Proposed definition and classification of cerebral palsy, April 2005.
Because of the availability of new knowledge about the neurobiology of developmental brain injury, information that epidemiology and modern brain imaging is providing, the availability of more precise measuring instruments of patient performance, and the increase in studies evaluating the efficacy of therapy for the consequences of injury, the need for reconsideration of the definition and classification of cerebral palsy (CP) has become evident. Pertinent material was reviewed at an international symposium participated in by selected leaders in the preclinical and clinical sciences. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, and health officials, and provide a common language for improved communication. With leadership and direction from an Executive Committee, panels utilized this information and have generated a revised Definition and Classification of Cerebral Palsy. The Executive Committee presents this revision and welcomes substantive comments about it.


Anomalous right subclavian artery and coarctation of the aorta. Surgical implications and the use of the right subclavian artery as a flap.
Coarctation of the aorta was repaired surgically in a 4 month old boy using the anomalous right subclavian artery as a flap. The role of the anomalous artery in providing collateral flow to the descending aorta should be determined so that injudicious clamping is avoided.


Urinary catheter policies for long-term bladder drainage.
People requiring long-term bladder draining commonly experience catheter-associated urinary tract infection and other problems. To determine if certain catheter policies are better than others in terms of effectiveness, complications, quality of life and cost-effectiveness in long-term catheterised adults and children. We searched the Cochrane Incontinence Group specialised trials register (searched 9 June 2003). Additionally, we examined all reference lists of identified trials. All randomised and quasi-randomised trials comparing catheter policies (route of insertion and use of antibiotics) for long-term (more than 14 days) catheterisation in adults and children. Data were extracted by both reviewers independently and compared. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook. If the data in trials have not been fully reported, clarification were sought from the authors. When necessary, the incidence-density rates (IDR) and/or the incidence-density differences (IDD) within a certain time period were calculated. Seven trials met the inclusion criteria involving 328 patients in four crossover and three parallel-group randomised controlled trials. Only two of the pre-stated six comparisons were addressed in these trials. Three trials compared antibiotic prophylaxis with antibiotics when clinically indicated. For patients using intermittent catheterisation, there were inconsistent findings about the effect of antibiotic prophylaxis on symptomatic urinary tract infection. For patients using indwelling urethral catheterisation, one small trial reported fewer episodes of symptomatic UTI in the prophylaxis group.Four trials compared antibiotic prophylaxis with giving antibiotics when microbiologically indicated. For patients using intermittent catheterisation, there was limited evidence that receiving antibiotics reduced the rate of bacteriuria (asymptomatic and symptomatic). There was weak evidence that prophylactic antibiotics were better in terms of fewer symptomatic bacteriuria. No eligible trials were identified that compared alternative routes of catheter insertion. The data from seven trials comparing differing antibiotic policies were sparse, particularly when intermittent catheterisation was considered separately from in-dwelling catheterisation. Possible benefits of antibiotic prophylaxis must be balanced against possible adverse effects, such as development of antibiotic resistant bacteria; these cannot be reliably estimated from currently available trials.


Rivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat.
This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats. This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.


Impact of ICD10 and secular changes on electronic medical record rheumatoid arthritis algorithms.
The objective of this study was to compare the performance of an RA algorithm developed and trained in 2010 utilizing natural language processing and machine learning, using updated data containing ICD10, new RA treatments, and a new electronic medical records (EMR) system. We extracted data from subjects with ≥1 RA International Classification of Diseases (ICD) codes from the EMR of two large academic centres to create a data mart. Gold standard RA cases were identified from reviewing a random 200 subjects from the data mart, and a random 100 subjects who only have RA ICD10 codes. We compared the performance of the following algorithms using the original 2010 data with updated data: (i) a published 2010 RA algorithm; (ii) updated algorithm, incorporating ICD10 RA codes and new DMARDs; and (iii) published algorithm using ICD codes only, ICD RA code ≥3. The gold standard RA cases had mean age 65.5 years, 78.7% female, 74.1% RF or antibodies to cyclic citrullinated peptide (anti-CCP) positive. The positive predictive value (PPV) for ≥3 RA ICD was 54%, compared with 56% in 2010. At a specificity of 95%, the PPV of the 2010 algorithm and the updated version were both 91%, compared with 94% (95% CI: 91, 96%) in 2010. In subjects with ICD10 data only, the PPV for the updated 2010 RA algorithm was 93%. The 2010 RA algorithm validated with the updated data with similar performance characteristics as the 2010 data. While the 2010 algorithm continued to perform better than the rule-based approach, the PPV of the latter also remained stable over time.


Gait adaptation during obstacle crossing reveals impairments in the visual control of locomotion in Williams syndrome.
Recent evidence indicates that individuals with Williams syndrome (WS), a rare genetically based neurodevelopmental disorder, show abnormalities of parietal and cerebellar regions of the brain that may be involved in the visual control of locomotion. Here we examined whether parietal and cerebellar abnormalities contribute to deficits in spatiotemporal characteristics and foot placement variability during obstacle crossing in adults with WS, when compared with an IQ-matched group of adults with Down syndrome (DS) and typically developing adult controls. We used the GAITRite walkway to examine the spatiotemporal characteristics and foot placement variability relative to a small ground-based obstacle in the travel path. We found that adults with WS showed late adjustments to spatiotemporal gait characteristics alongside an exaggerated and more spatially constrained visual guidance of foot positioning in the final steps prior to stepping over the obstacle. In contrast, the adults with DS showed longer step duration and more variable step length and step duration during the crossing and recovery steps after the obstacle, suggestive of cerebellar dysfunction. Although the controls were able to reduce the variability of foot placement across the obstacle crossing trials, both the WS and DS groups did not become more consistent with practice. These findings indicate a less flexible and overly constrained visuomotor system in WS, which is consistent with more widespread and diffuse abnormalities in parietal and cerebellar regions.


Reduced gene flow at pericentromeric loci in a hybrid zone involving chromosomal races of the house mouse Mus musculus domesticus.
The West European house mouse, Mus musculus domesticus, is a particularly suitable model to investigate the role of chromosomal rearrangements in reproductive isolation. In fact, it exhibits a broad range of chromosomal polymorphism due to Robertsonian (Rb) fusions leading to various types of contact zones between different chromosomal races. In the present study, we analyzed a parapatric contact in central Italy between the Cittaducale chromosomal race (CD: 2n= 22) and the surrounding populations with standard karyotype (2n= 40) to understand if Rb fusions play a causative role in speciation. One hundred forty-seven mice from 17 localities were genotyped by means of 12 microsatellite loci. A telomeric and a pericentromeric locus situated on six chromosome arms (four Rbs and one telocentric) were selected to detect differences in the amount of gene flow for each locus in different chromosomal positions. The analyses performed on the two subsets of loci show differences in the level of gene flow, which is more restricted near the centromeres of Rb chromosomes. This effect is less pronounced in the homozygotes populations settled at the border of the hybrid zone. We discuss the possible cause of the differential porosity of gene flow in Rbs considering "hybrid dysfunctions" and "suppressed recombination" models.


Phenotypic characterization of spatial cognition and social behavior in mice with 'knockout' of the schizophrenia risk gene neuregulin 1.
Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia.


Using social constructionist thinking in training social workers living and working under threat of political violence.
This article describes and analyzes an intervention program with social workers living and working in a situation of uncertainty created by political violence such as war and terrorism. The author used a social constructionist perspective as a theoretical framework, emphasizing the effect of the social and political context in constructing the experience and a recognition of the personal and professional knowledge acquired in the daily experience. The author used qualitative methods to evaluate the process and outcome. The narrative-holistic analysis focused on reconstructing meaning and adapting it to the new situation, the main thrust of the program. From the thematic analysis four main themes emerged: (1) loss as a result of political violence; (2) meaning of strength and weakness in situations of political violence; (3) preparation for terrorist attacks; and (4) definition of a safe place. The outcome evaluation describes the meaning of this kind of training program to the participants. The specific context of the training program is discussed as well as possibilities of using it in different contexts.


Using arm configuration to learn the effects of gyroscopes and other devices.
Previous studies have perturbed the association between motor commands and arm movements by applying forces to the arm during two-dimensional movements. These studies have revealed that, when the normal hand path is perturbed, subjects gradually adapt their motor commands to return to this path. The present study used the spin of a gyroscope to create a complex perturbation, as subjects reached to targets presented in three dimensions. Hand path did not change, but the whole-arm geometry ("arm configuration" in four dimensions) was altered. Over a series of several hundred reaches to various targets, subjects gradually returned the arm movement to its normal configuration. Furthermore, during the course of this learning, subjects used a strategy that involved manipulating arm posture. A similar strategy was observed when subjects made reaching movements with a rod attached to the upper arm to change its inertial characteristics. In both cases, the gradual return to the normal arm movement was accomplished without an increase in kinetic energy, suggesting that arm postures and movements (kinematics) and muscular forces (kinetics) may be mutually optimized. In contrast to previous studies, the present results highlight the role of arm configuration (rather than hand path) in learning and control.


