Heterogeneity in glutamic acid decarboxylase expression among single rat pancreatic beta cells.
An isoform of glutamic acid decarboxylase, (GAD)65 has been identified as a pancreatic beta-cell autoantigen in Type I (insulin dependent) diabetes mellitus. We investigated the expression of GAD isoforms among single rat beta cells in culture, under different conditions and the correlation between GAD65 expression and insulin secretion-rate. Independent of culture conditions, 100 % of fresh and cultured beta cells express GAD67. In contrast, considerable heterogeneity in GAD65 expression among single beta cells was observed. After 2 days in culture in 2.6 mmol/l glucose, only 24 % of the beta cells express GAD65. This percentage increases to 39 % in 5.6 mmol/l glucose and to 54 % and 56 % in 11.6 mmol/l and 20.6 mmol/l glucose, respectively. Moreover, reducing glucose concentration from 11.6 to 2.5 mmol/l for 2 days, reduces GAD65 expression by nearly 30 %. After 11 days in culture with 11.6 mmol/l glucose, 50 % of beta cells continue expressing GAD65, this percentage is further increased to nearly 75 % by including either nerve growth factor or dibutyryl cyclic AMP or both in the culture medium. When beta cells are challenged for 1 h with 20.6 mmol/l glucose, 67 % respond forming insulin-immunoplaques. More than two-thirds of insulin-secretors are GAD65-positive, in contrast to only 11 % of the non-secreting cells. Moreover, 87 % of beta cells that have a high insulin secretory rate express GAD65. These results show that the most active beta cells, which secrete more insulin, also express GAD65 and that manipulating extracellular glucose may modify the expression of the enzyme and possibly the autoimmune attack in Type I diabetes.


PRAME induces genomic instability in uveal melanoma.
PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME than can be targeted therapeutically in cancer.


Alteration of cortical functional connectivity as a result of traumatic brain injury revealed by graph theory, ICA, and sLORETA analyses of EEG signals.
In this paper, a novel approach to examine the cortical functional connectivity using multichannel electroencephalographic (EEG) signals is proposed. First we utilized independent component analysis (ICA) to transform multichannel EEG recordings into independent processes and then applied source reconstruction algorithm [i.e., standardize low resolution brain electromagnetic (sLORETA)] to identify the cortical regions of interest (ROIs). Second, we performed a graph theory analysis of the bipartite network composite of ROIs and independent processes to assess the connectivity between ROIs. We applied this proposed algorithm and compared the functional connectivity network properties under resting state condition using 29 student-athletes prior to and shortly after sport-related mild traumatic brain injury (MTBI). The major findings of interest are the following. There was 1) alterations in vertex degree at frontal and occipital regions in subjects suffering from MTBI, ( p < 0.05); 2) a significant decrease in the long-distance connectivity and significant increase in the short-distance connectivity as a result of MTBI, ( p < 0.05); 3) a departure from small-world network configuration in MTBI subjects. These major findings are discussed in relation to current debates regarding the brain functional connectivity within and between local and distal regions both in normal controls in pathological subjects.


Nab-paclitaxel monotherapy in refractory pancreatic adenocarcinoma.
The standard of care in patients with metastatic pancreatic adenocarcinoma is undefined beyond second line of treatment. There have been scant reports of benefit from nab-paclitaxel in patients with refractory pancreatic cancer. A retrospective review was carried out in patients with pancreatic adenocarcinoma at Siteman Cancer Center, who had received nab-paclitaxel monotherapy after experiencing disease progression on standard treatments. Nab-paclitaxel was given either two out of every three weeks or three out of every four weeks. Twenty patients were identified and included for data analysis. Median age was 63.5 years old. All patients had previously received gemcitabine, while 40% had also received FOLFIRINOX. Median number of prior lines of systemic treatment was 2. Patients were treated for a median of 15 weeks, with a range of 1 to 41.7 weeks. Median dose of nab-paclitaxel was 100 mg/m(2) with range of 75-125 mg/m(2). Best response imaging was available in 17 patients and 11 out of the 17 patients (64.7%) had stable disease. Median progression-free survival (PFS) was 3.7 months and overall survival (OS) were 5.2 months. Most common treatment related toxicities included grade 1 pneumonitis in five patients (25%), grade 3 or 4 neutropenia in three patients (15%), and dehydration resulting in hospitalization in one patient (5%). Nab-paclitaxel monotherapy had acceptable level of toxicity in a heavily pretreated patient population with pancreatic cancer and appeared to provide a clinical benefit. This agent is worthy of further prospective studies to evaluate extent of benefit after standard therapies have failed.


Conservative management of antenatally diagnosed cystic lung malformations.
To review the outcome of all antenatally diagnosed conservatively managed congenital lung malformations (CLMs) managed at our centre. All patients diagnosed antenatally with cystic lung malformations from 2001 to 2011, at a tertiary referral paediatric surgical centre practising a policy of conservative management of asymptomatic cases, were retrospectively reviewed. Data were collected from medical case notes and radiology reports. Ethical approval was obtained from our institutional research and development department. The complete records of 74 fetuses antenatally diagnosed with CLM were reviewed. There were 72 live births, at a median gestation of 39.6 weeks. Emergency lobectomy was performed in one symptomatic neonate. Elective lobectomies were performed at parental request in three asymptomatic infants, one of whom had a family history of synovial sarcoma. Two patients developed pneumonia in the affected lobe during early childhood and proceeded to lobectomy at the age of 3 years. One patient with a bronchopulmonary sequestration required embolisation for cyanotic episodes. The remaining 65 patients have been conservatively managed to date, and none have required hospital admission. Less than a quarter report mild respiratory symptoms such as cough or wheeze. Median follow-up is 5 years. This retrospective cohort study of 74 consecutive CLMs diagnosed antenatally over a 10-year period demonstrates that most of these lesions will remain asymptomatic throughout childhood. Although the natural history of CLMs in later years remains to be elucidated, we hope that this report on medium-term outcomes will be useful to clinicians who undertake antenatal counselling and may inform the discussion on how best to manage these children.


OPV strains circulation in HIV infected infants after National Immunisation Days in Bangui, Central African Republic.
Humans are the only host of polioviruses, thus the prospects of global polio eradication look reasonable. However, individuals with immunodeficiencies were shown to excrete vaccine derived poliovirus for long periods of time which led to reluctance to prolong the vaccination campaign for fear of this end result. Therefore, we aimed to assess the duration of excretion of poliovirus after the 2001 National Immunization Days according to Human immunodeficiency virus status. Fifty three children were enrolled. Sequential stool samples were collected in between National Immunisation Days rounds and then every month during one year. Children were classified into 2 groups: no immunodepression (n = 38), immunodepression (n = 15) according to CD4+ lymphocytes cells count. Thirteen poliovirus strains were isolated from 11 children: 5 Human immunodeficiency virus positive and 6 Human immunodeficiency virus negative. None of the children excreted poliovirus for more than 4 weeks. The restriction fragment length polymorphism analysis showed that all strains were of Sabin origin including a unique Polio Sabine Vaccine types 2 and 3 (S2/S3) recombinant. From these findings we assume that Human immunodeficiency virus positive children are not a high risk population for long term poliovirus excretion. More powerful studies are needed to confirm our findings.


