adherence to ART to avoid the re-emergence of the infection. So despite the existence and efficacy of ART, there is still substantial interest in development of a cure. But HIV cure trials can be risky, their success is as of yet unlikely, and the medical gain of being cured is limited against a baseline of ART access. The medical prospect associated with participation in cure research thus look poor. Are the risks and burdens that HIV cure research places on participants so high that it is unethical, at present, to conduct it? In this paper, I answer 'no'. I start my argument by describing a foundational way of thinking about the ethical justification for regulatory limits on research risk; I then apply this way of thinking to HIV cure trials. In offering this analysis, I confine my attention to studies enrolling competent adults and I also do not consider risks research may pose to third parties or society. Rather, my concern is to engage with the thought that some trials are so risky that performing them is an ethically unacceptable way to treat the participants themselves. I reject this thought and instead argue that there is no level of risk, no matter how high, that inherently mistreats a participant.


Walking and chewing reduce postprandial acid reflux.
Gastro-oesophageal reflux is worse after meals, and antacids are usually consumed after dietary indiscretion. To investigate whether walking or gum chewing affect meal-induced gastro-oesophageal reflux. The study population comprised 12 case subjects with gastro-oesophageal reflux disease and 24 healthy controls. Each subject was studied using pH-metry for 5 h on 3 separate days. After baseline recording of pH for 1 h, all subjects were fed a standard breakfast over a 20-min period. On one of the days, oesophageal pH was recorded after the 20-min eating period for an additional 4 h in the sitting position. On another day, postprandial oesophageal pH was recorded for the first hour whilst walking, and for 3 subsequent hours whilst sitting. During a third day, oesophageal pH was recorded for the first postprandial hour whilst gum-chewing, followed by 3 h of sitting. Food intake promoted gastro-oesophageal reflux in case subjects with GERD as well as in healthy controls, although postprandial reflux was more pronounced amongst the refluxers than amongst the controls. Chewing gum for 1 h after the meal reduced the acid contact time in both groups, with a more profound effect in refluxers than in controls. Whilst the beneficial effect of 1-h of gum-chewing lasted for up to 3 h in both groups, the beneficial effect of 1-h of walking was apparent only in refluxers, only to a mild degree, and only for a short duration. Chewing gum after a meal helps to reduce postprandial oesophageal acid exposure.


Therapeutic conflicts in emergency department patients with multimorbidity: a cross-sectional study.
Patients with multimorbidity are an increasing concern in healthcare. Clinical practice guidelines, however, do not take into account potential therapeutic conflicts caused by co-occurring medical conditions. This makes therapeutic decisions complex, especially in emergency situations. The aim of this study was to identify and quantify therapeutic conflicts in emergency department patients with multimorbidity. We reviewed electronic records of all patients ≥18 years with two or more concurrent active medical conditions, admitted from the emergency department to the hospital ward of the University Hospital Zurich in January 2009. We cross-tabulated all active diagnoses with treatments recommended by guidelines for each diagnosis. Then, we identified potential therapeutic conflicts and classified them as either major or minor conflicts according to their clinical significance. 166 emergency inpatients with multimorbidity were included. The mean number of active diagnoses per patient was 6.6 (SD±3.4). We identified a total of 239 therapeutic conflicts in 49% of the of the study population. In 29% of the study population major therapeutic conflicts, in 41% of the patients minor therapeutic conflicts occurred. Therapeutic conflicts are common among multimorbid patients, with one out of two experiencing minor, and one out of three experiencing major therapeutic conflicts. Clinical practice guidelines need to address frequent therapeutic conflicts in patients with co-morbid medical conditions.


Is there a divide between local medicinal knowledge and Western medicine? a case study among native Amazonians in Bolivia.
Interest in ethnomedicine has grown in the last decades, with much research focusing on how local medicinal knowledge can contribute to Western medicine. Researchers have emphasized the divide between practices used by local medical practitioners and Western doctors. However, researchers have also suggested that merging concepts and practices from local medicinal knowledge and Western science have the potential to improve public health and support medical independence of local people. In this article we study the relations between local and Western medicinal knowledge within a native Amazonian population, the Tsimane'. We used the following methods: 1) participant observation and semi-structured interviews to gather background information, 2) free-listing and pile-sorting to assess whether Tsimane' integrate local medicinal knowledge and Western medicine at the conceptual level, 3) surveys to assess to what extent Tsimane' combine local medicinal knowledge with Western medicine in actual treatments, and 4) a participatory workshop to assess the willingness of Tsimane' and Western medical specialists to cooperate with each other. We found that when asked about medical treatments, Tsimane' do not include Western treatments in their lists, however on their daily practices, Tsimane' do use Western treatments in combination with ethnomedical treatments. We also found that Tsimane' healers and Western doctors express willingness to cooperate with each other and to promote synergy between local and Western medical systems. Our findings contrast with previous research emphasizing the divide between local medical practitioners and Western doctors and suggests that cooperation between both health systems might be possible.


Voxel-based multimodel fitting method for modeling time activity curves in SPECT images.
Estimating the biodistribution and the pharmacokinetics from time-sequence SPECT images on a per-voxel basis is useful for studying activity nonuniformity or computing absorbed dose distributions by convolution of voxel kernels or Monte-Carlo radiation transport. Current approaches are either region-based, thus assuming uniform activity within the region, or voxel-based but using the same fitting model for all voxels. We propose a voxel-based multimodel fitting method (VoMM) that estimates a fitting function for each voxel by automatically selecting the most appropriate model among a predetermined set with Akaike criteria. This approach can be used to compute the time integrated activity (TIA) for all voxels in the image. To control fitting optimization that may fail due to excessive image noise, an approximated version based on trapezoid integration, named restricted method, is also studied. From this comparison, the number of failed fittings within images was estimated and analyzed. Numerical experiments were used to quantify uncertainties and feasibility was demonstrated with real patient data. Regarding numerical experiments, root mean square errors of TIA obtained with VoMM were similar to those obtained with bi-exponential fitting functions, and were lower (< 5% vs. > 10%) than with single model approaches that consider the same fitting function for all voxels. Failure rates were lower with VoMM and restricted approaches than with single-model methods. On real clinical data, VoMM was able to fit 90% of the voxels and led to less failed fits than single-model approaches. On regions of interest (ROI) analysis, the difference between ROI-based and voxel-based TIA estimations was low, less than 4%. However, the computation of the mean residence time exhibited larger differences, up to 25%. The proposed voxel-based multimodel fitting method, VoMM, is feasible on patient data. VoMM leads organ-based TIA estimations similar to conventional ROI-based method. However, for pharmacokinetics analysis, studies of spatial heterogeneity or voxel-based absorbed dose assessment, VoMM could be used preferentially as it prevents model overfitting.


A randomized double-blind noninferiority trial, evaluating migration of a cemented vitamin E-stabilized highly crosslinked component compared with a standard polyethylene component in reverse hybrid total hip arthroplasty.
Radiostereometric analysis (RSA) studies of vitamin E-doped, highly crosslinked polyethylene (VEPE) liners show low head penetration rates in cementless acetabular components. There is, however, currently no data on cemented VEPE acetabular components in total hip arthroplasty (THA). The aim of this study was to evaluate the safety of a new cemented VEPE component, compared with a conventional polyethylene (PE) component regarding migration, head penetration, and clinical results. We enrolled 42 patients (21 male, 21 female) with osteoarthritis and a mean age of 67 years (sd 5), in a double-blinded, noninferiority, randomized controlled trial. The subjects were randomized in a 1:1 ratio to receive a reverse hybrid THA with a cemented component of either argon-gas gamma-sterilized PE component (controls) or VEPE, with identical geometry. The primary endpoint was proximal implant migration of the component at two years postoperatively measured with RSA. Secondary endpoints included total migration of the component, penetration of the femoral head into the component, and patient-reported outcome measurements. In total, 19 control implants and 18 implants in the VEPE group were analyzed for the primary endpoint. We found a continuous proximal migration of the component in the VEPE group that was significantly higher with a difference at two years of a mean 0.21 mm (95% confidence interval (CI) 0.05 to 0.37; p = 0.013). The total migration was also significantly higher in the VEPE group, but femoral head penetration was lower. We found no difference in clinical outcomes between the groups. At two years, this cemented VEPE component, although having a low head penetration and excellent clinical results, failed to meet noninferiority compared with the conventional implant by a proximal migration above the proposed safety threshold of RSA. The early proximal migration pattern of the VEPE component is a reason for continued monitoring, although a specific threshold for proximal migration and risk for later failure cannot be defined and needs further study. Cite this article: Bone Joint J 2019;101-B:1192-1198.