Cirrhosis and rapid virological response to peginterferon plus ribavirin determine treatment outcome in HCV-1 IL28B rs12979860 CC patients.
The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07-6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics (P = 0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (-) (P = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (-) (10/13 (77%) versus 6/17 (35%) P = 0.03). In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy.


Myocardial Injury After Noncardiac Surgery (MINS) in Vascular Surgical Patients: A Prospective Observational Cohort Study.
To determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in vascular surgical patients. MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in vascular surgery patients are poorly described. This was an international prospective cohort study of 15,102 noncardiac surgery patients 45 years or older, of whom 502 patients underwent vascular surgery. All patients had fourth-generation plasma troponin T (TnT) concentrations measured during the first 3 postoperative days. MINS was defined as a TnT of 0.03 ng/mL of higher secondary to ischemia. The objectives of the present study were to determine (i) if MINS is prognostically important in vascular surgical patients, (ii) the clinical characteristics of vascular surgery patients with and without MINS, (iii) the 30-day outcomes for vascular surgery patients with and without MINS, and (iv) the proportion of MINS that probably would have gone undetected without routine troponin monitoring. The incidence of MINS in the vascular surgery patients was 19.1% (95% confidence interval (CI), 15.7%-22.6%). 30-day all-cause mortality in the vascular cohort was 12.5% (95% CI 7.3%-20.6%) in patients with MINS compared with 1.5% (95% CI 0.7%-3.2%) in patients without MINS (P < 0.001). MINS was independently associated with 30-day mortality in vascular patients (odds ratio, 9.48; 95% CI, 3.46-25.96). The 30-day mortality was similar in MINS patients with (15.0%; 95% CI, 7.1-29.1) and without an ischemic feature (12.2%; 95% CI, 5.3-25.5, P = 0.76). The proportion of vascular surgery patients who suffered MINS without overt evidence of myocardial ischemia was 74.1% (95% CI, 63.6-82.4). Approximately 1 in 5 patients experienced MINS after vascular surgery. MINS was independently associated with 30-day mortality. The majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.


An improved assembly assay for peptide binding to HLA-B*2705 and H-2K(k) class I MHC molecules.
The assembly assay for peptide binding to class I major histocompatibility complex (MHC) is based on the ability to stabilise MHC class I molecules from mutant cell lines by the addition of suitable peptides. Such cell lines lack a functional transporter associated with antigen presentation (TAP) and as a result accumulate empty, unstable class I molecules in the ER. These dissociate rapidly in cell lysates unless they are stabilised by the addition of an appropriate binding peptide during lysis. The extent of stabilisation of class I molecules is directly related to the binding affinity of the added peptide. However, some MHC class I molecules, including HLA-B * 2705 and H-2Kk are unusually stable in their peptide-receptive state making them inappropriate for analysis using this assay or assays which depend on the ability of peptides to stabilise MHC class I molecules at the cell surface. Here we present an improved method that permits reliable measurements of peptide binding to such class I MHC molecules that are unusually stable in the absence of peptide. Cells are lysed in the presence of peptide and incubated at 4 degrees C. After 2 h, during which peptide binding to empty MHC molecules occurs, the lysate is heated to a temperature which preferentially destabilises those MHC molecules that remain empty. We have used this technique to assay peptide binding to HLA-B * 2705, as well as to the murine allele H-2Kk which also displays a stable phenotype when transfected into TAP-deficient T2 cells and show that this method represents a marked improvement over previous methods in terms of lower background signal and higher recovery of peptide bound molecules.


Bias in amputation research; impact of subjects missed from a prospective study.
For research findings to be generalized, a sample must be representative of the actual population of interest. Lower limb amputation is most frequently performed in older patients with vascular disease, a population that is often under-represented in research. The aim of this study was to explore the impact of selection bias by comparing characteristics from a sample included in a prospective study of phantom pain with the actual population who underwent amputation. Only 27% of all potential patients were referred during the first year of the prospective study. The referred patients were 8 years younger (p<0.001) and less likely to have had amputation because of a vascular condition, diabetes or infection (p=0.003) than those not referred. There was also a significant difference in one year survival between the groups; 67% of referred patients survived compared with just 40% of non-referred patients (p=0.004). The biased population in the phantom pain study may have resulted in an underestimation of phantom pain in the original study and subsequent protective factors should be considered within the context of the younger population reported. Selection bias is common in amputation research, and research methods to minimize its impact must be given greater attention.


Ankylosing spondylitis is associated with the anthrax toxin receptor 2 gene (ANTXR2).
ANTXR2 variants have been associated with ankylosing spondylitis (AS) in two previous genome-wide association studies (GWAS) (p∼9×10(-8)). However, a genome-wide significant association (p<5×10(-8)) was not observed. We conducted a more comprehensive analysis of ANTXR2 in an independent UK sample to confirm and refine this association. A replication study was carried out with 2978 cases and 8365 controls. Then, these were combined with non-overlapping samples from the two previous GWAS in a meta-analysis. Human leukocyte antigen (HLA)-B27 stratification was also performed to test for ANTXR2-HLA-B27 interaction. Out of nine single nucleotide polymorphisms (SNP) in the study, five SNPs were nominally associated (p<0.05) with AS in the replication dataset. In the meta-analysis, eight SNPs showed evidence of association, the strongest being with rs12504282 (OR=0.88, p=6.7×10(-9)). Seven of these SNPs showed evidence for association in the HLA-B27-positive subgroup, but none was associated with HLA-B27-negative AS. However, no statistically significant interaction was detected between HLA-B27 and ANTXR2 variants. ANTXR2 variants are clearly associated with AS. The top SNPs from two previous GWAS (rs4333130 and rs4389526) and this study (rs12504282) are in strong linkage disequilibrium (r(2)≥0.76). All are located near a putative regulatory region. Further studies are required to clarify the role played by these ANTXR2 variants in AS.


Reperfusion of focal ischemia of varying duration: postischemic hyper- and hypo-perfusion.
Reperfusion into focal ischemia was studied in 25 cats after middle cerebral artery (mca) occlusion of 15 min to 2 hours duration. Changes in cerebral blood flow (CBF) were followed with the hydrogen clearance method in the center and periphery of the ischemic lesion expected. Postischemic hyperperfusion was found often after 15 and 30 min ischemia and regularly after 60 min mca occlusion. It was followed by normal flow after 15 and 30 min occlusion and by postischemic hypoperfusion after 1 hour ischemia. After 2 hours occlusion hypoperfusion generally was not preceded by hyperperfusion. After 60 min ischemia hyperperfusion could not prevent the development of severe hypoperfusion, but often was accompanied by a marked flow reduction in the periphery of the mca territory. The data indicate that hyperperfusion after ischemic periods lasting 60 min and more induces hypoperfusion in the area itself and in neighbouring regions by affecting perfusion pressure and thereby may enlarge ischemic damage.


Epicritic sensation in cervical spinal cord injury: diagnostic gains beyond testing light touch.
Abstract Applied as a bedside test of gross dorsal column function, the testing of light touch (LT) sensation is of high clinical value in the diagnosis of human spinal cord injury (SCI). However, the assessment of overall dorsal column deficit by testing only LT may be limited, because the dorsal column pathway conveys several large diameter afferent modalities (e.g., sensation of touch, two-point discrimination, and proprioception). Therefore, the objective of this study was to compare the epicritic sensation assessed by LT, Semmes-Weinstein monofilament (SWM), and electrical perception threshold (EPT) across cervical dermatomes (C3-C8) in individuals with cervical SCI. A multicenter cross-sectional study was performed at 6 months after cervical SCI, applying combined measures of LT, SWM, and EPT, bilaterally over predefined key sensory points (C3-C8). A total of 300 left- and right-sided dermatomes were tested for each outcome measure in 25 participants. The percentage agreement between classifications according to LT and SWM/EPT testing for all dermatomes between C3 and C8 ranged from 95.5% to 36.2%. The degree of agreement showed considerably variable κ coefficients (-0.1≥kw≤0.7) for each dermatome between C3 and C8. The additional measurements of epicritic sensation by SWM and EPT increased sensitivity by detecting and quantifying differences in sensory thresholds above, at, and below the LT level of injury. This is relevant for early clinical trials (phase 1/2), in which disclosing any biological activity of an intervention may be revealed by subtle sensory changes that might gain a clinical relevance.


miRNA-221 is elevated in cystic fibrosis airway epithelial cells and regulates expression of ATF6.
MicroRNA (miRNA) and messenger RNA (mRNA) expression differs in cystic fibrosis (CF) versus non-CF bronchial epithelium. Here, the role of miRNA in basal regulation of the transcription factor ATF6 was investigated in bronchial epithelial cells in vitro and in vivo. Using in silico analysis, miRNAs predicted to target the 3'untranslated region (3'UTR) of the human ATF6 mRNA were identified. Three of these miRNAs, miR-145, miR-221 and miR-494, were upregulated in F508del-CFTR homozygous CFBE41o- versus non-CF 16HBE14o- bronchial epithelial cells and also in F508del-CFTR homozygous or heterozygous CF (n = 8) versus non-CF (n = 9) bronchial brushings. ATF6 was experimentally validated as a molecular target of these miRNAs through the use of a luciferase reporter vector containing the full-length 3'UTR of ATF6. Expression of ATF6 was observed to be decreased in CF both in vivo and in vitro. miR-221 was also predicted to regulate murine ATF6, and its expression was significantly increased in native airway tissues of 6-week-old βENaC-overexpressing transgenic mice with CF-like lung disease versus wild-type littermates. These results implicate miR-145, miR-221 and miR-494 in the regulation of ATF6 in CF bronchial epithelium, with miR-221 demonstrating structural and functional conservation between humans and mice. The altered miRNA expression evident in CF bronchial epithelial cells can affect expression of transcriptional regulators such as ATF6.