Promoting interprofessional care in the peri-operative environment.
One of the key aspects of successful collaborative working is the relevant and effective exchange of information between professionals. Boundaries exist not only between health and social care in a community setting, but also in acute care between and within departments and professions. Patients continuously cross these boundaries during transfers and transitions, when nurses interact with other professionals and are in a prime position to demonstrate exemplary interprofessional relationships and seamless patient care to other staff and to students. Mentors act as role models for students of all professions and are expected to promote opportunities that will maximise student learning and enhance patient care. This article provides mentors with some suggestions for maximising these opportunities. Mentors are encouraged to reflect on practice-based learning opportunities for students, particularly situations that are challenging and involve critical judgement. The article focuses on learning opportunities in the peri-operative department, however the same challenges are experienced in other clinical areas and the principles of good interprofessional care can be applied to any team that aspires to work collaboratively.


Budesonide, fluticasone propionate, and azithromycin do not modulate the membrane vesicle release by THP-1 macrophages and respiratory pathogens during macrophage infection.
Patients with more severe chronic obstructive pulmonary disease frequently experience exacerbations and it is estimated that up to 50% of these exacerbations are associated with bacterial infections. The mainstay treatment for these infection-related exacerbations constitutes the administration of glucocorticoids, alone or in combination with antibiotics. A recent line of evidence demonstrates that many hormones including the steroid beclomethasone can also directly affect bacterial growth, virulence, and antibiotic resistance. The effect of these regimens on the release of potentially virulent and toxic membrane vesicles (MVs) is at present unclear. In this study, we determined the effect of several pharmacological agents on MVs release by and bacterial growth of common respiratory pathogens. We found that neither the release of MVs nor the bacterial growth was affected by the glucocorticoids budesonide and fluticasone. The macrolide antibiotic azithromycin only inhibited the growth of Moraxella catarrhalis but no effects were observed on bacterial MV release at a concentration that is achieved locally in the epithelial lining on administration. The macrophage pro-inflammatory response to MVs was significantly reduced after treatment with budesonide and fluticasone but not by azithromycin treatment. Our findings suggest that these glucocorticoids may have a positive effect on infection-related inflammation although the bacterial growth and MV release remained unaffected.


ApoE4 delays dendritic spine formation during neuron development and accelerates loss of mature spines in vitro.
The ε4 allele of the gene that encodes apolipoprotein E (APOE4) is the greatest genetic risk factor for Alzheimer's disease (AD), while APOE2 reduces AD risk, compared to APOE3. The mechanism(s) underlying the effects of APOE on AD pathology remains unclear. In vivo, dendritic spine density is lower in APOE4-targeted replacement (APOE-TR) mice compared with APOE2- and APOE3-TR mice. To investigate whether this apoE4-induced decrease in spine density results from alterations in the formation or the loss of dendritic spines, the effects of neuron age and apoE isoform on the total number and subclasses of spines were examined in long-term wild-type neurons co-cultured with glia from APOE2-, APOE3- and APOE4-TR mice. Dendritic spine density and maturation were evaluated by immunocytochemistry via the presence of drebrin (an actin-binding protein) with GluN1 (NMDA receptor subunit) and GluA2 (AMPA receptor subunit) clusters. ApoE isoform effects were analyzed via a method previously established that identifies phases of spine formation (day-in-vitro, DIV10-18), maintenance (DIV18-21) and loss (DIV21-26). In the formation phase, apoE4 delayed total spine formation. During the maintenance phase, the density of GluN1+GluA2 spines did not change with apoE2, while the density of these spines decreased with apoE4 compared to apoE3, primarily due to the loss of GluA2 in spines. During the loss phase, total spine density was lower in neurons with apoE4 compared to apoE3. Thus, apoE4 delays total spine formation and may induce early synaptic dysfunction via impaired regulation of GluA2 in spines.


Plus ça change, plus c'est la même chose: senior NHS managers' narratives of restructuring.
The UK National Health Service (NHS) is regularly restructured. Its smooth operation and organisational memory depends on the insights and capability of managers, especially those with experience of previous transitions. Narrative methods can illuminate complex change from the perspective of key actors. We used an adaptation of Wengraf's biographical narrative life interview method to explore how 20 senior NHS managers (chief executives, directors and assistant directors) had perceived and responded to major transitions since 1974. Data were analysed thematically using insights from phenomenology, neo-institutional theory and critical management studies. Findings were contextualised within a literature review of NHS policy and management 1974-2009. Managers described how experience in different NHS organisations helped build resilience and tacit knowledge, and how a strong commitment to the 'NHS brand' allowed them to weather a succession of policy changes and implement and embed such changes locally. By synthesising these personal and situated micro-narratives, we built a wider picture of macro-level institutional change in the NHS, in which the various visible restructurings in recent years appear to have masked a deeper continuity in terms of enduring values, norms and ways of working. We consider the implications of these findings for the future NHS.


Body dysmorphic disorder: case report.
The desire for self-mutilation in the absence of any discernible psychopathology is relatively rare. Self-mutilation is most commonly a manifestation of an underlying psychopathology such as depression, schizophrenia, personality disorder, transexuality, body dysmorphic disorder and factitious disorder. In this article, a case in which a 29-year-old single Kenyan lady of African origin demanded a surgical operation to modify and reduce the size of her external genitalia is presented. Although female genital mutilation is still widespread in the country, this case is of interest in that the woman did not seek the usual circumcision but sought to specifically reduce the size of her labia minora so that she could feel like a normal woman. The unique challenges in her management are discussed. Possible aetiological factors in patients who demand surgical removal or modification of parts of their bodies without an obvious cause is discussed.


The stable microbiome of inter and sub-tidal anemone species under increasing pCO2.
Increasing levels of pCO2 within the oceans will select for resistant organisms such as anemones, which may thrive under ocean acidification conditions. However, increasing pCO2 may alter the bacterial community of marine organisms, significantly affecting the health status of the host. A pH gradient associated with a natural volcanic vent system within Levante Bay, Vulcano Island, Italy, was used to test the effects of ocean acidification on the bacterial community of two anemone species in situ, Anemonia viridis and Actinia equina using 16 S rDNA pyrosequencing. Results showed the bacterial community of the two anemone species differed significantly from each other primarily because of differences in the Gammaproteobacteria and Epsilonproteobacteria abundances. The bacterial communities did not differ within species among sites with decreasing pH except for A. viridis at the vent site (pH = 6.05). In addition to low pH, the vent site contains trace metals and sulfide that may have influenced the bacteria community of A. viridis. The stability of the bacterial community from pH 8.1 to pH 7.4, coupled with previous experiments showing the lack of, or beneficial changes within anemones living under low pH conditions indicates that A. viridis and A. equina will be winners under future ocean acidification scenarios.