Differential force scaling of fine-graded power grip force in the sensorimotor network.
Force scaling in the sensorimotor network during generation and control of static or dynamic grip force has been the subject of many investigations in monkeys and human subjects. In human, the relationship between BOLD signal in cortical and subcortical regions and force still remains controversial. With respect to grip force, the modulation of the BOLD signal has been mostly studied for forces often reaching high levels while little attention has been given to the low range for which electrophysiological neuronal correlates have been demonstrated. We thus conducted a whole-brain fMRI study on the control of fine-graded force in the low range, using a power grip and three force conditions in a block design. Participants generated on a dynamometer visually guided repetitive force pulses (ca. 0.5 Hz), reaching target forces of 10%, 20%, and 30% of maximum voluntary contraction. Regions of interest analysis disclosed activation in the entire cortical and subcortical sensorimotor network and significant force-related modulation in several regions, including primary motor (M1) and somatosensory cortex, ventral premotor and inferior parietal areas, and cerebellum. The BOLD signal, however, increased monotonically with force only in contralateral M1 and ipsilateral anterior cerebellum. The remaining regions were activated with force in various nonlinear manners, suggesting that other factors such as visual input, attention, and muscle recruitment also modulate the BOLD signal in this visuomotor task. These findings demonstrate that various regions of the sensorimotor network participate differentially in the production and control of fine-graded grip forces.


The State of Cancer Care in the United Arab Emirates in 2020: Challenges and Recommendations, A report by the United Arab Emirates Oncology Task Force.
With cancer being the third leading cause of mortality in the United Arab Emirates (UAE), there has been significant investment from the government and private health care providers to enhance the quality of cancer care in the UAE. The UAE is a developing country with solid economic resources that can be utilized to improve cancer care across the country. There is limited data regarding the incidence, survival, and potential risk factors for cancer in the UAE. The UAE Oncology Task Force was established in 2019 by cancer care providers from across the UAE under the auspices of Emirates Oncology Society. In this paper we summarize the history of cancer care in the UAE, report the national cancer incidence, and outline current challenges and opportunities to enhance and standardize cancer care. We provide recommendations for policymakers and the UAE Oncology community for the delivery of high-quality cancer care. These recommendations are aligned with the UAE government's vision to reduce cancer mortality and provide high quality healthcare for its citizens.


Healthy Campus 2010: physical activity trends and the role information provision.
The primary purpose of this investigation was to examine the frequency and type of self-reported physical activity behavior in postsecondary students with reference to Healthy Campus 2010 objectives. The secondary purpose was to explore the role of information provision in terms of promoting physical activity behavior in postsecondary students. Postsecondary students were assessed (N = 127360). Employing a trend survey design, the frequency and type of physical activity behavior was assessed along with physical activity/fitness information provision across a five year period between 2000 to 2004. In 2004, respondents meeting Healthy Campus 2010 objectives for self-reported moderate and vigorous physical activity (MVPA) was 42.20% (95% CI = 41.75 to 42.65) and 48.60% (95% CI = 48.14 to 49.06) for strength (STRENGTH) training behavior. Progress quotients demonstrated that 12.93% and 7.87% of target objective for MVPA and STRENGTH respectively had been achieved from baseline. Those who received information reported engaging in more frequent physical activity behavior compared with those who did not (P < .001). Results suggest the need for continued commitment to increasing physical activity behavior. The provision of physical activity/fitness information may be one mechanism through which this can be achieved.


The role of the trigeminal sensory nuclear complex in the pathophysiology of craniocervical dystonia.
Isolated focal dystonia is a neurological disorder that manifests as repetitive involuntary spasms and/or aberrant postures of the affected body part. Craniocervical dystonia involves muscles of the eye, jaw, larynx, or neck. The pathophysiology is unclear, and effective therapies are limited. One mechanism for increased muscle activity in craniocervical dystonia is loss of inhibition involving the trigeminal sensory nuclear complex (TSNC). The TSNC is tightly integrated into functionally connected regions subserving sensorimotor control of the neck and face. It mediates both excitatory and inhibitory reflexes of the jaw, face, and neck. These reflexes are often aberrant in craniocervical dystonia, leading to our hypothesis that the TSNC may play a central role in these particular focal dystonias. In this review, we present a hypothetical extended brain network model that includes the TSNC in describing the pathophysiology of craniocervical dystonia. Our model suggests the TSNC may become hyperexcitable due to loss of tonic inhibition by functionally connected motor nuclei such as the motor cortex, basal ganglia, and cerebellum. Disordered sensory input from trigeminal nerve afferents, such as aberrant feedback from dystonic muscles, may continue to potentiate brainstem circuits subserving craniocervical muscle control. We suggest that potentiation of the TSNC may also contribute to disordered sensorimotor control of face and neck muscles via ascending and cortical descending projections. Better understanding of the role of the TSNC within the extended neural network contributing to the pathophysiology of craniocervical dystonia may facilitate the development of new therapies such as noninvasive brain stimulation.


Girls' and boys' perceptions of physical education teachers' feedback: effects on performance and psychological responses.
In this study, we examined the perceptions of physical education (PE) teachers' feedback patterns with female and male high school students (n = 325). Eight physical education teachers (4 females and 4 males) were involved. We examined (a) whether teachers' feedback was perceived differently by boys and girls, and how the sex of the teacher influenced these perceptions, and (b) the effects of types of feedback (praise, no response-successful, encouragement, technical information, criticism, no response-unsuccessful, and teacher's invested time) on students' perceived competence, effort, enjoyment, and their PE performance. A multivariate analysis revealed an interaction between teacher and student gender on perceptions of teacher feedback. Hierarchical regression analyses highlighted that the perceived feedback significantly predicted students' perceptions of competence (DeltaR(2) = 0.088), effort (DeltaR(2) = 0.119), enjoyment (DeltaR(2) = 0.085), and their PE performance (DeltaR(2) = 0.039) after accounting for the gender of the students and teachers and the students' initial PE performance. The perceptions of praise and teachers' invested time were positively linked with the dependent variables, whereas encouragement and technical information and criticism were negatively linked. The findings are discussed in terms of teaching effectiveness and gender equity.