A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation.
Postsynaptic differentiation of dendrites is an essential step in synapse formation. We report here a requirement for the transcription factor myocyte enhancer factor 2A (MEF2A) in the morphogenesis of postsynaptic granule neuron dendritic claws in the cerebellar cortex. A transcriptional repressor form of MEF2A that is sumoylated at lysine-403 promoted dendritic claw differentiation. Activity-dependent calcium signaling induced a calcineurin-mediated dephosphorylation of MEF2A at serine-408 and, thereby, promoted a switch from sumoylation to acetylation at lysine-403, which led to inhibition of dendritic claw differentiation. Our findings define a mechanism underlying postsynaptic differentiation that may modulate activity-dependent synapse development and plasticity in the brain.


Epstein-Barr virus transcription in nasopharyngeal carcinoma.
Sequences which encode Epstein-Barr virus (EBV) RNA in nasopharyngeal carcinoma (NPC) tissue have been identified. We utilized human biopsy material directly as well as NPC grown in nude mice. Total RNA was extracted from the tumor material and separated into polyadenylated and nonpolyadenylated fractions by oligodeoxythymidylate-cellulose chromatography. This material was used as template to construct 32P-labeled cDNA. The labeled cDNAs were hybridized to Southern blots of recombinant EBV DNA fragments. Three of the biopsies, F, 49, and 55, contained polyadenylated RNA homologous to the EBV BamHI fragments V and K, and EcoRI-DIJhet. These same fragments encode the most abundant polyribosomal RNAs in latently infected lymphoblastoid cell lines. The sequences which encoded nonpolyadenylated RNA in NPC tumor 49 were more extensive and included BamHI fragments C, V, B, E, and K, and EcoRI fragments DIJhet, E, F, and G1, a result that indicates selective polyadenylation in EBV RNA processing. A fourth biopsy, NPC tumor 18, contained polyadenylated RNA homologous to the BamHI fragments H, B, K, Y, B1, I1, and A and EcoRI fragments F and G2. A similar pattern of transcription was identified in three tumor specimens from nude mice, 4, 5, and 8. Transformation of lymphocytes did not occur after cocultivation in vitro with explants from these nude mice tumors. This transcriptional pattern may represent an activated state of the EBV genome, formerly not detected in tumor tissue, which is analogous to the state of abortive infection identified in induced in vitro cell systems.


Does the use of transgenic plants diminish or promote biodiversity?
The protection of biodiversity and of ecosystem services ought to be a top priority, taken into consideration in the course of all human activities, because we depend on it fully now and for the future. In this context, we note that the ecological problems related to the cultivation of GE crops fail to differ in any fundamental way from the ecological problems associated with agriculture in general, except that they usually involve the application of much lower quantities of chemicals and thus tend to leave the environments in and adjacent to where they are grown in better condition than do the conventional ones. Higher productivity on cultivated lands, which is one outcome of growing GE crops, protects biodiversity by sparing lands not intensively cultivated, whereas relatively non-productive agriculture practised is highly destructive to biodiversity, since it consumes more land in an often destructive way, even though more biodiversity may be preserved among the crops themselves than in industrialized, large fields, especially if hedgerows and woodlands are not encouraged in near proximity. The major preservation of biodiversity, however, does not take place among crops! If weeds are present that are closely related to the crops, they may acquire immunity to the effects from which the crops were protected and be more difficult to control among them. The production of superweeds as a result of hybridization between cultivated crops and their wild relatives is essentially a myth. The definition of 'organic' production in the U.S. and elsewhere unjustifiably rules out GE crops, often in such a way as to damage the environment more than would be the case otherwise. Unless the definition of 'organic' is a problem, or close relatives to the crops are weedy among them, there seems to be essentially no ecological risk involved in growing GE crops.


VC-dimension of univariate decision trees.
In this paper, we give and prove the lower bounds of the Vapnik-Chervonenkis (VC)-dimension of the univariate decision tree hypothesis class. The VC-dimension of the univariate decision tree depends on the VC-dimension values of its subtrees and the number of inputs. Via a search algorithm that calculates the VC-dimension of univariate decision trees exhaustively, we show that our VC-dimension bounds are tight for simple trees. To verify that the VC-dimension bounds are useful, we also use them to get VC-generalization bounds for complexity control using structural risk minimization in decision trees, i.e., pruning. Our simulation results show that structural risk minimization pruning using the VC-dimension bounds finds trees that are more accurate as those pruned using cross validation.


Color matching at high illuminances: photopigment optical density and pupil entry.
Changes in the effective optical density of the cones are sufficient to explain changes in color matches with retinal illuminance and pupil entry. We performed three experiments. In the first experiment, six observers made color matches under both bleached and unbleached conditions to a series of six standard wavelengths. The effects of bleaching could be modeled by a decrease in optical density of the L and M cone photopigments. Slight spectral shifts in the peak wavelengths of the photopigments were required for different observers. In the second experiment we varied retinal illuminance of the color-matching field from 2.4 to 5.4 log Td for a series of long-wavelength primaries. The shape of the color match versus the intensity function was unchanged by the wavelength composition of the matching field. In the third experiment we measured the change in color match with retinal illuminance for different pupil entry positions. At low luminances there was a marked dependence of the color match on pupil entry positions. At high illuminance there was only a small dependence. The half-bleach illuminance values varied as expected from the Stiles-Crawford I effect. We conclude that for wavelengths > 540 nm, changes in color matches with bleaching and pupil entry can be explained by changes in the effective optical density of the cones.


Short report: primaquine-tolerant Plasmodium vivax in an Italian traveler from Guatemala.
Plasmodium vivax infections caused by strains with low sensitivity to primaquine are widespread in the Western Pacific and Southeast Asia, and have been recently reported from Central America as well. We report a case of primaquine failure in a P. vivax infection acquired in Guatemala. A 28-year-old Italian woman developed two months after returning from Guatemala a vivax malaria attack that was treated with a standard chloroquine course (1,500 mg over three days) combined with primaquine (15 mg/day for 14 days). Two months later, she had a relapse that was again treated with chloroquine and primaquine at the same doses. After two more months, a second relapse occurred: this time primaquine (30 mg/day for 14 days was administered; the patient remained well during a follow-up period of six months and all parasitologic examination results were negative. Doses of primaquine as high as 6 mg/kg total dose may be indicated in the treatment of vivax malaria cases from Central America.


Temperament and externalizing behavior as mediators of genetic risk on adolescent substance use.
Understanding how specific genes contribute to risk for addiction remains challenging. This study tests whether childhood temperament and externalizing behavior in early adolescence account for a portion of the association between specific genetic variants and substance use problems in late adolescence. The sample consisted of 487 adolescents from the Michigan Longitudinal Study, a high-risk sample (70.2% male, 81.7% European American ancestry). Polymorphisms across serotonergic (SLC6A4, 5-HTTLPR), dopaminergic (DRD4, u-VNTR), noradrenergic (SLC6A2, rs36021), and GABAergic (GABRA2, rs279858; GABRA6, rs3811995) genes were examined given prior support for associations with temperament, externalizing behavior, and substance use problems. The temperament traits behavioral control and resiliency were assessed using interviewer ratings (ages 9-11), and externalizing behavior (ages 12-14) was assessed using teacher ratings. Self-reported substance use outcomes (ages 15-17) included maximum alcoholic beverages consumed in 24 hours, and frequency of past year cigarette and marijuana use. Behavioral control, resiliency, and externalizing behavior accounted for the associations between polymorphisms in noradrenergic and GABAergic genes and substance use in late adolescence. Individual differences in emotional coping and behavioral regulation represent nonspecific neurobiological underpinnings for an externalizing pathway to addiction. (PsycINFO Database Record


Implementing Family-Centered Care Through Facilitated Sensemaking.
The Society of Critical Care Medicine has released updated recommendations for care of the family in neonatal, pediatric, and adult intensive care units. Translation of the recommendations into practice may benefit from a supporting theoretical framework. Facilitated sensemaking is a mid-range theory built from the same literature that formed the basis for recommendations within the guidelines. The process of facilitated sensemaking may be used to help nurses adopt the SCCM recommendations into practice through the development of caring relationships, promoting family presence, teaching family engagement strategies, and supporting families with communication, information gathering, and participation in decision-making.