First Report of Pectobacterium wasabiae Causing Aerial Stem Rot of Potato in Washington State.
Aerial stem rot of potato (Solanum tuberosum), also known as bacterial stem rot, is often caused by the pectolytic bacteria Pectobacterium (Erwinia) carotovorum subsp. carotovorum, P. atrosepticum, or Dickeya spp. (3). A survey was carried out in August 2008 in 'Russet Burbank' potato fields exhibiting aerial stem rot symptoms in the Columbia Basin of Washington State. One bacterial strain isolated during the survey, PwO405, exhibited pectolytic ability on crystal violet pectate (CVP) agar and potato slices and failed to grow at 37°C, but physiological tests did not conclusively distinguish the bacterium as P. atrosepticum (1). The bacterium was positive for ONPG, N-acetylglucosaminyl transferase, gelatin liquefaction, and acid production from D-galactose, lactose, melibiose, raffinose, citrate, and trehalose. The bacterium was negative for indole production and acid production from maltose, α-methyl-D-glucoside, sorbitol, D-arabitol, inositol, inulin, and melezitose. Molecular identification of the bacterium was performed with 16S rRNA, aconitase (acnA), and malate dehydrogenase (mdh) coding sequences as previously described (2,4). Partial sequences of 16S rRNA (1,408 bp) and acnA (412 bp) genes (GenBank Accession Nos. JQ723958 and JQ723959, respectively) exhibited 99% shared identities with P. wasabiae strain WPP163, while the mdh sequence (435 bp) (GenBank Accession No. JQ723960) exhibited 100% shared identity with mdh sequences from three P. wasabiae strains (NZEC9, NZEC10, and NZEC8974). Maximum parsimony analysis using concatenated acnA and mdh sequences from this study and Pectobacterium sequences previously deposited in GenBank (2,4) clustered strain PwO405 with other P. wasabiae strains. Three 7-week-old 'Russet Norkotah' potato plants were wound-inoculated by inserting a sterile 23 gauge needle just above a central leaf axil at a depth of 1 mm. A 10-μl drop of inoculum (104 CFU) was placed on the wound. Plants were exposed to a 24-h leaf wetness period (90 to 100% RH in a mist chamber) and lesions were measured. All three inoculated plants exhibited aerial stem rot symptoms similar to those observed in the field, including brown water-soaked lesions that spread acropetally and basipetally. Upon drying, the lesions became shriveled and turned dark brown to black. Some plants exhibited hollowing of the stems and unilateral wilt on the side of the lesion. Symptoms were not observed on water-inoculated controls. The bacteria that were reisolated into pure culture from all three inoculated stems caused pitting on CVP and exhibited the same morphology as the original culture and were confirmed as P. wasabiae using 16S rRNA, acnA, and mdh coding sequences, fulfilling Koch's postulates. Stem rot ability of the bacterium was also confirmed on four potato cultivars: 'Ranger Russet,' 'Russet Burbank,' 'Russet Norkotah,' and 'Umatilla Russet' by wound-inoculating six single-stem plants of each cultivar as described above. To our knowledge, this is the first report of aerial stem rot of potato caused by P. wasabiae in Washington State. References: (1) S. De Boer and A. Kelman. Page 56 in: Laboratory Guide for Identification of Plant Pathogenic Bacteria, 3rd ed. N. Schaad et al., ed. APS Press, St. Paul, 2001. (2) A. Pitman et al. Eur. J. Plant Pathol. 32:211, 2010. (3) M. Powelson and G. Franc. Page 10 in: Compendium of Potato Diseases. W. Stevenson et al., ed. APS Press, St. Paul, 2002. (4) M. Yap et al. Appl. Environ. Microbiol. 70:3013, 2004.


Persistent pain after motor vehicle collision: comparative effectiveness of opioids vs nonsteroidal antiinflammatory drugs prescribed from the emergency department-a propensity matched analysis.
Each year millions of Americans present to the emergency department (ED) for care after a motor vehicle collision (MVC); the majority (>90%) are discharged to home after evaluation. Acute musculoskeletal pain is the norm in this population, and such patients are typically discharged to home with prescriptions for oral opioid analgesics or nonsteroidal antiinflammatory drugs (NSAIDs). The influence of acute pain management on subsequent pain outcomes in this common ED population is unknown. We evaluated the effect of opioid analgesics vs NSAIDs initiated from the ED on the presence of moderate to severe musculoskeletal pain and ongoing opioid use at 6 weeks in a large cohort of adult ED patients presenting to the ED after MVC (n = 948). The effect of opioids vs NSAIDs was evaluated using an innovative quasi-experimental design method using propensity scores to account for covariate imbalances between the 2 treatment groups. No difference in risk for moderate to severe musculoskeletal pain at 6 weeks was observed between those discharged with opioid analgesics vs NSAIDs (risk difference = 7.2% [95% confidence interval: -5.2% to 19.5%]). However, at follow-up participants prescribed opioids were more likely than those prescribed NSAIDs to report use of prescription opioids medications at week 6 (risk difference = 17.5% [95% confidence interval: 5.8%-29.3%]). These results suggest that analgesic choice at ED discharge does not influence the development of persistent moderate to severe musculoskeletal pain 6 weeks after an MVC, but may result in continued use of prescription opioids. Supported by NIAMS R01AR056328 and AHRQ 5K12HS022998.


Management of perioperative low cardiac output state without extracorporeal life support: What is feasible?
A transient and reversible reduction in cardiac output-low cardiac output state (LCOS) often occurs following surgery for congenital heart disease. Inappropriately managed LCOS is a risk factor for increased morbidity and death. LCOS may occasionally be progressive and refractory needing a period of "myocardial rest" with extracorporeal life support (ECLS). ECLS is currently considered a routine tool available for rapid deployment in most industrialized countries. Accumulated experience and refinements in technology have led to improving survivals - discharge survivals of 35%-50%, with almost 100% survival in select groups on elective left ventricular assist device. Thus, there is an increasing trend to initiate ECLS "early or electively in the operating room" in high-risk patients. India has a huge potential need for ECLS given the large number of infants presenting late with preexisting ventricular dysfunction or in circulatory collapse. ECLS is an expensive and resource consuming treatment modality and is not a viable therapeutic option in our country. The purpose of this paper is to reiterate an anticipatory, proactive approach to LCOS: (1) methods for early detection of evolving LCOS and (2) timely initiation of individualized therapy. This paper also explores what is feasible with the refinement of "simple, conventional, inexpensive strategies" for the management of LCOS. Therapy for LCOS should be multimodal based on the type of circulation and physiology. Our approach to LCOS includes: (1) intraoperative strategies, (2) aggressive afterload reduction, (3) lusitropy, (4) exclusion of structural defects, (5) harnessing cardiopulmonary interactions, and (6) addressing metabolic and endocrine abnormalities. We have achieved a discharge survival rate of greater than 97% with these simple methods.


Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices.
Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼ 30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence-specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequence-specific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D(V12) activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.


Root bacterial endophytes alter plant phenotype, but not physiology.
Plant traits, such as root and leaf area, influence how plants interact with their environment and the diverse microbiota living within plants can influence plant morphology and physiology. Here, we explored how three bacterial strains isolated from the Populus root microbiome, influenced plant phenotype. We chose three bacterial strains that differed in predicted metabolic capabilities, plant hormone production and metabolism, and secondary metabolite synthesis. We inoculated each bacterial strain on a single genotype of Populus trichocarpa and measured the response of plant growth related traits (root:shoot, biomass production, root and leaf growth rates) and physiological traits (chlorophyll content, net photosynthesis, net photosynthesis at saturating light-Asat, and saturating CO2-Amax). Overall, we found that bacterial root endophyte infection increased root growth rate up to 184% and leaf growth rate up to 137% relative to non-inoculated control plants, evidence that plants respond to bacteria by modifying morphology. However, endophyte inoculation had no influence on total plant biomass and photosynthetic traits (net photosynthesis, chlorophyll content). In sum, bacterial inoculation did not significantly increase plant carbon fixation and biomass, but their presence altered where and how carbon was being allocated in the plant host.


Quantifying cognition at the bedside: a novel approach combining cognitive symptoms and signs in HIV.
Up to half of all people with HIV infection have some degree of cognitive impairment. This impairment is typically mild, but nonetheless often disabling. Although early detection of cognitive impairment offers the greatest hope of effective intervention, there are important barriers to this goal in most clinical settings. These include uncertainty about how self-reported cognitive symptoms relate to objective impairments, and the paucity of bedside measurement tools suitable for mild deficits. Clinicians need guidance in interpreting cognitive symptoms in this population, and a brief cognitive measurement tool targeted to mild impairment. We addressed these two problems together here. The objective of this study was to determine the extent to which performance on cognitive tests and self-reported cognitive symptoms form a unidimensional construct. Two hundred three HIV+ individuals completed the Montreal Cognitive Assessment, computerized cognitive tasks and a questionnaire eliciting cognitive symptoms. Rasch measurement theory was applied to determine whether patient-reported and performance items could be combined to measure cognition as a unidimensional latent construct. Performance-based items and cognitive symptoms are arranged hierarchically along the same continuum of cognitive ability, forming a measure with thresholds covering a broad spectrum of ability that has good internal reliability. The cognitive symptoms that fit the measurement model relate to important aspects of everyday life, providing evidence that the identified construct is meaningful. This finding lays the foundation for a rapid measure of cognitive ability in people with HIV infection that is feasible for routine clinical use, and shows that some cognitive symptoms are systematically related to performance in this population.


Comparison of state-of-art phase modulators and parametric mixers in time-lens applications under different repetition rates.
Ever since the discovery of space-time duality, several methods have been developed to perform temporal imaging, and there are two major categories: the quadratic signal onto the phase modulator and the parametric mixer with a linear chirped pump. The features of each mechanism have been thoroughly and quantitatively explored and optimized for certain kinds of applications, but a comparison of some key parameters, especially in the aspect of the repetition rate, is required. In this paper, we will first review the theoretical models and existing performance of these two mechanisms and, consequently, compare them quantitatively in different aspects: the focal group delay dispersion, the pupil size, the effective duty ratio, and the temporal numerical aperture. All these fundamental parameters are related to the repetition rate. The results obtained in this study would provide some important guidelines for the time-lens design, so as to be optimized in different kinds of applications with different repetition rate requirements, such as ultrafast optical communication and real-time bio-imaging systems.


Spindle-shaped archaeal viruses evolved from rod-shaped ancestors to package a larger genome.
Spindle- or lemon-shaped viruses infect archaea in diverse environments. Due to the highly pleomorphic nature of these virions, which can be found with cylindrical tails emanating from the spindle-shaped body, structural studies of these capsids have been challenging. We have determined the atomic structure of the capsid of Sulfolobus monocaudavirus 1, a virus that infects hosts living in nearly boiling acid. A highly hydrophobic protein, likely integrated into the host membrane before the virions assemble, forms 7 strands that slide past each other in both the tails and the spindle body. We observe the discrete steps that occur as the tail tubes expand, and these are due to highly conserved quasiequivalent interactions with neighboring subunits maintained despite significant diameter changes. Our results show how helical assemblies can vary their diameters, becoming nearly spherical to package a larger genome and suggest how all spindle-shaped viruses have evolved from archaeal rod-like viruses.


Single-channel data and missed events: analysis of a two-state Markov model.
Patch-clamp recording permits investigation of the gating kinetics of single ion channels. Careful statistical analysis of kinetic data can yield clues as to the molecular events underlying channel gating. However, it is important that such analysis should take full account of the limitations that arise from the finite time resolution of patch-clamp recording techniques. Single-ion-channel data are generally interpreted in terms of Markov process models of channel gating mechanisms. Experimental channel records suffer from time interval omission, i.e. failure to detect brief channel openings and closings. This leads to an identifiability problem when analysing single-channel data, i.e. different gating mechanisms provide equally convincing descriptions of the same experimental data. We consider a two-state Markov model of receptor-channel gating in which the channel opening rate is proportional to the agonist concentration, C in equilibrium with OA. By using computer-simulated data, the approximate likelihood of the data is maximized to yield parameter estimates for the model. At a single agonist concentration there is an identifiability problem in that two pairs of parameter estimates are obtained. The 'true' parameter estimates cannot be distinguished from the 'false' ones. By considering data corresponding to a range of agonist concentrations one may identify the 'true' parameter estimates as those that do not change as the agonist concentration is increased. Alternatively, one may identify the 'true' parameter estimates directly by maximizing a global likelihood, the latter being obtained by simultaneous consideration of data obtained at several different agonist concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)


Relaxation rate of constituent muscle-fibre types in human quadriceps.
1. Muscle fibres may be subdivided into type I (with slow-twitch contractile properties) and type II (fast-twitch) depending on their myosin adenosine triphosphatase activity. In voluntary isometric contractions type I fibres are utilized at low forces (less than 20% of maximum) whereas type II fibres are recruited in addition at high forces. This physiological recruitment order has enabled us to measure the relaxtion rate of type I and II fibres in vivo in normal human subjects. 2. Relaxation rate was measured in 16 subjects from low (10% of maximum) and maximum isometric quadriceps contractions and the muscle-fibre type composition determined from needle-biopsy specimens in 10 subjects. The relaxation rate of type II fibres was calculated to be twice as fast as that of type I. 3. It was not possible to estimate, from studies in 33 quadriceps muscles (25 normal subjects), the contribution of type II fibres to overall fibre area from the relaxation rate as determined from electrically stimulated isometric contractions.