Swiss paediatrician survey on complementary medicine.
In Switzerland, complementary medicine (CM) is officially recognised within the healthcare system and mainly practised in an integrative manner, in conjunction with conventional medicine. As in other countries, there is high demand for and use of CM with children. However, there has so far been no research into the attitude towards, training in and offer of CM among paediatricians in Switzerland. Our study addresses this gap by investigating these topics with an online survey of paediatricians in Switzerland. We conducted a national online survey using a 19-item, self-reporting questionnaire among all ordinary and junior members of the Swiss Society of Paediatrics (SSP). A comparison of the study sample with the population of all paediatricians registered with the Swiss Medical Association (FMH) allowed an assessment of the survey's representativeness. The data analysis was performed on the overall group level as well as for predefined subgroups (e.g. sex, age, language, workplace and professional experience). 1890 paediatricians were approached and 640, from all parts of Switzerland, responded to the survey (response rate 34%). Two thirds of respondents were female, were aged between 35 and 55 years, trained as paediatric generalist and worked in a practice. Apart from young paediatricians in training, the study sample was representative of all Swiss paediatricians. 23% had attended training in CM, most frequently in phytotherapy, homeopathy, acupuncture/traditional Chinese medicine (TCM) and anthroposophic medicine. 65% were interested in CM courses and training. 16% provide CM services to their patients and almost all paediatricians (97%) are asked by patients/parents about CM therapies. More than half of the responding paediatricians use CM for themselves or their families. 42% were willing to contribute to paediatric CM research. In a representative sample of paediatricians in Switzerland, their personal attitude towards CM is positive, emphasised by great interest in CM training, a willingness to contribute to CM research and a high rate of paediatricians who use CM for themselves and their families. In contrast, the percentage of paediatricians offering CM is currently rather low despite strong demand for CM for children. This study provides key pointers for the future development of complementary and integrative medicine for children in Switzerland.


Flp1, a fission yeast orthologue of the s. cerevisiae CDC14 gene, is not required for cyclin degradation or rum1p stabilisation at the end of mitosis.
In Saccharomyces cerevisiae, the phosphoprotein phosphatase Cdc14p plays a central role in exit from mitosis, by promoting B-type cyclin degradation and allowing accumulation of the cyclin-dependent kinase inhibitor Sic1p. Cdc14p is sequestered in the nucleolus during interphase, from where it is released at the end of mitosis, dependent upon mitotic exit network function. The CDC14 gene is essential and loss-of-function mutants arrest at the end of mitosis. We have identified a fission yeast orthologue of CDC14 through database searches. A Schizosaccharomyces pombe flp1 (cdc fourteen-like-phosphatase) null mutant is viable, divides at a reduced size and shows defects in septation. flp1p is not the essential effector of the S. pombe septation initiation network, but may potentiate signalling of the onset of septation. In contrast to S. cerevisiae Cdc14p, flp1p is not required for the accumulation or destruction of the B-type cyclin cdc13p, the cyclin-dependent kinase inhibitor rum1p, or for dephosphorylation of the APC/C specificity factor ste9p in G1. Like its budding yeast counterpart, flp1p is restricted to the nucleolus until mitosis, when it is dispersed through the nucleus. In contrast to S. cerevisiae Cdc14p, flp1p is also present on the mitotic spindle and contractile ring. The potential roles of flp1p in cell cycle control are discussed.


Towards Making Unlabeled Data Never Hurt.
It is usually expected that learning performance can be improved by exploiting unlabeled data, particularly when the number of labeled data is limited. However, it has been reported that, in some cases existing semi-supervised learning approaches perform even worse than supervised ones which only use labeled data. For this reason, it is desirable to develop safe semi-supervised learning approaches that will not significantly reduce learning performance when unlabeled data are used. This paper focuses on improving the safeness of semi-supervised support vector machines (S3VMs). First, the S3VM-us approach is proposed. It employs a conservative strategy and uses only the unlabeled instances that are very likely to be helpful, while avoiding the use of highly risky ones. This approach improves safeness but its performance improvement using unlabeled data is often much smaller than S3VMs. In order to develop a safe and well-performing approach, we examine the fundamental assumption of S3VMs, i.e., low-density separation. Based on the observation that multiple good candidate low-density separators may be identified from training data, safe semi-supervised support vector machines (S4VMs) are here proposed. This approach uses multiple low-density separators to approximate the ground-truth decision boundary and maximizes the improvement in performance of inductive SVMs for any candidate separator. Under the assumption employed by S3VMs, it is here shown that S4VMs are provably safe and that the performance improvement using unlabeled data can be maximized. An out-of-sample extension of S4VMs is also presented. This extension allows S4VMs to make predictions on unseen instances. Our empirical study on a broad range of data shows that the overall performance of S4VMs is highly competitive with S3VMs, whereas in contrast to S3VMs which hurt performance significantly in many cases, S4VMs rarely perform worse than inductive SVMs.


Stereodynamics of Ne(3P2) reacting with Ar, Kr, Xe, and N2.
Stereodynamics experiments of Ne(3P2) reacting with Ar, Kr, Xe, and N2 leading to Penning and associative ionization have been performed in a crossed molecular beam apparatus. A curved magnetic hexapole was used to state-select and polarize Ne(3P2) atoms which were then oriented in a rotatable magnetic field and crossed with a beam of Ar, Kr, Xe, or N2. The ratio of associative to Penning ionization was recorded as a function of the magnetic field direction for collision energies between 320 cm-1 and 500 cm-1. Reactivities are obtained for individual states that differ only in Ω, the projection of the neon total angular momentum vector on the inter-particle axis. The results are rationalized on the basis of a model involving a long-range and a short-range reaction mechanism. Substantially lower probability for associative ionization was observed for N2, suggesting that predissociation plays a critical role in the overall reaction pathway.


The CLAMP protein links the MSL complex to the X chromosome during Drosophila dosage compensation.
The Drosophila male-specific lethal (MSL) dosage compensation complex increases transcript levels on the single male X chromosome to equal the transcript levels in XX females. However, it is not known how the MSL complex is linked to its DNA recognition elements, the critical first step in dosage compensation. Here, we demonstrate that a previously uncharacterized zinc finger protein, CLAMP (chromatin-linked adaptor for MSL proteins), functions as the first link between the MSL complex and the X chromosome. CLAMP directly binds to the MSL complex DNA recognition elements and is required for the recruitment of the MSL complex. The discovery of CLAMP identifies a key factor required for the chromosome-specific targeting of dosage compensation, providing new insights into how subnuclear domains of coordinate gene regulation are formed within metazoan genomes.


Evaluating the motivation of Red Cross Health volunteers in the COVID-19 pandemic: a mixed-methods study protocol.
Voluntary organisations provide essential support to vulnerable populations and front-line health responders to the COVID-19 pandemic. The French Red Cross (FRC) is prominent among organisations offering health and support services in the current crisis. Comprised primarily of lay volunteers and some trained health workers, FRC volunteers in the Paris (France) region have faced challenges in adapting to pandemic conditions, working with sick and vulnerable populations, managing limited resources and coping with high demand for their services. Existing studies of volunteers focus on individual, social and organisational determinants of motivation, but attend less to contextual ones. Public health incertitude about the COVID-19 pandemic is an important feature of this pandemic. Whether and how uncertainty interacts with volunteer understandings and experiences of their work and organisational relations to contribute to Red Cross worker motivation is the focus of this investigation. This mixed-methods study will investigate volunteer motivation using ethnographic methods and social network listening. Semi-structured interviews and observations will illuminate FRC volunteer work relations, experiences and concerns during the pandemic. A questionnaire targeting a sample of Paris region volunteers will allow quantification of motivation. These findings will iteratively shape and be influenced by a social media (Twitter) analysis of biomedical and public health uncertainties and debates around COVID-19. These tweets provide insight into a French lay public's interpretations of these debates. We evaluate whether and how socio-political conditions and discourses concerning COVID-19 interact with volunteer experiences, working conditions and organisational relations to influence volunteer motivation. Data collection began on 15 June 2020 and will continue until 15 April 2021. The protocol has received ethical approval from the Institut Pasteur Institutional Review Board (no 2020-03). We will disseminate findings through peer-reviewed articles, conference presentations and recommendations to the FRC.