Neonatal hypothyroidism permanently alters follicle-stimulating hormone and luteinizing hormone production in the male rat.
Transient neonatal hypothyroidism, induced with the goitrogen 6-n-propyl-2-thiouracil (PTU), results in dramatic increases in both testis size and sperm production in the adult rat. The observed increases in testis size and function occur in the presence of normal circulating testosterone levels. However, circulating gonadotropin levels are chronically reduced by 30-50% at all times in treated males. To better understand the permanent reduction in serum gonadotropin levels following transient neonatal hypothyroidism, we conducted a series of experiments to evaluate pituitary and hypothalamic function in the adult male PTU-treated rat. PTU treatment led to a significant reduction in GnRH-stimulated LH production. Castration resulted in 3.9- to 8.5-fold increases in circulating gonadotropin levels in both treated and control males; however, the absolute increases were significantly reduced in treated males. In contrast to circulating levels, pituitary gonadotropin contents did not increase in treated males after castration. PTU treatment did not lead to a reduction in the density of either luteotropes or folliculotropes, and both cell types increased in size and density after castration. The relative concentrations of both gonadotropin beta-subunit messenger RNAs increased more slowly in treated males than in controls after castration. Thus, although treated rats have the intrinsic ability to produce normal circulating levels of LH and FSH, gonadal feedback and an overall reduction in gonadotrope synthetic ability combine to produce the chronically reduced circulating levels of these hormones.


Studies on the mechanism of phagocytosis. I. Requirements for circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane.
These experiments were designed to evaluate the role of macrophage plasma membrane receptors for the third component of complement (C) and for the Fc portion of IgG in the ingestion phase of phagocytosis. Sheep erythrocyte (E) were coated with anti-E IgG [E(IgG)]; these E(IgG) were then attached to cultivated monolayers of mouse peritoneal macrophages under conditions which reversibly inhibit ingestion of E(IgG). The E(IgG)-macrophage complexes were further incubated under similar conditions with an antimacrophage IgG fraction which blocks Fc receptor-mediated ingestion but has no effect upon ingestion mediated by other phagocytic receptors. When these cultures were subsequently incubated under conditions optimal for particle ingestion, phagocytosis of the IgG-coated erythrocytes did not occur; the erythrocytes remained bound to the Fc receptors of the macrophage plasma membrane. To determine whether ligands must cover the entire surface of an attached particle to permit ingestion of that particle, C-coated E [E(IgM)C] were bound to the C receptors of thioglycollate-induced (activated) macrophages at 4 degrees C. E(IgM)C-macrophage complexes were then trypsinized at 4 degrees C, a procedure which resulted in cleavage of erythrocyte-bound C3b molecules to a form of C3 not recognized by the macrophage receptors for C3b. Under the conditions used, trypsin did not affect the attachment of E(IgM)C to the macrophage surface or the macrophage receptors for C3b. When these trypsin treated E(IgM)C-macrophage complexes were incubated at 37 degrees C, the bound E(IgM)C were not ingested; the erythrocytes remained attached to the macrophage plasma membrane via the macrophage's C receptors. These results indicate that attachment of a particle to specific receptors on the macrophage plasma membrane is not sufficient to trigger ingestion of that particle. Rather, ingestion requires the sequential, circumferential interaction of particle-bound ligands with specific plasma membrane receptors not involved in the initial attachment process.


How good is communication between primary care physicians and subspecialty consultants?
We prospectively studied the communication between 27 referring practitioners and their consultants for 464 consecutive patient referrals from a general internal medicine group practice at a university medical center. The rates of referral among practitioners varied from 0 to 28.1 per 100 patients visits. Though referring physicians provided patient background information in 98% of the cases, they made explicit the purpose of the referral in only 76% of the cases. They contacted consultants directly in only 9% of the cases. In return, consultants communicated their findings to referring practitioners in only 55% of the consultations. Referring physicians who personally contacted consultants or who supplied them with more clinical information were more likely to learn the results of the consultation. While communication between the referring physicians and consultants in this setting is limited, it may be improved if referring physicians supply more clinical information to consultants and contact them directly.


Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells.
The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit+ cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c-kit+ cells that colocalize with tyrosine kinase receptor 2 (VEGF-R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia-induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia-inducible factor (HIF)-1α. Furthermore, sildenafil depressed the number of CXCR4+ cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM-derived c-kit+ cells in the pulmonary tissue. The attenuation of the recruitment of BM-derived c-kit+ cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling.


Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses.
A network of conserved proteases known as the intramitochondrial quality control (IMQC) system is central to mitochondrial protein homeostasis and cellular health. IMQC proteases also appear to participate in establishment of signaling cues for mitochondrion-to-nucleus communication. However, little is known about this process. Here, we show that in Saccharomyces cerevisiae, inactivation of the membrane-bound IMQC protease Oma1 interferes with oxidative-stress responses through enhanced production of reactive oxygen species (ROS) during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic prevention of ROS accumulation in Oma1-deficient cells restores this defective TOR signaling. Additionally, inactivation of the Oma1 ortholog in the human fungal pathogen Candida albicans also alters TOR signaling and, unexpectedly, leads to increased resistance to neutrophil killing and virulence in the invertebrate animal model Galleria mellonella Our findings reveal a novel and evolutionarily conserved link between IMQC and TOR-mediated signaling that regulates physiological plasticity and pancellular oxidative-stress responses.


Separation and purification of the antioxidant compound hispidin from mushrooms by molecularly imprinted polymer.
A new molecularly imprinted polymer (MIP), prepared by hispidin as the template molecule, was synthesized and applied as an adsorbent phase for solid phase extraction (SPE) to isolate and enrich hispidin from eight species of mushrooms. The optimization of synthesis and the adsorption behaviors of the MIPs were investigated in detail. In comparison with C18-SPE, MIP-SPE displayed high selectivity and good affinity for hispidin for extract of Phellinus igniarius. The antioxidant activity of the extracts after using the MIPs was evaluated by free radical scavenging activity, and inhibition of erythrocyte hemolysis, and lipid peroxidation. This developed method provided a rapid, selective, and effective approach for separation and enrichment of active compounds from the natural products.


Processing of angular motion and gravity information through an internal model.
The vestibular organs in the base of the skull provide important information about head orientation and motion in space. Previous studies have suggested that both angular velocity information from the semicircular canals and information about head orientation and translation from the otolith organs are centrally processed in an internal model of head motion, using the principles of optimal estimation. This concept has been successfully applied to model behavioral responses to classical vestibular motion paradigms. This study measured the dynamic of the vestibuloocular reflex during postrotatory tilt, tilt during the optokinetic afternystagmus, and off-vertical axis rotation. The influence of otolith signal on the VOR was systematically varied by using a series of tilt angles. We found that the time constants of responses varied almost identically as a function of gravity in these paradigms. We show that Bayesian modeling could predict the experimental results in an accurate and consistent manner. In contrast to other approaches, the Bayesian model also provides a plausible explanation of why these vestibulooculo motor responses occur as a consequence of an internal process of optimal motion estimation.


Attitudes of Israeli Rheumatologists to the Use of Medical Cannabis as Therapy for Rheumatic Disorders.
While medical cannabis has been used for thousands of years in the treatment of pain and other symptoms, evidence-based use is limited and practitioners face multiple areas of uncertainty regarding the rational use of these compounds. Nonetheless, an increasing public interest and advocacy in favor of medical cannabis is causing the issue to be encountered ever more frequently by physicians in different fields of medicine and particularly in rheumatology. In view of this situation, we have surveyed the attitudes of Israeli rheumatologists to the use of medical cannabis. As rheumatologists are specialized in caring for patients presenting with musculoskeletal complaints, the confidence of rheumatologists' knowledge of cannabinoids was surveyed. All members of the Israeli Society of Rheumatology were surveyed by e-mail for their confidence and knowledge of cannabinoids and their perceived competence to prescribe herbal cannabis. A total of 23 out of 119 (19.3%) Israeli rheumatologists approached returned the questionnaire. Three-quarters of responders were not confident about their knowledge of cannabinoid molecules or ability to write a prescription for herbal cannabis, and 78% were not confident to write a prescription for herbal cannabis; 74% of responders held the opinion that there was some role for cannabinoids in the management of rheumatic disease. Israeli rheumatologists lack confidence in their knowledge of cannabinoids in general, yet are open to the possibility of introducing this treatment. Additional data and guidance are necessary in order to allow rational utilization of cannabinoids for management of rheumatic pain.


Translation and construct validity of the Trunk Control Measurement Scale in children and youths with brain lesions.
Trunk control is essential for the performance of everyday tasks. Children with neurological impairments such as cerebral palsy (CP) or acquired brain injury (ABI) commonly show impaired trunk control, which leads to restriction in functional activities. The aim of this study was to provide construct validity of the German version of the Trunk Control Measurement Scale (TCMS). We investigated convergent and discriminant construct validity by comparing the TCMS with the Gross Motor Function Classification System (GMFCS) and the modified Timed up and Go (mTUG). Several TCMS items were validated with force plate measurements. The centre of pressure (COP) parameters included the standard deviation of amplitude, the COP displacement and the area. Fifty-two children with CP and ten children with ABI (mean age 10.9 years 4.9 months, range 5-18 years, GMFCS levels I-IV) participated. Spearman rank correlation coefficients calculated between the TCMS and the GMFCS and mTUG amounted to -0.75 and -0.42, respectively. Validating TCMS items with COP parameters was difficult. Nevertheless, the results support the validity of the TCMS in children with brain lesions. This study provides paediatric therapists working in German speaking countries with a valid tool to assess impaired trunk control in these children. Although originally designed for children with CP, our results show that the TCMS may also be applicable to children with ABI, but more research is needed on a larger population.