Pattern of impaired working memory during major depression.
The aim of this study was to assess working memory (WM) in patients with major depressive disorder (MDD), using a robust parametric WM task (the n-back task). Twenty patients with MDD and twenty healthy controls completed a visual version of the paradigm, comprising four levels of task difficulty (i.e. 0-, 1-, 2-, and 3-back). Performance accuracy and reaction time (RT) were measured at each difficulty level. In comparison with controls, patients with MDD exhibited slower RTs (F((1,38)) = 25.16, p < 0.001), and reduced accuracy (F((1,38)) = 5.93, p < 0.001). There was no diagnosis-specific effect of task difficulty on performance accuracy. However, the faster response to memory (1-3-back) than to shadowing (0-back) tasks observed in controls was not as pronounced in patients. These observations support a relatively specific impairment of WM/central executive function in MDD, which may potentially mediate the diverse pattern of cognitive dysfunction noted in MDD. The parametric n-back task is applicable to subjects with MDD and yields results interpretable across the dimensions of task difficulty and performance in controls and patients.


Emotion processes in normal and abnormal development and preventive intervention.
We present an analysis of the role of emotions in normal and abnormal development and preventive intervention. The conceptual framework stems from three tenets of differential emotions theory (DET). These principles concern the constructs of emotion utilization; intersystem connections among modular emotion systems, cognition, and action; and the organizational and motivational functions of discrete emotions. Particular emotions and patterns of emotions function differentially in different periods of development and in influencing the cognition and behavior associated with different forms of psychopathology. Established prevention programs have not emphasized the concept of emotion as motivation. It is even more critical that they have generally neglected the idea of modulating emotions, not simply to achieve self-regulation, but also to utilize their inherently adaptive functions as a means of facilitating the development of social competence and preventing psychopathology. The paper includes a brief description of a theory-based prevention program and suggestions for complementary targeted interventions to address specific externalizing and internalizing problems. In the final section, we describe ways in which emotion-centered preventions can provide excellent opportunities for research on the development of normal and abnormal behavior.


Gene Ontology Consortium: going forward.
The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology.


The tissue-specific aspect of genome-wide DNA methylation in newborn and placental tissues: implications for epigenetic epidemiologic studies.
Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues.


Rapid reduction of maternal mortality in Uganda and Zambia through the saving mothers, giving life initiative: results of year 1 evaluation.
Achieving maternal mortality reduction as a development goal remains a major challenge in most low-resource countries. Saving Mothers, Giving Life (SMGL) is a multi-partner initiative designed to reduce maternal mortality rapidly in high mortality settings through community and facility evidence-based interventions and district-wide health systems strengthening that could reduce delays to appropriate obstetric care. An evaluation employing multiple studies and data collection methods was used to compare baseline maternal outcomes to those during Year 1 in SMGL pilot districts in Uganda and Zambia. Studies include health facility assessments, pregnancy outcome monitoring, enhanced maternal mortality detection in facilities, and population-based investigation of community maternal deaths. Population-based evaluation used standard approaches and comparable indicators to measure outcome and impact, and to allow comparison of the SMGL implementation in unique country contexts. The evaluation found a 30% reduction in the population-based maternal mortality ratio (MMR) in Uganda during Year 1, from 452 to 316 per 100,000 live births. The MMR in health facilities declined by 35% in each country (from 534 to 345 in Uganda and from 310 to 202 in Zambia). The institutional delivery rate increased by 62% in Uganda and 35% in Zambia. The number of facilities providing emergency obstetric and newborn care (EmONC) rose from 10 to 25 in Uganda and from 7 to 11 in Zambia. Partial EmONC care became available in many more low and mid-level facilities. Cesarean section rates for all births increased by 23% in Uganda and 15% in Zambia. The proportion of women with childbirth complications delivered in EmONC facilities rose by 25% in Uganda and 23% in Zambia. Facility case fatality rates fell from 2.6 to 2.0% in Uganda and 3.1 to 2.0% in Zambia. Maternal mortality ratios fell significantly in one year in Uganda and Zambia following the introduction of the SMGL model. This model employed a comprehensive district system strengthening approach. The lessons learned from SMGL can inform policymakers and program managers in other low and middle income settings where similar approaches could be utilized to rapidly reduce preventable maternal deaths.


Sedum takesimense Protects PC12 Cells against Corticosterone-Induced Neurotoxicity by Inhibiting Neural Apoptosis.
Neuronal cell death induced by chronic stress in the central nervous system is a cause of neurological dysfunction. We investigated the neuroprotective potential of a water extract of S. takesimense (WEST) against corticosterone-induced apoptosis in PC12 cells and the possible underlying mechanisms. Cells were pretreated with 50 µg/mL of WEST to evaluate its neuroprotective effect based on endoplasmic reticulum (ER) stress inhibition and mitochondrial function improvement. Pretreatment with WEST prevented corticosterone-induced injury in PC12 cells, resulting in increased cell survival, decreased lactate dehydrogenase (LDH) release, and potent apoptosis inhibition by a reduction in apoptotic nuclei demonstrated by Hoechst 33,342 and propidium iodide (PI) double staining, and TUNEL staining. WEST strongly attenuated calcium (Ca2+) elevation, inducing the closure of mitochondrial permeability transition pores (mPTPs), which were opened by corticosterone. It also stabilized mitochondrial membrane potential (MMP) loss and inhibited the corticosterone-induced decrease in adenosine triphosphate (ATP) levels. Furthermore, the increased reactive oxygen species (ROS) production induced by corticosterone was prevented in PC12 cells treated with WEST. WEST also downregulated the expression of glucose-regulated protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153), the pro-apoptotic protein Bcl-2-associated X (Bax), cytochrome c, cysteine-aspartic protease (caspase)-9, and caspase-3, and upregulated the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). Thus, WEST exerts a neuroprotective effect by inhibiting the apoptosis pathway in ER stress and the mitochondrial dysfunction induced by corticosterone. These results demonstrate that WEST reduces neuronal damage from the neurotoxicity caused by chronic stress.