Sex differences in blood flow restricted isotonic knee extensions to fatigue.
It has been shown that females have greater muscular endurance than males and that this advantage is eliminated when blood flow is restricted. It is unknown if sex differences in dynamic endurance exist during low-load blood flow restricted (BFR) resistance exercise. The purpose of this study was to investigate sex differences in quadriceps femoris fatigability during isotonic knee extension exercise coupled with a blood flow restriction. Ten males and ten females completed three sets of low-load isotonic knee extension exercises (20% of peak torque) to volitional failure under two conditions: blood flow restricted (BFR) and non-restricted free flow (FF). The number of repetitions, exercise volume, post-exercise strength loss and surface electromyography (EMG) were measured. Females performed more repetitions than males in the FF (252±37 vs. 112±17 repetitions; P<0.01) and BFR conditions (165±29 vs. 79±8 repetitions; P<0.01). Both sexes performed ~30% fewer repetitions during the BFR condition. MVC torque decreased approximately 37% following both conditions (P<0.01) and EMG activity increased (P<0.05) during the exercise bouts. Similar fatigue characteristics were evident in FF and BFR conditions for both sexes, and females demonstrated greater endurance, as determined by the number of repetitions completed, in both conditions. It may be beneficial to increase the relative exercise load for females in order to decrease the time under BFR.


Approximate Bayesian Computation Reveals the Crucial Role of Oceanic Islands for the Assembly of Continental Biodiversity.
The perceived low levels of genetic diversity, poor interspecific competitive and defensive ability, and loss of dispersal capacities of insular lineages have driven the view that oceanic islands are evolutionary dead ends. Focusing on the Atlantic bryophyte flora distributed across the archipelagos of the Azores, Madeira, the Canary Islands, Western Europe, and northwestern Africa, we used an integrative approach with species distribution modeling and population genetic analyses based on approximate Bayesian computation to determine whether this view applies to organisms with inherent high dispersal capacities. Genetic diversity was found to be higher in island than in continental populations, contributing to mounting evidence that, contrary to theoretical expectations, island populations are not necessarily genetically depauperate. Patterns of genetic variation among island and continental populations consistently fitted those simulated under a scenario of de novo foundation of continental populations from insular ancestors better than those expected if islands would represent a sink or a refugium of continental biodiversity. We, suggest that the northeastern Atlantic archipelagos have played a key role as a stepping stone for transoceanic migrants. Our results challenge the traditional notion that oceanic islands are the end of the colonization road and illustrate the significant role of oceanic islands as reservoirs of novel biodiversity for the assembly of continental floras.


Pathophysiologic response to severe burn injury.
To improve clinical outcome and to determine new treatment options, we studied the pathophysiologic response postburn in a large prospective, single center, clinical trial. A severe burn injury leads to marked hypermetabolism and catabolism, which are associated with morbidity and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated. Two hundred forty-two severely burned pediatric patients [>30% total body surface area (TBSA)], who received no anabolic drugs, were enrolled in this study. Demographics, clinical data, serum hormones, serum cytokine expression profile, organ function, hypermetabolism, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout acute hospital course. Average age was 8 +/- 0.2 years, and average burn size was 56 +/- 1% TBSA with 43 +/- 1% third-degree TBSA. All patients were markedly hypermetabolic throughout acute hospital stay and had significant muscle protein loss as demonstrated by a negative muscle protein net balance (-0.05% +/- 0.007 nmol/100 mL leg/min) and loss of lean body mass (LBM) (-4.1% +/- 1.9%); P < 0.05. Patients lost 3% +/- 1% of their bone mineral content (BMC) and 2 +/- 1% of their bone mineral density (BMD). Serum proteome analysis demonstrated profound alterations immediately postburn, which remained abnormal throughout acute hospital stay; P < 0.05. Cardiac function was compromised immediately after burn and remained abnormal up to discharge; P < 0.05. Insulin resistance appeared during the first week postburn and persisted until discharge. Patients were hyperinflammatory with marked changes in IL-8, MCP-1, and IL-6, which were associated with 2.5 +/- 0.2 infections and 17% sepsis. In this large prospective clinical trial, we delineated the complexity of the postburn pathophysiologic response and conclude that the postburn response is profound, occurring in a timely manner, with derangements that are greater and more protracted than previously thought.


Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae.
Secondary bacterial infections are a leading cause of illness and death during epidemic and pandemic influenza. Experimental studies suggest a lethal synergism between influenza and certain bacteria, particularly Streptococcus pneumoniae, but the precise processes involved are unclear. To address the mechanisms and determine the influences of pathogen dose and strain on disease, we infected groups of mice with either the H1N1 subtype influenza A virus A/Puerto Rico/8/34 (PR8) or a version expressing the 1918 PB1-F2 protein (PR8-PB1-F2(1918)), followed seven days later with one of two S. pneumoniae strains, type 2 D39 or type 3 A66.1. We determined that, following bacterial infection, viral titers initially rebound and then decline slowly. Bacterial titers rapidly rise to high levels and remain elevated. We used a kinetic model to explore the coupled interactions and study the dominant controlling mechanisms. We hypothesize that viral titers rebound in the presence of bacteria due to enhanced viral release from infected cells, and that bacterial titers increase due to alveolar macrophage impairment. Dynamics are affected by initial bacterial dose but not by the expression of the influenza 1918 PB1-F2 protein. Our model provides a framework to investigate pathogen interaction during coinfections and to uncover dynamical differences based on inoculum size and strain.


ss-TEA: Entropy based identification of receptor specific ligand binding residues from a multiple sequence alignment of class A GPCRs.
G-protein coupled receptors (GPCRs) are involved in many different physiological processes and their function can be modulated by small molecules which bind in the transmembrane (TM) domain. Because of their structural and sequence conservation, the TM domains are often used in bioinformatics approaches to first create a multiple sequence alignment (MSA) and subsequently identify ligand binding positions. So far methods have been developed to predict the common ligand binding residue positions for class A GPCRs. Here we present 1) ss-TEA, a method to identify specific ligand binding residue positions for any receptor, predicated on high quality sequence information. 2) The largest MSA of class A non olfactory GPCRs in the public domain consisting of 13324 sequences covering most of the species homologues of the human set of GPCRs. A set of ligand binding residue positions extracted from literature of 10 different receptors shows that our method has the best ligand binding residue prediction for 9 of these 10 receptors compared to another state-of-the-art method. The combination of the large multi species alignment and the newly introduced residue selection method ss-TEA can be used to rapidly identify subfamily specific ligand binding residues. This approach can aid the design of site directed mutagenesis experiments, explain receptor function and improve modelling. The method is also available online via GPCRDB at http://www.gpcr.org/7tm/.


Acute pathological effects of inorganic mercury and copper in gills of rainbow trout.
Lesions induced in the gills of rainbow trout (Salmo gairdneri) by exposure to acutely lethal aqueous concentrations of inorganic mercury and copper were examined by light and electron microscopy. Lesions were most severe during the first 48 hours of exposure to the metals and were characterized primarily by apoptosis of lamellar epithelial cells and lamellar fusion. The latter process occurred either by simple apposition of adjacent lamellae to each other or through epithelial hypertrophy and hyperplasia. Except for hypertrophy of and increased number of primary lysosomes in lamellar epithelial cells of animals exposed to mercury, branchial lesions were not prominent in fish collected between 48 and 96 hours. The branchial lesions observed in this study are compared with pathological processes occurring in mammals.


A link between aurora kinase and Clp1/Cdc14 regulation uncovered by the identification of a fission yeast borealin-like protein.
The chromosomal passenger complex (CPC) regulates various events in cell division. This complex is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin. Together, these four subunits interdependently regulate CPC function, and they are highly conserved among eukaryotes. However, a Borealin homologue has never been characterized in the fission yeast, Schizosaccharomyces pombe. Here, we isolate a previously uncharacterized S. pombe protein through association with the Cdc14 phosphatase homologue, Clp1/Flp1, and identify it as a Borealin-like member of the CPC. Nbl1 (novel Borealin-like 1) physically associates with known CPC components, affects the kinase activity and stability of the S. pombe Aurora B homologue, Ark1, colocalizes with known CPC subunits during mitosis, and shows sequence similarity to human Borealin. Further analysis of the Clp1-Nbl1 interaction indicates that Clp1 requires CPC activity for proper accumulation at the contractile ring (CR). Consistent with this, we describe negative genetic interactions between mutant alleles of CPC and CR components. Thus, this study characterizes a fission yeast Borealin homologue and reveals a previously unrecognized connection between the CPC and the process of cytokinesis in S. pombe.