Making experimental data tables in the life sciences more FAIR: a pragmatic approach.
Making data compliant with the FAIR Data principles (Findable, Accessible, Interoperable, Reusable) is still a challenge for many researchers, who are not sure which criteria should be met first and how. Illustrated with experimental data tables associated with a Design of Experiments, we propose an approach that can serve as a model for research data management that allows researchers to disseminate their data by satisfying the main FAIR criteria without insurmountable efforts. More importantly, this approach aims to facilitate the FAIR compliance process by providing researchers with tools to improve their data management practices.


1H and 31P benchtop NMR of liquids and solids used in and/or produced during the manufacture of methamphetamine by the HI reduction of pseudoephedrine/ephedrine.
In this study, the use of benchtop NMR spectroscopy in the analysis of solids and liquids used and/or produced during the HI reduction of pseudoephedrine was evaluated. The study focused on identifying organic precursors and phosphorus containing compounds used in and/or produced during the manufacturing process. Samples taken from clandestine laboratories, where this synthesis process was suspected of occurring, were also analysed and evaluated. Benchtop NMR was able to distinguish between ephedrine, pseudoephedrine and methamphetamine as the free base and hydrochloride salt. This technique was also effective at identifying and distinguishing between phosphorus containing compounds used and/or produced during the manufacture of methamphetamine. Benchtop NMR was also determined to be effective at analysing samples from suspected clandestine laboratories.


Salivary antioxidants of male athletes after aerobic exercise and garlic supplementation on: A randomized, double blind, placebo-controlled study.
Production of reactive oxygen species and reactive nitrogen species is a natural biological event in metabolism. However, the presence of antioxidants can highly reduce the negative effect of free radicals. Thus, the efficiency of antioxidant system in the physiology of exercise is very important. Considering the known antioxidant capacity of garlic, the purpose of this study was to evaluate the effect on combining 14 days aerobic exercise till exhaustion with garlic extract supplementation on the antioxidant capacity of saliva. Sixteen young men volunteered to participate in this randomized, double blind, placebo-controlled study and were randomly placed into two groups, placebo (Group I) and garlic extract (Group II). The participants performed exhaustive aerobic exercise on a treadmill before and after supplementation. Their unstimulated salivary samples were collected before, immediately after, and 1 h after the activity. The antioxidant activity in terms of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) was then measured in the collected samples using their specific substrates. A significant increase in salivary antioxidant activity of SOD, POD, and CAT was observed in saliva of the supplement group compared to the placebo group (P ≤ 0.05). The findings from this study suggest that increased activity of antioxidant enzymes could possibly decrease exercise-induced oxidative damage in male athletes.


Adiponectin, Free Fatty Acids, and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Acute Coronary Syndrome.
In observational cohorts, adiponectin is inversely associated and free fatty acids (FFAs) are directly associated with incident coronary heart disease (CHD). Adiponectin tends to be reduced and FFAs elevated in type 2 diabetes. We investigated relationships of adiponectin and FFA and major adverse cardiovascular events (MACEs) and death in patients with acute coronary syndrome (ACS) and type 2 diabetes using data from the AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus) trial, which compared the PPAR-α/γ agonist aleglitazar with placebo. Using Cox regression adjusted for demographic, laboratory, and treatment variables, we determined associations of baseline adiponectin and FFAs, or the change in adiponectin and FFAs from baseline, with MACEs (cardiovascular death, myocardial infarction, or stroke) and death. A twofold higher baseline adiponectin (n = 6,998) was directly associated with risk of MACEs (hazard ratio [HR] 1.17 [95% CI 1.08-1.27]) and death (HR 1.53 [95% CI 1.35-1.73]). A doubling of adiponectin from baseline to month 3 (n = 6,325) was also associated with risk of death (HR 1.20 [95% CI 1.03-1.41]). Baseline FFAs (n = 7,038), but not change in FFAs from baseline (n = 6,365), were directly associated with greater risk of MACEs and death. There were no interactions with study treatment. In contrast to prior observational data for incident CHD, adiponectin is prospectively associated with MACEs and death in patients with type 2 diabetes and ACS, and an increase in adiponectin from baseline is directly related to death. These findings raise the possibility that adiponectin has different effects in patients with type 2 diabetes and ACS than in populations without prevalent cardiovascular disease. Consistent with prior data, FFAs are directly associated with adverse outcomes.


Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets.
Platelets store self-agonists such as ADP and serotonin in dense core granules. Although exocytosis of these granules is crucial for hemostasis and thrombosis, the underlying mechanism is not fully understood. Here, we show that incubation of permeabilized platelets with unprenylated active mutant Rab27A-Q78L, wild type Rab27A, and Rab27B inhibited the secretion, whereas inactive mutant Rab27A-T23N and other GTPases had no effects. Furthermore, we affinity-purified a GTP-Rab27A-binding protein in platelets and identified it as Munc13-4, a homologue of Munc13-1 known as a priming factor for neurotransmitter release. Recombinant Munc13-4 directly bound to GTP-Rab27A and -Rab27B in vitro, but not other GTPases, and enhanced secretion in an in vitro assay. The inhibition of secretion by unprenylated Rab27A was rescued by the addition of Munc13-4, suggesting that Munc13-4 mediates the function of GTP-Rab27. Thus, Rab27 regulates the dense core granule secretion in platelets by employing its binding protein, Munc13-4.


Protection from chemotherapy-induced alopecia in a rat model.
Alopecia (hair loss) is among the most distressing side effects of cancer chemotherapy. Little progress has been made, however, in its prevention or treatment, partly because of the lack of suitable experimental model. In recent work on the treatment of myelogenous leukemia in the rat, the following observations were made: (i) treatment of 8-day-old rats with cytosine arabinoside consistently produced alopecia, and (ii) ImuVert, a biologic response modifier derived from the bacterium Serratia marcescens, uniformly produced complete protection against the alopecia. In subsequent experiments, both cyclophosphamide and doxorubicin also produced alopecia in this model, and the doxorubicin-induced alopecia was prevented by treatment with ImuVert. The potential relevance of these observations to chemotherapy-induced alopecia in the clinical setting should be examined.


Effect of Chlorogenic Acid Supplementation in MPTP-Intoxicated Mouse.
Oxidative stress and neuroinflammation play a key role in dopaminergic (DA) neuronal degeneration, which results in the hindrance of normal ongoing biological processes in the case of Parkinson's disease. As shown in several studies, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, different behavioral parameters have suggested motor impairment and damage of antioxidant defence. Thus, some specific biological molecules found in medicinal plants can be used to inhibit the DA neuronal degeneration through their antioxidant and anti-inflammatory activities. With this objective, we studied chlorogenic acid (CGA), a naturally occurring polyphenolic compound, for its antioxidant and anti-inflammatory properties in MPTP-intoxicated mice. We observed significant reoccurrence of motor coordination and antioxidant defence on CGA supplementation, which has been in contrast with MPTP-injected mice. Moreover, in the case of CGA-treated mice, the enhanced expression of tyrosine hydroxylase (TH) within the nigrostriatal region has supported its beneficial effect. The activation of glial cells and oxidative stress levels were also estimated using inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP) immunoreactivity within substantia nigra (SN) and striatum of MPTP-injected mice. Administration of CGA has prevented the neuroinflammation in SN by regulating the nuclear factor-κB expression in the MPTP-induced group. The significant release of certain pro-inflammatory mediators such as tumor necrosis factor-α and interleukin (IL)-1β has also been inhibited by CGA with the enhanced expression of anti-inflammatory cytokine IL-10. Moreover, reduced GFAP staining within the nigrostriatal region has supported the fact that CGA has significantly helped in the attenuation of astrocyte activation. Hence, our study has shown that CGA supplementation shows its therapeutic ability by reducing the oxidative stress and neuroinflammation in MPTP-intoxicated mice.


Pump-limited, 203 W, single-frequency monolithic fiber amplifier based on laser gain competition.
We present high power results of a Yb-doped fiber amplifier seeded with a combination of broad and single-frequency laser signals. This two-tone concept was used in conjunction with externally applied or intrinsically formed thermal gradients to demonstrate combined stimulated Brillouin scattering suppression in a copumped monolithic, polarization-maintaining (PM) fiber. Depending on the input parameters and the thermal gradient, the output power of the single-frequency signal ranged from 80 to 203 W with slope efficiencies from 70% to 80%. The 203 W amplifier was pump limited and is, to the best of our knowledge, the highest reported in the literature for monolithic, PM single-frequency fiber amplifiers.


Assessing Biological Response to Bevacizumab Using 18F-Fluoromisonidazole PET/MR Imaging in a Patient with Recurrent Anaplastic Astrocytoma.
We present our initial experience in using single modality fluoromisonidazole (FMISO) PET/MR imaging to noninvasively evaluate the biological effects induced by bevacizumab therapy in a patient treated for recurrent high grade glioma. In this index patient, bevacizumab therapy resulted in the development of nonenhancing tumor characterized by reduced diffusion and markedly decreased FMISO uptake in the setting of maintained CBF and CBV. These observations suggest that the dynamic biological interplay between tissue hypoxia and vascular normalization occurring within treated recurrent high grade glioma can be captured utilizing FMISO PET/MR imaging.