Cognitive effects of calligraphy therapy for older people: a randomized controlled trial in Hong Kong.
This pilot study investigated the effects of calligraphy therapy on cognitive function in older Hong Kong Chinese people with mild cognitive impairment. A single-blind, randomized controlled trial was carried out in a sample of 31 adults aged 65 years or older with mild cognitive impairment. They were randomly assigned to receive either intensive calligraphy training led by a trained research assistant for eight weeks (calligraphy group, n = 14) or no calligraphy treatment (control group, n = 17). Participants' cognitive function was assessed by the Chinese version of the Mini-Mental State Examination (CMMSE) before and after calligraphy treatment. Repeated measures analysis of variance and paired samples t-tests were used to analyze the data. A significant interaction effect of time and intervention was detected [F (1, 29) = 9.11, P = 0.005, η(2) = 0.24]. The calligraphy group was found to have a prominent increase in CMMSE global score, and scores in the cognitive areas of orientation, attention, and calculation after two months (ΔM = 2.36, P < 0.01), whereas their counterparts in the control group experienced a decline in CMMSE score (ΔM = -0.41, P < 0.05). Calligraphy therapy was effective for enhancing cognitive function in older people with mild cognitive impairment and should be incorporated as part of routine programs in both community and residential care settings.


Deciphering bartonella diversity, recombination, and host specificity in a rodent community.
Host-specificity is an intrinsic feature of many bacterial pathogens, resulting from a long history of co-adaptation between bacteria and their hosts. Alpha-proteobacteria belonging to the genus Bartonella infect the erythrocytes of a wide range of mammal orders, including rodents. In this study, we performed genetic analysis of Bartonella colonizing a rodent community dominated by bank voles (Myodes glareolus) and wood mice (Apodemus sylvaticus) in a French suburban forest to evaluate their diversity, their capacity to recombine and their level of host specificity. Following the analysis of 550 rodents, we detected 63 distinct genotypes related to B. taylorii, B. grahamii, B. doshiae and a new B. rochalimae-like species. Investigating the most highly represented species, we showed that B. taylorii strain diversity was markedly higher than that of B. grahamii, suggesting a possible severe bottleneck for the latter species. The majority of recovered genotypes presented a strong association with either bank voles or wood mice, with the exception of three B. taylorii genotypes which had a broader host range. Despite the physical barriers created by host specificity, we observed lateral gene transfer between Bartonella genotypes associated with wood mice and Bartonella adapted to bank voles, suggesting that those genotypes might co-habit during their life cycle.


Emergency Department Communication in Persons Living With Dementia and Care Partners: A Scoping Review.
To synthesize published research exploring emergency department (ED) communication strategies and decision-making with persons living with dementia (PLWD) and their care partners as the basis for a multistakeholder consensus conference to prioritize future research. Systematic scoping review. PLWD and their care partners in the ED setting. Informed by 2 Patient-Intervention-Comparison-Outcome (PICO) questions, we conducted systematic electronic searches of medical research databases for relevant publications following standardized methodological guidelines. The results were presented to interdisciplinary stakeholders, including dementia researchers, clinicians, PLWD, care partners, and advocacy organizations. The PICO questions included: How does communication differ for PLWD compared with persons without dementia? Are there specific communication strategies that improve the outcomes of ED care? Future research areas were prioritized. From 5451 studies identified for PICO-1, 21 were abstracted. From 2687 studies identified for PICO-2, 3 were abstracted. None of the included studies directly evaluated communication differences between PLWD and other populations, nor the effectiveness of specific communication strategies. General themes emerging from the scoping review included perceptions by PLWD/care partners of rushed ED communication, often exacerbated by inconsistent messages between providers. Care partners consistently reported limited engagement in medical decision-making. In order, the research priorities identified included: (1) Barriers/facilitators of effective communication; (2) valid outcome measures of effective communication; (3) best practices for care partner engagement; (4) defining how individual-, provider-, and system-level factors influence communication; and (5) understanding how each member of ED team can ensure high-quality communication. Research exploring ED communication with PLWD is sparse and does not directly evaluate specific communication strategies. Defining barriers and facilitators of effective communication was the highest-ranked research priority, followed by validating outcome measures associated with improved information exchange.


Management of Acute Otitis Media: update.
Acute Otitis Media (AOM), a viral or bacterial infection of the ear, is the most common childhood infection for which antibiotics are prescribed in the United States. In 2001, the Southern California Evidence-based Practice Center conducted a systematic review of the evidence comparing treatments of AOM. This review updates the 2001 review findings on diagnosis and treatment of uncomplicated AOM, assesses the evidence for treatment of recurrent AOM, and assesses the impact of the heptavalent pneumococcal conjugate (PCV7) vaccine on the microbiology of AOM. Searches of PubMed® and the Cochrane databases were conducted from January 1998 to July 2010 using the same search strategies used for the 2001 report, with the addition of terms not considered in the 2001 review. The Web of Science was also searched for citations of the 2001 report and its peer-reviewed publications. After review by two investigators against pre-determined inclusion/exclusion criteria, we included existing systematic reviews and randomized controlled clinical trials for assessment of treatment efficacy and safety. Pooled analysis was performed for comparisons with three or more trials. Few studies were found that examined the accuracy and precision of the diagnosis of AOM. Since PCV7's introduction, AOM microbiology has shifted significantly, with Streptococcus pneumoniae becoming less prevalent and Haemophilus influenzae (HF) increasing in importance. For uncomplicated AOM, pooled analysis indicates that nine children (95% CI: 6, 20) would need to be treated with ampicillin or amoxicillin rather than placebo to note a difference in the rate of clinical success. However, in four studies of delayed treatment approaches for uncomplicated AOM, two had higher rates of clinical success with immediate antibiotic therapy while two did not, and in three studies, a marked decrease in antibiotic utilization was noted. We are unable to draw definitive conclusions regarding the comparative effectiveness of different antibiotics for AOM in children with recurrent otitis media (ROM). For ROM, long-term antibiotic administration will decrease AOM episodes from 3 to 1.5 for every 12 months of treatment per otitis prone child during active treatment (95% CI: 1.2, 2.1); however, potential consequences of long-term treatment need to be considered. Data were insufficient to draw conclusions about comparative effectiveness of different treatment strategies in subgroups of children with uncomplicated AOM. Adverse events were generally more frequent for amoxicillin-clavulanate than for cefdinir, ceftriaxone, or azithromycin. Higher quality studies and improved reporting of study characteristics related to quality are needed to provide definitive conclusions for AOM and ROM treatment options.


'They just walk away' - women's perception of being silenced by antenatal health workers: a qualitative study on women survivors of domestic violence in Nepal.
Domestic violence during pregnancy has detrimental effects on the health of the mother and the newborn. Antenatal care provides a 'window of opportunity' to identify and assist victims of domestic violence during pregnancy. Little is known about the experience, needs, and expectations from the women's perspective in relation to domestic violence in Nepal. Our study aims to explore how women who have experienced domestic violence evaluate their antenatal care and their expectations and needs from health centers. Twelve in-depth interviews were conducted among women who had experienced domestic violence during pregnancy and utilized antenatal care. The women were recruited from two different organizations in Nepal. Women in our study concealed their experience of domestic violence due to fear of being insulted, discriminated, and negative attitudes of the health care providers. The women wished that the health care providers were compassionate and asked them about their experience, ensured confidentiality and privacy, and referred them to services that is free of cost. Findings from our study may help the health care providers to change their attitudes toward women survivors of domestic violence. Identifying and assisting these women through antenatal care could result in improved services for them and their newborns.