Human-started wildfires expand the fire niche across the United States.
The economic and ecological costs of wildfire in the United States have risen substantially in recent decades. Although climate change has likely enabled a portion of the increase in wildfire activity, the direct role of people in increasing wildfire activity has been largely overlooked. We evaluate over 1.5 million government records of wildfires that had to be extinguished or managed by state or federal agencies from 1992 to 2012, and examined geographic and seasonal extents of human-ignited wildfires relative to lightning-ignited wildfires. Humans have vastly expanded the spatial and seasonal "fire niche" in the coterminous United States, accounting for 84% of all wildfires and 44% of total area burned. During the 21-y time period, the human-caused fire season was three times longer than the lightning-caused fire season and added an average of 40,000 wildfires per year across the United States. Human-started wildfires disproportionally occurred where fuel moisture was higher than lightning-started fires, thereby helping expand the geographic and seasonal niche of wildfire. Human-started wildfires were dominant (>80% of ignitions) in over 5.1 million km2, the vast majority of the United States, whereas lightning-started fires were dominant in only 0.7 million km2, primarily in sparsely populated areas of the mountainous western United States. Ignitions caused by human activities are a substantial driver of overall fire risk to ecosystems and economies. Actions to raise awareness and increase management in regions prone to human-started wildfires should be a focus of United States policy to reduce fire risk and associated hazards.


Surface vulnerability of cerebral cortex to major depressive disorder.
Major depressive disorder (MDD) is accompanied by atypical brain structure. This study first presents the alterations in the cortical surface of patients with MDD using multidimensional structural patterns that reflect different neurodevelopment. Sixteen first-episode, untreated patients with MDD and 16 matched healthy controls underwent a magnetic resonance imaging (MRI) scan. The cortical maps of thickness, surface area, and gyrification were examined using the surface-based morphometry (SBM) approach. Increase of cortical thickness was observed in the right posterior cingulate region and the parietal cortex involving the bilateral inferior, left superior parietal and right paracentral regions, while decreased thickness was noted in the parietal cortex including bilateral pars opercularis and left precentral region, as well as the left rostral-middle frontal regions in patients with MDD. Likewise, increased or decreased surface area was found in five sub-regions of the cingulate gyrus, parietal and frontal cortices (e.g., bilateral inferior parietal and superior frontal regions). In addition, MDD patients exhibited a significant hypergyrification in the right precentral and supramarginal region. This integrated structural assessment of cortical surface suggests that MDD patients have cortical alterations of the frontal, parietal and cingulate regions, indicating a vulnerability to MDD during earlier neurodevelopmental process.


Factors influencing bone mass accrual: focus on nutritional aspects.
Until recently, much of the research exploring the role of nutrition on bone mass accrual has focused on single nutrients. Although randomised controlled trials have provided key information about the effects of calcium and vitamin D on bone, they also have limitations, e.g. generalisation, implementation of the results and long-term consequences. Human subjects do not eat single nutrients, but foods, and describing healthy food patterns for optimising bone mineral accrual is warranted. Recent advances in research suggest that the effects of whole diet are larger than those of single nutrients on bone health. Research should focus on younger age groups to identify the life-course determinants of osteoporosis during prenatal, infancy, childhood and adolescence that would help to maximise peak bone mass. Food patterns that describe the variability, quality and choices of individuals give broader insight and may provide new strategies for preventing osteoporosis.


The dimeric structure and the bivalent recognition of H3K4me3 by the tumor suppressor ING4 suggests a mechanism for enhanced targeting of the HBO1 complex to chromatin.
The INhibitor of Growth (ING) family of tumor suppressors regulates the transcriptional state of chromatin by recruiting remodeling complexes to sites with histone H3 trimethylated at position K4 (H3K4me3). This modification is recognized by the plant homeodomain (PHD) present at the C-terminus in the five members of the ING family. ING4 facilitates histone H3 acetylation by the HBO1 complex. Here, we show that ING4 forms homodimers through its N-terminal domain, which folds independently into an elongated coiled-coil structure. The central region of ING4, which contains the nuclear localization sequence, is disordered and flexible and does not directly interact with p53, or does it with very low affinity, in contrast to previous findings. The NMR analysis of the full-length protein reveals that the two PHD fingers of the dimer are chemically equivalent and independent of the rest of the molecule. The detailed NMR analysis of the full-length dimeric protein binding to histone H3K4me3 shows essentially the same binding site and affinity as the isolated PHD finger. Therefore, the ING4 dimer has two identical and independent binding sites for H3K4me3 tails, which, in the context of the chromatin, could belong to the same or to different nucleosomes. These results show that ING4 is a bivalent reader of the chromatin H3K4me3 modification and suggest a mechanism for enhanced targeting of the HBO1 complex to specific chromatin sites. This mechanism could be common to other ING-containing remodeling complexes.


Medical costs of CKD in the Medicare population.
Estimates of the medical costs associated with different stages of CKD are needed to assess the economic benefits of interventions that slow the progression of kidney disease. We combined laboratory data from the National Health and Nutrition Examination Survey with expenditure data from Medicare claims to estimate the Medicare program's annual costs that were attributable to CKD stage 1-4. The Medicare costs for persons who have stage 1 kidney disease were not significantly different from zero. Per person annual Medicare expenses attributable to CKD were $1700 for stage 2, $3500 for stage 3, and $12,700 for stage 4, adjusted to 2010 dollars. Our findings suggest that the medical costs attributable to CKD are substantial among Medicare beneficiaries, even during the early stages; moreover, costs increase as disease severity worsens. These cost estimates may facilitate the assessment of the net economic benefits of interventions that prevent or slow the progression of CKD.


Hemodynamic effects of middle cerebral artery stenosis and occlusion.
Middle cerebral artery (MCA) stenosis and occlusion may cause ischemic symptoms through both hemodynamic and embolic mechanisms. The purpose of this investigation was to determine the hemodynamic effects of these lesions. Ten patients with angiographically confirmed symptomatic occlusion (n = 5) or stenosis (n = 5) of the M1 segment of the MCA were studied by clinical examination, arteriography, and positron emission tomography (PET). Arterial supply to the distal MCA territory was classified from a review of the angiogram as being through the stenosis or from pial collaterals from anterior or posterior cerebral arteries. Regional measurements of cerebral blood flow, cerebral blood volume, cerebral rate of oxygen metabolism, oxygen extraction fraction, and ratio of cerebral blood volume/cerebral blood flow (mean vascular transit time, MTT) were obtained using PET. Hemodynamic status was categorized from PET scans as stage 0, normal hemodynamics; stage 1, autoregulatory vasodilatation (increased MTT); or stage 2, increased oxygen extraction fraction. Of five patients with MCA occlusion, three had autoregulatory vasodilatation (stage 1) and two had increased oxygen extraction fraction distal to the lesion (stage 2). The MCA territory was supplied solely by pial collaterals in all five patients. Four of the five patients with focal MCA stenosis had normal hemodynamics (stage 0). One patient had stage 1 hemodynamic status. Blood flow to the MCA territory was through the stenosis in all patients; no pial collaterals were identified. The frequency of hemodynamic compromise in patients with MCA occlusion is high. Pial collateralization is not a specific sign of increased oxygen extraction fraction in patients with MCA occlusion.