Suppression of radiation in a momentum-nonconserving nonlinear interaction.
We have considered the quadratic nonlinear radiation from a thin dipole sheet in front of a mirror. Radiation at the second-harmonic (SH) frequency on incidence of a fundamental field can be inhibited or enhanced independently of the SH field intensity stored between the nonlinear layer and the mirror. We have shown that this apparent contradiction can be fully understood only if the quadratic nonlinear interaction includes terms with a momentum mismatch equal to the magnitude of the SH field wave vector, such as the term that accounts for transfer of energy from the reflected SH field back to the incident fundamental.


Low power resonant optical excitation of an optomechanical cavity.
We demonstrate the actuation of a double beam opto-mechanical cavity with a sinusoidally varying optical input power. We observe the driven mechanical motion with only 200 nW coupled to the optical cavity mode. We also investigate the pump power dependence of the radio-frequency response for both the driving power and the probe power. Finally, we investigate the dependence of the amplitude of the mechanical motion on mechanical cavity quality factor.


Caring for Carers: Positive and Normative Challenges for Future Research on Carer Spillover Effects in Economic Evaluation.
Many individuals rely on family and friends to provide care outside of the formal healthcare sector. The need for caring is driven by many factors, including government policies toward health and social care, and increased prevalence of chronic and comorbid conditions. Informal care may give rise to "spillover" effects from the health of a cared-for individual to the health of carers. Spillover effects are rarely reflected in economic evaluations, in spite of growing research interest in this area, and recommendations from bodies such as the National Institute for Health and Care Excellence (NICE) and the Second Panel on Cost-Effectiveness that effects of this type be included in cost-effectiveness analysis. We explore the positive and normative issues to which the inclusion of carer spillover effects in economic evaluation may give rise and how future research might begin to address these challenges. Positive challenges include the identification of causal rather than coincidental impacts on carers, selection into caring, and the measurement and treatment of spillover effects. The normative issues are related to these challenges, and particularly include impacts on equity, and spillovers that improve rather than reduce the health of carers. We argue that challenges including spillover effects in economic evaluation are considerable. Avenues for future research and possible solutions to these challenges include a re-orientation of analytic perspectives so that the impacts of caring on carers are accounted for where appropriate, and the design of studies to collect robust evidence to inform debate and guidance development in this area.


Transcatheter occlusion of antegrade pulmonary blood flow in children with univentricular heart.
This study aims to evaluate the results of transcatheter occlusion of antegrade pulmonary blood flow in children with univentricular heart. Medical data of a total of seven patients (4 females, 3 males; median age 11.7 years; range, 1 to 24 years) who underwent transcatheter occlusion of the antegrade pulmonary blood flow following Glenn shunt or Fontan operation between September 2014 and January 2017 were retrospectively analyzed. Data including demographic and clinical characteristics of the patients, type of surgery, echocardiographic and cardiac catheterization findings were recorded. Four patients had a previous pulmonary artery banding operation, while three had pulmonary stenosis. Two patients had facial and upper extremity edema after Glenn operation, one had prolonged pleural effusion, one had prolonged pleural effusion after Fontan operation, and one developed dyspnea and effort intolerance several years after Fontan operation. In two patients, antegrade pulmonary blood flow was occluded to decrease systemic ventricular load before surgery. The Amplatzer Septal Occluder was used in five patients and the Amplatzer Vascular Plug-2 was used in two patients. Two patients developed transient, complete atrioventricular block during the procedure and the procedure was terminated early in one of these patients. Transient hemolysis was observed in one patient following the operation. Transcatheter occlusion of antegrade pulmonary blood flow is an effective alternative to surgery in patients with hemodynamic compromise after Glenn shunt or Fontan operation.


Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.
Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.


Exploring the utility of assistive artificial intelligence for ultrasound scanning in regional anesthesia.
Ultrasound-guided regional anesthesia (UGRA) involves the acquisition and interpretation of ultrasound images to delineate sonoanatomy. This study explores the utility of a novel artificial intelligence (AI) device designed to assist in this task (ScanNav Anatomy Peripheral Nerve Block; ScanNav), which applies a color overlay on real-time ultrasound to highlight key anatomical structures. Thirty anesthesiologists, 15 non-experts and 15 experts in UGRA, performed 240 ultrasound scans across nine peripheral nerve block regions. Half were performed with ScanNav. After scanning each block region, participants completed a questionnaire on the utility of the device in relation to training, teaching, and clinical practice in ultrasound scanning for UGRA. Ultrasound and color overlay output were recorded from scans performed with ScanNav. Experts present during the scans (real-time experts) were asked to assess potential for increased risk associated with use of the device (eg, needle trauma to safety structures). This was compared with experts who viewed the AI scans remotely. Non-experts were more likely to provide positive and less likely to provide negative feedback than experts (p=0.001). Positive feedback was provided most frequently by non-experts on the potential role for training (37/60, 61.7%); for experts, it was for its utility in teaching (30/60, 50%). Real-time and remote experts reported a potentially increased risk in 12/254 (4.7%) vs 8/254 (3.1%, p=0.362) scans, respectively. ScanNav shows potential to support non-experts in training and clinical practice, and experts in teaching UGRA. Such technology may aid the uptake and generalizability of UGRA. NCT04918693.


Changes in children's wellbeing in Bradford during COVID-19: The Born in Bradford COVID-19 longitudinal research study.
Background: Concerns have been raised about the potential impact of COVID-19 and associated lockdown measures on child mental wellbeing, but emerging evidence suggests mixed results and there is a dearth of information from ethnically diverse samples. The current study aims to explore the impact of the pandemic on wellbeing using longitudinal data collected from the multi-ethnic Born in Bradford family cohort study. Methods: Within-child changes in wellbeing were explored using data collected pre-pandemic and again during the first UK lockdown for 500 children aged 7-13 from a range of ethnic and socioeconomic backgrounds, using self-reported feelings of happiness and sadness. Associations between changes in wellbeing, demographic factors, quality of social relationships and physical activity levels were explored using multinomial logistic regression models. Results: In this sample, 55% of children reported no change in their wellbeing from pre-pandemic to during the first lockdown (n=264). Children of Pakistani heritage were more than twice as likely to report feeling sad less often than White British children (RRR: 2.61, 95% CI: 1.23, 5.51) during the first lockdown. Those who reported being left out by other children before the pandemic were over three times as likely than those who did not (RRR: 3.72: 1.51, 9.20) to report feeling sad less often during the pandemic. Around a third of children reported feeling happier (n=152, 31.6%), but these changes did not relate to any of the explanatory variables included in this analysis. Conclusion: Many children in this study reported no changes in their wellbeing during the first UK lockdown compared to before the pandemic and some described improved wellbeing. These findings suggest that children have coped well with the significant changes over the past year, though targeted support, particularly for those children who felt excluded before the pandemic, would be beneficial.


From image processing to computational neuroscience: a neural model based on histogram equalization.
There are many ways in which the human visual system works to reduce the inherent redundancy of the visual information in natural scenes, coding it in an efficient way. The non-linear response curves of photoreceptors and the spatial organization of the receptive fields of visual neurons both work toward this goal of efficient coding. A related, very important aspect is that of the existence of post-retinal mechanisms for contrast enhancement that compensate for the blurring produced in early stages of the visual process. And alongside mechanisms for coding and wiring efficiency, there is neural activity in the human visual cortex that correlates with the perceptual phenomenon of lightness induction. In this paper we propose a neural model that is derived from an image processing technique for histogram equalization, and that is able to deal with all the aspects just mentioned: this new model is able to predict lightness induction phenomena, and improves the efficiency of the representation by flattening both the histogram and the power spectrum of the image signal.


The initial effects of an elbow mobilization with movement technique on grip strength in subjects with lateral epicondylalgia.
This preliminary study indicates the proportion of patients with lateral epicondylalgia that demonstrate a favourable initial response to a manual therapy technique - the mobilization with movement (MWM) for tennis elbow. Twenty-five subjects with lateral epicondylalgia participated. In a one-group pretest - post-test design, we measured (1) pain with active motion, (2) pain-free grip strength and, (3) maximum grip strength before and after a single intervention of MWM. Results of the study indicate that MWM was effective in allowing 92% of subjects to perform previously painful movements pain-free, and improving grip strength immediately afterwards. Significant differences were found between the grip strength of the affected and unaffected limbs prior to the intervention. Both pain-free grip strength and maximum grip strength of the affected limb increased significantly following the intervention. Pain-free grip strength increased by a greater magnitude than maximum grip strength. It can be concluded that MWM is a promising intervention modality for the treatment of patients with Lateral Epicondylalgia. Pain-free grip strength is a more responsive measure of outcome than maximum grip strength for patients with Lateral Epicondylalgia. Further research is warranted to investigate the long-term effectiveness of MWM in the treatment of impairment and disability resulting from Lateral Epicondylalgia.