Differential effects of ethanol on memory in adolescent and adult rats.
Previous studies have shown that ethanol inhibits memory-related synaptic activity and plasticity more potently in hippocampal slices from immature rats, compared with those taken from adults. We therefore hypothesized that ethanol would more potently attenuate the acquisition of spatial memory in adolescents, compared with adult rats. Adult (65 days of age) and adolescent (30 days of age) male rats were given five daily trials on a spatial memory task in a Morris Water Maze. The animals from each age group were subdivided into three subgroups. Each day, thirty minutes before training, the animals in each subgroup were given an intraperitoneal injection of 1.0 g/kg of ethanol, 2.0 g/kg of ethanol, or the saline vehicle. Training continued daily until the control animals had reached a performance criterion. Ethanol treatment significantly impaired spatial memory acquisition in the adolescent rats, but did not impair acquisition in adult rats. A separate experiment with identical treatment groups showed that ethanol did not impair acquisition of a nonspatial memory task in the water maze in animals from either age group. These experiments show that the acquisition of spatial, but not nonspatial, memory is more potently impaired by ethanol in adolescent animals, compared with adults.


Visual search by action category.
Humans are sensitive to different categories of actions due to their importance in social interactions. However, biological motion research has been heavily tilted toward the use of walking figures. Employing point-light animations (PLAs) derived from motion capture data, we investigated how different activities (boxing, dancing, running, and walking) related to each other during action perception, using a visual search task. We found that differentiating between actions requires attention in general. However, a search asymmetry was revealed between boxers and walkers, i.e., searching for a boxer among walkers is more efficient than searching for a walker among boxers, suggesting the existence of a critical feature for categorizing these two actions. The similarities among the various actions were derived from hierarchical clustering of search slopes. Walking and running proved to be most related, followed by dancing and then boxing. Signal detection theory was used to conduct a non-parametric ROC analysis, revealing that human performance in visual search is not fully explained by low-level motion information.


[Identity of the deaf and interventions in health from the perspective of a community of sign language users].
The biomedical view sees deafness as a physiological loss of audition and the deaf as individuals with an organic abnormality to be corrected; healthcare interventions support this perception. This study sought to understand deafness from the standpoint of the deaf, in order to identify elements for public policies addressed to them in the context of the ethical dimension of care. The research adopted the qualitative approach (focus groups) and 9 members of a deaf community in Fortaleza (Ceará-Brazil), all fluent in Brazilian Sign Language-LIBRAS, took part. The results show deafness is perceived as a way of being based on day-to-day experiences of visual interaction with nature and society, giving the deaf a different identity in terms of culture (being deaf) and linguistics (LIBRAS). Some public policies for oral training and technological interventions, like cochlear implants, are seen as a setback by the deaf, as it negates their status in the world and involves a loss of identity for the deaf. It is necessary to consider the deaf from a socio-historic, symbolic and cultural standpoint where different discourses co-exist, over and above the physiological dimension.


Effectiveness of Immersive Virtual Reality on Orthopedic Surgical Skills and Knowledge Acquisition Among Senior Surgical Residents: A Randomized Clinical Trial.
Video learning prior to surgery is common practice for trainees and surgeons, and immersive virtual reality (IVR) simulators are of increasing interest for surgical training. The training effectiveness of IVR compared with video training in complex skill acquisition should be studied. To evaluate whether IVR improves learning effectiveness for surgical trainees and to validate a VR rating scale through correlation to real-world performance. This block randomized, intervention-controlled clinical trial included senior (ie, postgraduate year 4 and 5) orthopedic surgery residents from multiple institutions in Canada during a single training course. An intention-to-treat analysis was performed. Data were collected from January 30 to February 1, 2020. An IVR training platform providing a case-based module for reverse shoulder arthroplasty (RSA) for advanced rotator cuff tear arthropathy. Participants were permitted to repeat the module indefinitely. The primary outcome measure was a validated performance metric for both the intervention and control groups (Objective Structured Assessment of Technical Skills [OSATS]). Secondary measures included transfer of training (ToT), transfer effectiveness ratio (TER), and cost-effectiveness (CER) ratios of IVR training compared with control. Additional secondary measures included IVR performance metrics measured on a novel rating scale compared with real-world performance. A total of 18 senior surgical residents participated; 9 (50%) were randomized to the IVR group and 9 (50%) to the control group. Participant demographic characteristics were not different for age (mean [SD] age: IVR group, 31.1 [2.8] years; control group, 31.0 [2.7] years), gender (IVR group, 8 [89%] men; control group, 6 [67%] men), surgical experience (mean [SD] experience with RSA: IVR group, 3.3 [0.9]; control group, 3.2 [0.4]), or prior simulator use (had experience: IVR group 6 [67%]; control group, 4 [44%]). The IVR group completed training 387% faster considering a single repetition (mean [SD] time for IVR group: 4.1 [2.5] minutes; mean [SD] time for control group: 16.1 [2.6] minutes; difference, 12.0 minutes; 95% CI, 8.8-14.0 minutes; P < .001). The IVR group had significantly better mean (SD) OSATS scores than the control group (15.9 [2.5] vs 9.4 [3.2]; difference, 6.9; 95% CI, 3.3-9.7; P < .001). The IVR group also demonstrated higher mean (SD) verbal questioning scores (4.1 [1.0] vs 2.2 [1.7]; difference, 1.9; 95% CI, 0.1-3.3; P = .03). The IVR score (ie, Precision Score) had a strong correlation to real-world OSATS scores (r = 0.74) and final implant position (r = 0.73). The ToT was 59.4%, based on the OSATS score. The TER was 0.79, and the system was 34 times more cost-effective than control, based on CER. In this study, surgical training with IVR demonstrated superior learning efficiency, knowledge, and skill transfer. The TER of 0.79 substituted for 47.4 minutes of operating room time when IVR was used for 60 minutes. ClinicalTrials.gov Identifier: NCT04404010.