Unifying latitudinal gradients in range size and richness across marine and terrestrial systems.
Many marine and terrestrial clades show similar latitudinal gradients in species richness, but opposite gradients in range size-on land, ranges are the smallest in the tropics, whereas in the sea, ranges are the largest in the tropics. Therefore, richness gradients in marine and terrestrial systems do not arise from a shared latitudinal arrangement of species range sizes. Comparing terrestrial birds and marine bivalves, we find that gradients in range size are concordant at the level of genera. Here, both groups show a nested pattern in which narrow-ranging genera are confined to the tropics and broad-ranging genera extend across much of the gradient. We find that (i) genus range size and its variation with latitude is closely associated with per-genus species richness and (ii) broad-ranging genera contain more species both within and outside of the tropics when compared with tropical- or temperate-only genera. Within-genus species diversification thus promotes genus expansion to novel latitudes. Despite underlying differences in the species range-size gradients, species-rich genera are more likely to produce a descendant that extends its range relative to the ancestor's range. These results unify species richness gradients with those of genera, implying that birds and bivalves share similar latitudinal dynamics in net species diversification.


Neopterin concentrations in pediatric human immunodeficiency virus infection as predictor of disease activity.
Neopterin concentrations in 50 children with human immunodeficiency virus infection were correlated with disease course. The neopterin concentrations ranged from 4 to 70 nM with a mean of 34.7 +/- 25.1 (SD) nM compared with a mean of 6.1 +/- 1.6 nM in the human immunodeficiency virus-negative control group. Elevated neopterin concentrations above the upper range of the control group were detected as early as 5 months of age. Nineteen of 20 patients (95%) with neopterin concentrations above 20 nM either died or have severe clinical disease. Increasing neopterin concentrations were also associated with poor prognosis even though the first value was below 20 nM. Conversely neopterin concentrations less than 20 nM or declining concentrations were associated with a stable clinical course, except in terminal illness. With stepwise logistic regression analysis neopterin concentrations were predictive for disease progression. This predictive value was further improved by the addition of CD4 cell counts.


Super resolution imaging with noise reduction and aberration elimination via random structured illumination and processing.
Hereby we describe an improved aberration-free super resolution imaging system that uses binary speckle patterns (BSP) for encoding and decoding. According to the scheme, the object is multiplied by a fine random speckle pattern and subsequently the poorly resolved acquired image is multiplied by the same pattern, stored digitally. Summing many samples of similar operations restores a high quality image. In this paper we define encoding and decoding BSP that form complementary sets. Contrary to using totally random BSP, the use of complementary sets reduces the noise of the resulting image significantly. Moreover, they allow reducing the number of operations necessary to restore the image. We found out that using sparse BSP followed by a stochastic noise reduction algorithm, fitted for the decoding process, reduces the noise significantly and allows use of even a single set of complementary BSP for obtaining excellent results. Simulation results are presented both for binary images as well as for gray level objects.


Implications of a vertex bulge following modified strip craniectomy for sagittal synostosis.
Modified strip craniectomy is a common treatment for early isolated sagittal synostosis. The authors assessed the significance of the development of a progressive vertex bulge following strip craniectomy as a predictor of raised intracranial pressure or multiple suture synostosis. All cases of sagittal synostosis treated by modified strip craniectomy (removal of the sagittal suture with lateral barrel staving) at the authors' institution were reviewed. Eighty-nine patients with isolated sagittal synostosis were treated by modified strip craniectomy, usually before 6 months of age, between 1995 and 2005. Seven patients were noted to have developed a progressive vertex bulge. The vertex bulge was noted an average of 8 months postoperatively (range, 2 to 25 months). The clinical records of these seven patients were evaluated with regard to their clinical course, radiologic investigations, genetics testing, intracranial pressure monitoring, and the need for further surgery. Computed tomographic scanning demonstrated new synostosis involving other calvarial sutures in five patients. Five patients underwent intracranial pressure monitoring, and this was elevated in four patients. One patient required a ventriculoperitoneal shunt for hydrocephalus. All patients underwent genetic screening, and two were found to have fibroblast growth factor receptor (FGFR) mutations (one FGFR2 and one FGFR3 mutation). All patients required reoperation (calvarial remodeling) for either raised intracranial pressure, deteriorating head shape, or both. A progressive vertex bulge after modified strip craniectomy is a sign of possible raised intracranial pressure, the development of progressive multiple suture synostosis, or both. It is an indication for genetic testing for FGFR mutations.


Antiproinflammatory effects of iodixanol (OptiPrep)-based density gradient purification on human islet preparations.
Islet isolation and purification using a continuous density gradient may reduce the volume of tissue necessary for implantation into patients, therefore minimizing the risks associated with intraportal infusion in islet transplantation. On the other hand, the purification procedure might result in a decreased number of islets recovered due to various stresses such as exposure to cytokine/chemokine. While a Ficoll-based density gradient has been widely used in purification for clinical trials, purification with iodixanol (OptiPrep) has been recently reported in islet transplant series with successful clinical outcomes. The aim of the current study was to compare the effects of the purification method using OptiPrep-based and Ficoll-based density gradients. Human islet isolations were performed using a modified automated method. After the digestion phase, pre-purification digests were divided into two groups and purified using a semiautomated cell processor with either a continuous Ficoll- or OptiPrep-based density gradient. The quantity, purity, viability, and cellular composition of islet preparations from each group were assessed. Cytokine/chemokine and tissue factor production from islet preparations after 48-h culture were also measured. Although islet purity, post-purification IEQ, islet recovery rate, FDA/PI, and fractional β-cell viability were comparable, β-cell mass after 48-h culture significantly improved in the OptiPrep group when compared to the Ficoll group. The production of cytokine/chemokine including IL-1β, TNF-α, IFN-γ, IL-6, IL-8, MIP-1β, MCP-1, and RANTES but not tissue factor from the OptiPrep group was significantly lower during 48-h culture after isolation. Each preparation contained the similar number of ductal cells and macrophages. Endotoxin level in both gradient medium was also comparable. The purification method using OptiPrep gradient media significantly reduced cytokine/chemokine production but not tissue factor from human islet preparations and improved β-cell survival during pretransplant culture. Our results suggest that the purification method using OptiPrep gradient media may be of assistance in increasing successful islet transplantation.


[Of bugs and joints. Oligoarthritis caused by Tropheryma whipplei].
Whipple's disease is a rare, chronic infection caused by Tropheryma whipplei, an ubiquitary gram positive bacterium. The disease is associated with a high mortality in absence of an antibiotic treatment. The disease can be detected in affected tissues and body fluids by light and electron microscopy, as well as by polymerase chain reaction (PCR). Musculoskeletal symptoms such as arthralgia and arthritis frequently represent the first manifestation of this multi-system disease; typical subsequent symptoms are weight loss, diarrhea, and abdominal pain. Symptoms of central nervous system involvement are present in 10-40% of cases. We report on a 67 year-old male with a history of migratory oligoarthritis over three decades in whom the causative agent was detected by PCR in synovial fluid only. This case illustrates that searches for the characteristic PAS-positive macrophages and PCR in biopsies from the duodenum may be insufficient and that diagnostic efforts should be complemented with PCR assays from affected tissues or body fluids. It is recommended that antibiotic treatment be carried out with an agent that penetrates well into the cerebrospinal fluid, e.g. ceftriaxone, followed by cotrimoxazole. Antibiotics should be maintained over several months to years. It is prudent to document the disappearance of the pathogen in the affected compartments prior to the discontinuation of the antibiotic therapy.