Fiber-optic polarization and phase modulator utilizing transparent piezofilm with indium tin oxide electrodes.
A highly efficient optical polarization and phase modulator formed by the placement of a thin transparent piezofilm with indium tin oxide electrodes directly in the path of the output from an optical fiber is presented. Various configurations that differ in the clamping conditions, utilization of epoxy, and optical arrangement are presented. For a film thickness of 63.9 µm, a linear phase-shifting coefficient of 0.131 rad/voltage peak (Vp) at 2 kHz and of 0.508 rad/Vp at 7.4 kHz is demonstrated. An intrinsic birefringence of 0.0328 between the directions along the stretch and its perpendicular in the plane of the film has been measured. The polarization modulation coefficient was determined to be 0.323 rad/Vp at 8.423 kHz, corresponding to a half-wave voltage of 8.353 Vp. Applications of the device involving concurrent spatiotemporal polarization and phase modulation are indicated.


Chitosan hemostatic dressing for renal parenchymal wound sealing in a porcine model: implications for laparoscopic partial nephrectomy technique.
This study was to evaluate the feasibility of using a novel chitosan hemostatic dressing to control hemorrhage and urinary leakage by sealing off the parenchymal wound following LPN. Nine heparinized domestic swine underwent bilateral laparoscopic partial nephrectomies involving either a polar or wedge resection. Estimated blood loss (EBL), hemostatic score, operative time, and adhesion score of the chitosan dressing were documented during LPN. Retrograde pyelography was performed to assess urinary leakage. Of 18 procedures, complete hemostasis after deployment of the chitosan dressing was successfully achieved in 17 of them. The hemostasis score improved significantly after the deployment in both polar (P<0.001) and wedge (P=0.017) resections. The rate of successful pyelocaliceal sealing was 85% (11/13) in polar and 60% (3/5) in wedge resections. Application of a bandage in wedge resections was fraught with greater difficulties in terms of number of applications required and prolonged operative time. However, the differences between this group and polar resection were not statistically significant. The chitosan hemostatic dressing is capable of being used in LPN procedures as a primary or supplemental material for controlling parenchymal hemorrhage and sealing the renal collecting system in the animal model.


The PfRCR complex bridges malaria parasite and erythrocyte during invasion.
The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex1, containing PfRH5 (refs. 2,3), PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies3-6 or nanobodies1 against each of these conserved proteins, making them the leading blood-stage malaria vaccine candidates. However, little is known about how PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex7,8, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane9, instead showing that a rigid, disulfide-locked PfRH5 can mediate efficient erythrocyte invasion. We show, through modelling and an erythrocyte-binding assay, that PfCyRPA-binding antibodies5 neutralize invasion through a steric mechanism. We determine the structure of PfRIPR, showing that it consists of an ordered, multidomain core flexibly linked to an elongated tail. We also show that the elongated tail of PfRIPR, which is the target of growth-neutralizing antibodies6, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. A modular PfRIPR is therefore linked to the merozoite membrane through an elongated tail, and its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides fresh insight into the molecular mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.


Cardiometabolic health disparities in native Hawaiians and other Pacific Islanders.
Elimination of health disparities in the United States is a national health priority. Cardiovascular disease, diabetes, and obesity are key features of what is now referred to as the "cardiometabolic syndrome," which disproportionately affects racial/ethnic minority populations, including Native Hawaiians and other Pacific Islanders (NHOPI). Few studies have adequately characterized the cardiometabolic syndrome in high-risk populations such as NHOPI. The authors systematically assessed the existing literature on cardiometabolic disorders among NHOPI to understand the best approaches to eliminating cardiometabolic health disparities in this population. Articles were identified from database searches performed in PubMed and MEDLINE from January 1998 to December 2008; 43 studies were included in the review. There is growing confirmatory evidence that NHOPI are one of the highest-risk populations for cardiometabolic diseases in the United States. Most studies found increased prevalences of diabetes, obesity, and cardiovascular risk factors among NHOPI. The few experimental intervention studies found positive results. Methodological issues included small sample sizes, sample bias, inappropriate racial/ethnic aggregation of NHOPI with Asians, and a limited number of intervention studies. Significant gaps remain in the understanding of cardiometabolic health disparities among NHOPI in the United States. More experimental intervention studies are needed to examine promising approaches to reversing the rising tide of cardiometabolic health disparities in NHOPI.


Identification of a novel gene, OASIS, which encodes for a putative CREB/ATF family transcription factor in the long-term cultured astrocytes and gliotic tissue.
Gliosis is a characteristic response of astrocytes to inflammation and trauma of the central nervous system (CNS). To study the mechanisms underlying gliosis, we performed differential display screening for genes specifically induced in long-term cultured astrocytes used as an in vitro gliosis model. We identified and characterized a gene (named OASIS, for old astrocyte specifically-induced substance) expressed in long-term cultured mouse astrocytes, or 'old astrocytes (OA)'. The OASIS gene encoded a putative transcription factor belonging to the cyclic AMP responsive element binding protein/activating transcription factor (CREB/ATF) gene family, with homology to box B-binding factor-2 (BBF-2), a Drosophila transcription factor. Its expression was developmentally regulated; OASIS mRNA was primarily expressed in the salivary gland and cartilage in the mouse embryo and it was transiently upregulated in the brain during postnatal two weeks. The expression became weaker in the adult brain. We also demonstrated that an expression of the OASIS mRNA was induced in response to the cryo-injury of the mouse cerebral cortex. The distribution pattern of the OASIS-positive cells in the injured cortex was very similar to that of the glial fibrillary acidic protein (GFAP)-positive cells. These results suggest that OASIS protein may play a role in gliotic events.


Differential regulation of genes encoding synaptic proteins by members of the Brn-3 subfamily of POU transcription factors.
The three members of the Brn-3 subfamily of POU transcription factors have distinct effects on target gene expression. We show that the promoter of the gene encoding the presynaptic nerve terminal protein SNAP-25 resembles previously characterised target genes in being activated by Brn-3a and Brn-3c, but being repressed by Brn-3b. Unlike other target genes, however, the SNAP-25 promoter can be activated by either the N- or C-terminal activation domains of Brn-3a. In contrast to the SNAP-25 gene, the gene encoding the synaptic vesicle protein synapsin 1 is activated by all the Brn-3 factors, the first gene for which this activation pattern has been reported Interestingly, however, similar activation by all three Brn-3 factors can be observed if the SNAP-25 promoter is truncated by removal of sequences from -2200 to -288 relative to the transcriptional start site. Moreover, a region of the SNAP-25 promoter from -283 to -126 can render a heterologous promoter responsive to activation by all three Brn-3 factors. Differences in promoter structure may thus result in differences in the response to different Brn-3 factors, thus allowing these factors to produce diverse activation patterns of neuronally expressed genes, such as those encoding different synaptic proteins.


Mathematical modelling of bacterial resistance to multiple antibiotics and immune system response.
Resistance of developed bacteria to antibiotic treatment is a very important issue, because introduction of any new antibiotic is after a little while followed by the formation of resistant bacterial isolates in the clinic. The significant increase in clinical resistance to antibiotics is a troubling situation especially in nosocomial infections, where already defenseless patients can be unsuccessful to respond to treatment, causing even greater health issue. Nosocomial infections can be identified as those happening within 2 days of hospital acceptance, 3 days of discharge or 1 month of an operation. They influence 1 out of 10 patients admitted to hospital. Annually, this outcomes in 5000 deaths only in UK with a cost to the National Health Service of a billion pounds. Despite these problems, antibiotic therapy is still the most common method used to treat bacterial infections. On the other hand, it is often mentioned that immune system plays a major role in the progress of infections. In this context, we proposed a mathematical model defining population dynamics of both the specific immune cells produced according to the properties of bacteria by host and the bacteria exposed to multiple antibiotics synchronically, presuming that resistance is gained through mutations due to exposure to antibiotic. Qualitative analysis found out infection-free equilibrium point and other equilibrium points where resistant bacteria and immune system cells exist, only resistant bacteria exists and sensitive bacteria, resistant bacteria and immune system cells exist. As a result of this analysis, our model highlights the fact that when an individual's immune system weakens, he/she suffers more from the bacterial infections which are believed to have been confined or terminated. Also, these results was supported by numerical simulations.