Effect of myocardial shortening velocity on duration of electrical and mechanical systole. S2T interval as measure of shortening rate.
To determine the effect of myocardial shortening velocity on the duration of electrical and mechanical systole, five healthy men, ages 32 to 41, were studied. Carotid message and atropine were used to define the effects of changes in heart rate without changes in shortening rate. The effects of amyl nitrite, which produced approximately the same degree of tachycardia as atropine but a significantly higher maximum shortening rate, were compared with those of atropine to assess the effects of faster shortening velocities. The increased heart rate produced by both agents caused a substantial decrease in both the QT and the S1S2 intervals, but the QT interval was longer and the S1S2 interval shorter with the amyl nitrite. Thus, the S2T interval was substantially longer after amyl nitrite. The results are in keeping with the finding in isolated cardiac muscle that active shortening increases action potential duration and decreases the duration of mechanical activation. These observations raise the possibility that longer QT intervals and shorter S1S2 intervals would also be seen in patients with hypokinetic ventricular segments when the healthy muscle contracts more vigorously to compensate for the weaker segments.


Physiological Synchronization in a Vigilance Dual Task.
The synchronization of autonomic arousal levels and other physio-logical responses between people is a potentially important component of work team performance, client-therapist relationships, and other types of human interaction. This study addressed several problems: What statistical models are viable for identifying synchronization for loosely coupled human systems? How is the level of synchronization related to psychosocial variables such as empathy, subjective ratings of workload, and actual performance? Participants were 70 undergraduates who worked in pairs on a vigilance dual task in which they watched a virtual reality security camera, rang a bell when they saw the target intruder, and completed a jig-saw puzzle. Event rates either increased or decreased during the 90 min work period. The average R2 values for each person were .66, .66, .62, and .53 for the linear autoregressive model, linear autoregressive model with a synchronization component, the nonlinear autoregressive model, and the nonlinear autoregressive model with a synchronization component, respectively. All models were more accurate at a lag of 20 sec compared to 50 sec or customized lag lengths. Although the linear models were more accurate overall, the nonlinear synchronization parameters were more often related to psychological variables and performance. In particular, greater synchronization was observed with the nonlinear model when the target event rate increased, compared to when it decreased, which was expected from the general theory of synchronization. Nonlinear models were also more effective for uncovering inhibitory or dampening relationships between the co-workers as well as mutually excitatory relationships. Future research should explore the comparative model results for tasks that induce higher levels of synchronization and involve different types of internal group coordination.


Understanding waiting lists as the matching of surgical capacity to demand: are we wasting enough surgical time?
If surgical 'capacity' always matched or exceeded 'demand' then there should be no waiting lists for surgery. However, understanding what is meant by 'demand', 'capacity' and 'matched' requires some mathematical concepts that we outline in this paper. 'Time' is the relevant measure: 'demand' for a surgical team is best understood as the total min required for the surgery booked from outpatient clinics every week; and 'capacity' is the weekly operating time available. We explain how the variation in demand (not just the mean demand) influences the analysis of optimum capacity. However, any capacity chosen in this way is associated with only a likelihood (that is, a probability rather than certainty) of absorbing the prevailing demand. A capacity that suitably absorbs the demand most of the time (for example, > 80% of weeks) will inevitably also involve considerable waste (that is, many weeks in which there is spare, unused capacity). Conversely, a level of capacity chosen to minimise wasted time will inevitably cause an increase in size of the waiting list. Thus the question of how to balance demand and capacity is intimately related to the question of how to balance utilisation and waste. These mathematical considerations enable us to consider objectively how to manage the waiting list. They also enable us critically to analyse the extent to which philosophies adopted by the National Health Service (such as 'Lean' or 'Six Sigma') will be successful in matching surgical capacity to demand.


Winter warming in Alaska accelerates lignin decomposition contributed by Proteobacteria.
In a warmer world, microbial decomposition of previously frozen organic carbon (C) is one of the most likely positive climate feedbacks of permafrost regions to the atmosphere. However, mechanistic understanding of microbial mediation on chemically recalcitrant C instability is limited; thus, it is crucial to identify and evaluate active decomposers of chemically recalcitrant C, which is essential for predicting C-cycle feedbacks and their relative strength of influence on climate change. Using stable isotope probing of the active layer of Arctic tundra soils after depleting soil labile C through a 975-day laboratory incubation, the identity of microbial decomposers of lignin and, their responses to warming were revealed. The β-Proteobacteria genus Burkholderia accounted for 95.1% of total abundance of potential lignin decomposers. Consistently, Burkholderia isolated from our tundra soils could grow with lignin as the sole C source. A 2.2 °C increase of warming considerably increased total abundance and functional capacities of all potential lignin decomposers. In addition to Burkholderia, α-Proteobacteria capable of lignin decomposition (e.g. Bradyrhizobium and Methylobacterium genera) were stimulated by warming by 82-fold. Those community changes collectively doubled the priming effect, i.e., decomposition of existing C after fresh C input to soil. Consequently, warming aggravates soil C instability, as verified by microbially enabled climate-C modeling. Our findings are alarming, which demonstrate that accelerated C decomposition under warming conditions will make tundra soils a larger biospheric C source than anticipated. Video Abstract.


Optical properties of red emitting self-assembled InP/(Al0.20Ga0.80)0.51In0.49P quantum dot based micropillars.
Using focused ion beam etching techniques, micropillar cavities were fabricated from a high reflective AlAs/AlGaAs distributed Bragg reflector planar cavity containing self-assembled InP quantum dots in (Al(0.20)Ga(0.80))(0.51)In(0.49)P barrier layers. The mode spectra of pillars with different diameters were investigated using micro-photoluminescence, showing excellent agreement with theory. Quality factors of the pillar cavities up to 3650 were observed. Furthermore, for a microcavity pillar with 1.26 mum diameter, single-photon emission is demonstrated by performing photon correlation measurements under pulsed excitation.


EST analysis of the cnidarian Acropora millepora reveals extensive gene loss and rapid sequence divergence in the model invertebrates.
A significant proportion of mammalian genes are not represented in the genomes of Drosophila, Caenorhabditis or Saccharomyces, and many of these are assumed to have been vertebrate innovations. To test this assumption, we conducted a preliminary EST project on the anthozoan cnidarian, Acropora millepora, a basal metazoan. More than 10% of the Acropora ESTs with strong metazoan matches to the databases had clear human homologs but were not represented in the Drosophila or Caenorhabditis genomes; this category includes a surprising diversity of transcription factors and metabolic proteins that were previously assumed to be restricted to vertebrates. Consistent with higher rates of divergence in the model invertebrates, three-way comparisons show that most Acropora ESTs match human sequences much more strongly than they do any Drosophila or Caenorhabditis sequence. Gene loss has thus been much more extensive in the model invertebrate lineages than previously assumed and, as a consequence, some genes formerly thought to be vertebrate inventions must have been present in the common metazoan ancestor. The complexity of the Acropora genome is paradoxical, given that this organism contains apparently few tissue types and the simplest extant nervous system consisting of a morphologically homogeneous nerve net.


Physiology and immunology of the cholinergic antiinflammatory pathway.
Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.


Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial.
The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children. ClinicalTrials.gov: NCT01536275 on 16 February 2012.


Using a Novel Absolute Ontogenetic Age Determination Technique to Calculate the Timing of Tooth Eruption in the Saber-Toothed Cat, Smilodon fatalis.
Despite the superb fossil record of the saber-toothed cat, Smilodon fatalis, ontogenetic age determination for this and other ancient species remains a challenge. The present study utilizes a new technique, a combination of data from stable oxygen isotope analyses and micro-computed tomography, to establish the eruption rate for the permanent upper canines in Smilodon fatalis. The results imply an eruption rate of 6.0 millimeters per month, which is similar to a previously published average enamel growth rate of the S. fatalis upper canines (5.8 millimeters per month). Utilizing the upper canine growth rate, the upper canine eruption rate, and a previously published tooth replacement sequence, this study calculates absolute ontogenetic age ranges of tooth development and eruption in S. fatalis. The timing of tooth eruption is compared between S. fatalis and several extant conical-toothed felids, such as the African lion (Panthera leo). Results suggest that the permanent dentition of S. fatalis, except for the upper canines, was fully erupted by 14 to 22 months, and that the upper canines finished erupting at about 34 to 41 months. Based on these developmental age calculations, S. fatalis individuals less than 4 to 7 months of age were not typically preserved at Rancho La Brea. On the whole, S. fatalis appears to have had delayed dental development compared to dental development in similar-sized extant felids. This technique for absolute ontogenetic age determination can be replicated in other ancient species, including non-saber-toothed taxa, as long as the timing of growth initiation and growth rate can be determined for a specific feature, such as a tooth, and that growth period overlaps with the development of the other features under investigation.


Simultaneous Clostridium difficile-associated colitis and late-onset intestinal cytomegalovirus disease in a renal transplant recipient.
Infection remains the most common complication following renal transplantation (RT). Cytomegalovirus (CMV) is one of the most important pathogens in this patient population and Clostridium difficile-associated colitis (CDAC) has emerged as one of the most frequent gastrointestinal complications. Only few cases of simultaneous CMV enterocolitis and CDAC have been reported. A 73-year-old woman who underwent RT more than 10 years earlier developed severe abdominal pain and profound bloody diarrhea. She was diagnosed with simultaneous CMV enterocolitis and CDAC and treated with ganciclovir and metronidazole. She was unable to clear the infections and underwent colonic and small bowel resection, but ultimately died from indirect complications following the two severe infections. Late-onset CMV disease in this patient who was CMV negative prior to transplantation and received a CMV-negative graft was an unexpected event; the simultaneous occurrence of CDAC aggravated the clinical picture ultimately leading to surgery, graft failure and death. Clinicians should be aware that opportunistic infections may develop many years post transplant and may occur simultaneously.


Understanding the failure of CD8+ T-cell vaccination against simian/human immunodeficiency virus.
Although CD8+ T cells play an important role in controlling viral infections, boosting specific CD8+ T cells by prophylactic vaccination with simian immunodeficiency virus (SIV) epitopes fails to provide sterilizing immunity. Viral replication rates and viral contraction rates after the peak viremia hardly depend on the presence of memory CD8+ T cells. To study these paradoxical findings, we parameterize novel mathematical models for acute SIV and human immunodeficiency virus infection. These models explain that failure of vaccination is due to the fact that effector/target ratios are too low during the viral expansion phase. Because CD8+ T cells require cell-to-cell contacts, immune protection requires high effector/target ratios at the primary site of infection. Effector/target ratios become favorable for immune control at the time of the peak in the viral load when the virus becomes limited by other factors, such as the availability of uninfected target cells. At the viral set point, effector/target ratios are much higher, and perturbations of the number of CD8+ effector cells have a large impact on the viral load. Such protective effector/target ratios are difficult to achieve with nucleic acid- or protein-based vaccines.


Civic engagement and the transition to adulthood.
Constance Flanagan and Peter Levine survey research on civic engagement among U.S. adolescents and young adults. Civic engagement, they say, is important both for the functioning of democracies and for the growth and maturation it encourages in young adults, but opportunities for civic engagement are not evenly distributed by social class or race and ethnicity. Today's young adults, note the authors, are less likely than those in earlier generations to exhibit many important characteristics of citizenship, raising the question of whether these differences represent a decline or simply a delay in traditional adult patterns of civic engagement. Flanagan and Levine also briefly discuss the civic and political lives of immigrant youth in the United States, noting that because these youth make up a significant share of the current generation of young adults, their civic engagement is an important barometer of the future of democracy. The authors next survey differences in civic participation for youth from different social, racial, and ethnic backgrounds. They explore two sets of factors that contribute to a lower rate of civic engagement among low-income and minority young adults. The first is cumulative disadvantage-unequal opportunities and influences before adulthood, especially parental education. The second is different institutional opportunities for civic engagement among college and non-college youth during the young-adult years. Flanagan and Levine survey various settings where young adults spend time-schools and colleges, community organizations, faith-based institutions, community organizing and activism projects, and military and other voluntary service programs-and examine the opportunities for civic engagement that each affords. As the transition to adulthood has lengthened, say the authors, colleges have become perhaps the central institution for civic incorporation of younger generations. But no comparable institution exists for young adults who do not attend college. Opportunities for sustained civic engagement by year-long programs such as City Year could provide an alternative opportunity for civic engagement for young adults from disadvantaged families, allowing them to stay connected to mainstream opportunities and to adults who could mentor and guide their way.


Encouraging early preventive dental visits for preschool-aged children enrolled in Medicaid: using the extended parallel process model to conduct formative research.
Preventive dental visits for preschool-aged children can result in better oral health outcomes, especially for children from lower income families. Many children, however, still do not see a dentist for preventive visits. This qualitative study examined the potential for the Extended Parallel Process Model (EPPM) to be used to uncover potential antecedents to parents' decisions about seeking preventive dental care. Seventeen focus groups including 41 parents were conducted. The focus group protocol centered on constructs (perceived severity, perceived susceptibility, perceived self-efficacy, and perceived response efficacy) of the EPPM. Transcripts were analyzed by three coders who employed closed coding strategies. Parents' perceptions of severity of dental issues were high, particularly regarding negative health and appearance outcomes. Parents perceived susceptibility of their children to dental problems as low, primarily because most children in this study received preventive care, which parents viewed as highly efficacious. Parents' self-efficacy to obtain preventive care for their children was high. However, they were concerned about barriers including lack of dentists, especially dentists who are good with young children. Findings were consistent with EPPM, which suggests this model is a potential tool for understanding parents' decisions about seeking preventive dental care for their young children. Future research should utilize quantitative methods to test this model.


The capsid protein of Turnip crinkle virus overcomes two separate defense barriers to facilitate systemic movement of the virus in Arabidopsis.
The capsid protein (CP) of Turnip crinkle virus (TCV) is a multifunctional protein needed for virus assembly, suppression of RNA silencing-based antiviral defense, and long-distance movement in infected plants. In this report, we have examined genetic requirements for the different functions of TCV CP and evaluated the interdependence of these functions. A series of TCV mutants containing alterations in the CP coding region were generated. These alterations range from single-amino-acid substitutions and domain truncations to knockouts of CP translation. The latter category also contained two constructs in which the CP coding region was replaced by either the cDNA of a silencing suppressor of a different virus or that of green fluorescent protein. These mutants were used to infect Arabidopsis plants with diminished antiviral silencing capability (dcl2 dcl3 dcl4 plants). There was a strong correlation between the ability of mutants to reach systemic leaves and the silencing suppressor activity of mutant CP. Virus particles were not essential for entry of the viral genome into vascular bundles in the inoculated leaves in the absence of antiviral silencing. However, virus particles were necessary for egress of the viral genome from the vasculature of systemic leaves. Our experiments demonstrate that TCV CP not only allows the viral genome to access the systemic movement channel through silencing suppression but also ensures its smooth egress by way of assembled virus particles. These results illustrate that efficient long-distance movement of TCV requires both functions afforded by the CP.


Cytokine-like activities of some aminoacyl-tRNA synthetases and auxiliary p43 cofactor of aminoacylation reaction and their role in oncogenesis.
Multifunctionality of proteins is among mechanisms accounting for the complexity of interactome networks in higher eukaryotes. During oncogenesis and other pathologic conditions many proteins perform additional functions without changes in three dimensional structures. One family of these moonlighting proteins is represented by enzymes and cofactors of aminoacylation reactions, by means of which tRNAs are attached to their cognate amino acids. Tyrosyl-tRNA synthetase (TyrRS), tryptophanyl-tRNA synthetases (TrpRS) and auxiliary factor of mammalian multi-aminoacyl-tRNA synthetases, p43 (precusor of endothelial monocyte activating polypeptide II - EMAP II) upon their release in intracellular environment become proinflammatory cytokines with multiple activities during apoptosis, angiogenesis and inflammation. In addition, these proteins play important role in cancer progression, modulating tumor angiogenesis and its escape from surveillance by immune system.