Aerobic Exercise Performance During Load Carriage and Acute Altitude Exposure.
Coffman, KE, Luippold, AJ, Salgado, RM, Heavens, KR, Caruso, EM, Fulco, CS, and Kenefick, RW. Aerobic exercise performance during load carriage and acute altitude exposure. J Strength Cond Res 34(4): 946-951, 2020-This study quantified the impact of combined load carriage and acute altitude exposure on 5-km running time-trial (TT) performance and self-selected pacing strategy. Furthermore, this study developed a velocity prediction tool (nomogram) for similar aerobic exercise tasks performed under various combinations of altitude and load stress. Nine volunteers (6M/3F, age: 24 ± 7 years, height: 171 ± 6 cm, body mass: 72 ± 7 kg, and V[Combining Dot Above]O2peak: 50.5 ± 5.2 ml·min·kg) completed a randomized, repeated-measures design protocol. Volunteers performed 3 familiarization (FAM) trials at sea level (SL; 250 m) with no-load carriage. Experimental testing included 3 self-paced, blinded 5-km running TT on a treadmill while carrying a 30% body mass external load at SL, moderate altitude (MA; 2000 m), and high altitude (HA; 3000 m). At SL, load carriage resulted in a 36% decrement in 5-km exercise performance in comparison with FAM trials (43 ± 7 vs. 32 ± 3 minutes; p < 0.001). Time required to complete the 5-km distance while carrying an external load was increased by 11% when performed at HA vs. SL (48 ± 7 vs. 43 ± 7 minutes; p = 0.001). TT pace was not different among experimental conditions (load carriage at SL, MA, and HA) until after 1 km of the running distance had been completed. Heart rate was not different among experimental conditions throughout the entire TT (170 ± 17 b·min). These data quantify the anticipated reduction in aerobic exercise performance under various combinations of acute altitude exposure and load carriage conditions. The self-paced running TT approach used presently allowed for development of an altitude-load nomogram for use in recreational, occupational, or military settings.


Apparent life-threatening events, facial dysmorphia and sleep-disordered breathing.
A standardized clinical evaluation and questionnaire was, beginning in 1985, applied to infants referred for an apparent life-threatening event (ALTE). All children who underwent this "core evaluation protocol" during a 10-year period were reviewed. Documentation of clinical complaints, symptoms and signs of sleep-disordered breathing, sleep/wake evaluation, systematic evaluation of the face and naso-oro-pharynx, nocturnal polygraphic recording, and systematic follow-up was conducted. A total of 346 infants had complete data sets, with a smaller group of 46 age-matched healthy infants as controls. A scorer blind to the clinical data analyzed the polygraphic investigation and divided the 346 referred into two groups. Group A, 42.6% of the population, included infants with no abnormal findings based on nocturnal polygraphic recording. These infants were no different from controls at initial evaluation and during follow-up. Group B, 57.4% of the population, included infants who had obstructive breathing during sleep which became more obvious over time. Two-thirds of these infants not only had clinical symptoms of sleep-disordered breathing but also had mild facial dysmorphia that could be seen clearly at 6 months of age. A subgroup of infants with apparent life-threatening events present an indication of a sleep-disordered breathing syndrome which is associated with a mild dysmorphia. This mild facial dysmorphia needs to be recognized early to distinguish these infants from other infants with apparent life-threatening events and to initiate appropriate treatment.


Colletotrichum species associated with anthracnose of Pyrus spp. in China.
Colletotrichum species are plant pathogens, saprobes, and endophytes on a range of economically important hosts. However, the species occurring on pear remain largely unresolved. To determine the morphology, phylogeny and biology of Colletotrichum species associated with Pyrus plants, a total of 295 samples were collected from cultivated pear species (including P. pyrifolia, P. bretschneideri, and P. communis) from seven major pear-cultivation provinces in China. The pear leaves and fruits affected by anthracnose were sampled and subjected to fungus isolation, resulting in a total of 488 Colletotrichum isolates. Phylogenetic analyses based on six loci (ACT, TUB2, CAL, CHS-1, GAPDH, and ITS) coupled with morphology of 90 representative isolates revealed that they belong to 10 known Colletotrichum species, including C. aenigma, C. citricola, C. conoides, C. fioriniae, C. fructicola, C. gloeosporioides, C. karstii, C. plurivorum, C. siamense, C. wuxiense, and two novel species, described here as C. jinshuiense and C. pyrifoliae. Of these, C. fructicola was the most dominant, occurring on P. pyrifolia and P. bretschneideri in all surveyed provinces except in Shandong, where C. siamense was dominant. In contrast, only C. siamense and C. fioriniae were isolated from P. communis, with the former being dominant. In order to prove Koch's postulates, pathogenicity tests on pear leaves and fruits revealed a broad diversity in pathogenicity and aggressiveness among the species and isolates, of which C. citricola, C. jinshuiense, C. pyrifoliae, and C. conoides appeared to be organ-specific on either leaves or fruits. This study also represents the first reports of C. citricola, C. conoides, C. karstii, C. plurivorum, C. siamense, and C. wuxiense causing anthracnose on pear.


Phylogenetic turnover along local environmental gradients in tropical forest communities.
While the importance of local-scale habitat niches in shaping tree species turnover along environmental gradients in tropical forests is well appreciated, relatively little is known about the influence of phylogenetic signal in species' habitat niches in shaping local community structure. We used detailed maps of the soil resource and topographic variation within eight 24-50 ha tropical forest plots combined with species phylogenies created from the APG III phylogeny to examine how phylogenetic beta diversity (indicating the degree of phylogenetic similarity of two communities) was related to environmental gradients within tropical tree communities. Using distance-based redundancy analysis we found that phylogenetic beta diversity, expressed as either nearest neighbor distance or mean pairwise distance, was significantly related to both soil and topographic variation in all study sites. In general, more phylogenetic beta diversity within a forest plot was explained by environmental variables this was expressed as nearest neighbor distance versus mean pairwise distance (3.0-10.3 % and 0.4-8.8 % of variation explained among plots, respectively), and more variation was explained by soil resource variables than topographic variables using either phylogenetic beta diversity metric. We also found that patterns of phylogenetic beta diversity expressed as nearest neighbor distance were consistent with previously observed patterns of niche similarity among congeneric species pairs in these plots. These results indicate the importance of phylogenetic signal in local habitat niches in shaping the phylogenetic structure of tropical tree communities, especially at the level of close phylogenetic neighbors, where similarity in habitat niches is most strongly preserved.


Yeast Volatomes Differentially Affect Larval Feeding in an Insect Herbivore.
Yeasts form mutualistic interactions with insects. Hallmarks of this interaction include provision of essential nutrients, while insects facilitate yeast dispersal and growth on plant substrates. A phylogenetically ancient chemical dialogue coordinates this interaction, where the vocabulary, the volatile chemicals that mediate the insect response, remains largely unknown. Here, we used gas chromatography-mass spectrometry, followed by hierarchical cluster and orthogonal partial least-squares discriminant analyses, to profile the volatomes of six Metschnikowia spp., Cryptococcus nemorosus, and brewer's yeast (Saccharomyces cerevisiae). The yeasts, which are all found in association with insects feeding on foliage or fruit, emit characteristic, species-specific volatile blends that reflect the phylogenetic context. Species specificity of these volatome profiles aligned with differential feeding of cotton leafworm (Spodoptera littoralis) larvae on these yeasts. Bioactivity correlates with yeast ecology; phylloplane species elicited a stronger response than fruit yeasts, and larval discrimination may provide a mechanism for establishment of insect-yeast associations. The yeast volatomes contained a suite of insect attractants known from plant and especially floral headspace, including (Z)-hexenyl acetate, ethyl (2E,4Z)-deca-2,4-dienoate (pear ester), (3E)-4,8-dimethylnona-1,3,7-triene (DMNT), linalool, α-terpineol, β-myrcene, or (E,E)-α-farnesene. A wide overlap of yeast and plant volatiles, notably floral scents, further emphasizes the prominent role of yeasts in plant-microbe-insect relationships, including pollination. The knowledge of insect-yeast interactions can be readily brought to practical application, as live yeasts or yeast metabolites mediating insect attraction provide an ample toolbox for the development of sustainable insect management.IMPORTANCE Yeasts interface insect herbivores with their food plants. Communication depends on volatile metabolites, and decoding this chemical dialogue is key to understanding the ecology of insect-yeast interactions. This study explores the volatomes of eight yeast species which have been isolated from foliage, from flowers or fruit, and from plant-feeding insects. These yeasts each release a rich bouquet of volatile metabolites, including a suite of known insect attractants from plant and floral scent. This overlap underlines the phylogenetic dimension of insect-yeast associations, which according to the fossil record long predate the appearance of flowering plants. Volatome composition is characteristic for each species, aligns with yeast taxonomy, and is further reflected by a differential behavioral response of cotton leafworm larvae, which naturally feed on foliage of a wide spectrum of broad-leaved plants. Larval discrimination may establish and maintain associations with yeasts and is also a substrate for designing sustainable insect management techniques.


Solid-state NMR studies of metal-free SOD1 fibrillar structures.
Copper-zinc superoxide dismutase 1 (SOD1) is present in the protein aggregates deposited in motor neurons of amyotrophic lateral sclerosis (ALS) patients. ALS is a neurodegenerative disease that can be either sporadic (ca. 90%) or familial (fALS). The most widely studied forms of fALS are caused by mutations in the sequence of SOD1. Ex mortuo SOD1 aggregates are usually found to be amorphous. In vitro SOD1, in its immature reduced and apo state, forms fibrillar aggregates. Previous literature data have suggested that a monomeric SOD1 construct, lacking loops IV and VII, (apoSODΔIV-VII), shares the same fibrillization properties of apoSOD1, both proteins having the common structural feature of the central β-barrel. In this work, we show that structural information can be obtained at a site-specific level from solid-state NMR. The residues that are sequentially assignable are found to be located at the putative nucleation site for fibrillar species formation in apoSOD, as detected by other experimental techniques.