Enalapril and renal injury in spontaneously hypertensive rats.
Rats of the spontaneously hypertensive strain develop kidney damage that resembles the nephropathy seen in some cases of human essential hypertension. Previous studies with a triple drug antihypertensive regimen indicated that proteinuria and glomerular histopathology in spontaneously hypertensive rats might develop despite long-term effective control of systemic blood pressure. To investigate further the relation between hypertension and kidney disease, a group of spontaneously hypertensive rats were treated with enalapril at 15 weeks of age. Blood pressure, protein excretion, and kidney function were measured in those rats at regular intervals during the next year and a half and were compared with untreated spontaneously hypertensive rats and the normotensive Wistar-Kyoto parent strain. Kidney tissue samples from all three groups, collected at autopsy, were stained by immunohistochemical and conventional methods to assess the relative severity and nature of kidney damage. Although enalapril therapy was completely effective in controlling the blood pressure of spontaneously hypertensive rats, it only postponed the onset of kidney disease. Enalapril-treated spontaneously hypertensive rats eventually exhibited albuminuria as severe as that found in hypertensive rats. Kidney vessel pathology was completely prevented with enalapril, but the abnormal accumulation of mononuclear cells in tubulointerstitial and periglomerular sites was the same as in untreated spontaneously hypertensive rats. We have concluded that elevated protein excretion in rats of the spontaneously hypertensive rat strain is not a secondary consequence of systemic hypertension. Structural abnormalities of renal vessels also do not appear to contribute significantly to the pathogenesis of albuminuria in spontaneously hypertensive rats. Other explanations must be sought to account for the close link between spontaneous hypertension and kidney damage in this animal model. The clear dissociation of kidney disease from systemic hypertension exhibited by spontaneously hypertensive rats may also be relevant for human disease.


Telephone counseling helps maintain long-term adherence to a high-vegetable dietary pattern.
Achieving long-term adherence to a dietary pattern is a challenge in many studies investigating the relationship between diet and disease. The Women's Healthy Eating and Living Study was a multi-institutional randomized trial in 3088 women at risk for breast cancer recurrence. At baseline, the average participant followed a healthy dietary pattern of 7 vegetable and fruit servings, 21 g/d of fiber, and 28.7% energy from fat, although fat intake increased over the enrollment period. Using primarily telephone counseling, the intervention group was encouraged to substantially increase intakes of vegetables, fruits, and fiber while decreasing fat intake. Sets of 24-h dietary recalls were completed on 90% of eligible participants at 1 y and 86% at 4 y. Using a conservative imputation analysis, at 1 y, the intervention group consumed 38% more vegetable servings (100% when including juice) than the comparison group, 20% more fruit, 38% more fiber, 50% more legumes, and 30% more whole grain foods, with a 20% lower intake of energy from fat. At 4 y, the between-group differences were 65% for vegetables (including juice), 25% fruit, 30% fiber, 40% legumes, 30% whole grain foods, and 13% lower intake of energy from fat. The intervention effect on fat intake was similar for early vs. late enrollees. Plasma carotenoid concentrations on a random 28% sample validated self-reported vegetable and fruit intake, with a between-group difference of 66% at 1 y and over 40% at 4 y. This large change will allow testing of hypotheses on the role of dietary change in preventing additional breast cancer events.


Characteristics of endogenous γ-aminobutyric acid (GABA) in human platelets: functional studies of a novel collagen glycoprotein VI inhibitor.
gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, and it also appears in peripheral tissues. Platelets are anuclear blood cells that play a central role in hemostatic processes. Although platelets possess a GABA uptake system, the functional activity of GABA in platelets has remained unclear. We determined that GABA is abundantly distributed in the platelets at a concentration of approximately 1.03 ng/10(6) cells. GABA (0.5 μM) specifically inhibited collagen-induced platelet activation accompanied by [Ca(2+)]i mobilization, phospholipase Cγ2, protein kinase C, Akt phosphorylation, and hydroxyl radical formation. In addition, GABA interfered with fluorescein isothiocyanate-collagen binding to platelet membranes and produced a concentration-dependent shift in the collagen concentration-response curve and a Schild plot slope of -0.96 ± 0.11, indicating competitive inhibition. Platelet activation induced by convulxin, a glycoprotein VI agonist, was inhibited by GABA, whereas activation induced by the integrin α(2)β(1) agonist, aggretin, was not. Immunoprecipitation and surface plasmon resonance revealed that GABA binds directly to glycoprotein VI in human platelets with equilibrium dissociation (binding) constant (K(D)) of 41.4 nM. The closure time of whole blood and the occlusion time of platelet plug formation were significantly prolonged by GABA in vivo. In this study, GABA is a specific inhibitor of collagen glycoprotein VI and may be involved in an endogenous negative feedback mechanism for platelet activation. Thus, GABA may represent a potential target for the development of novel interventions for the treatment of cardiovascular diseases associated with platelet activation, such as stroke and myocardial infarction. GABA is abundantly distributed in the platelets. GABA inhibited platelet activation stimulated by convulxin. GABA directly associated with glycoprotein VI in platelet membrane. GABA prolonged the closure time of whole blood and the occlusion time of platelet plug formation in vivo.


A Cochrane review of treatment for childhood apraxia of speech.
The diagnosis of Childhood Apraxia of Speech (CAS) remains heavily debated, and there is no agreement upon the etiology for the disorder. Whilst there is some consensus on the potential broad array of presenting features of children with CAS, only three key features are recognised as ubiquitous for diagnosis: 1) inconsistent error production on both consonants and vowels across repeated productions of syllables or words; 2) lengthened and impaired coarticulatory transitions between sounds and syllables; and 3) inappropriate prosody. Despite the typically severe and complex presentation of CAS, there is little evidence reported on intervention approaches for the disorder, perhaps as a result of the ongoing deliberation over etiology and diagnosis. The aim of this paper was to assess the efficacy of intervention delivered by Speech and Language Pathologists(s)/Speech and Language Therapists targeting CAS in children and adolescents. Several electronic databases were searched up to January 2007. The review considered randomised controlled trials (RCTs) and quasi-randomised studies of children aged 3 to 16 years with CAS, grouped by treatment types (e.g., perceptual and instrumentally-based biofeedback treatment techniques). Two authors independently assessed references identified from the searches and obtained full text versions of all potentially relevant articles. Of 825 titles and abstracts searched, only 31 abstracts appeared to meet inclusion criteria. The remaining 794 papers were excluded predominantly on the basis of not including participants with CAS (e.g., focused on other developmental speech disorders or adult acquired apraxia of speech), or for not being intervention studies (i.e. being diagnostic or descriptive). All 31 full text articles obtained were excluded following evaluation as they did not meet inclusion criteria on design. The review demonstrates a critical lack of well controlled treatment studies addressing treatment efficacy for CAS, making it impossible for conclusions to be drawn about which interventions are most effective for treating CAS in children or adolescents.


Resistin levels in women with ischemic stroke.
Resistin may be an independent inflammatory marker of atherosclerosis. Therefore, its circulating level might be important prognostic factor of cardiovascular disease in humans. We aimed in this study to assess plasma resistin concentration in Polish women with acute ischemic stroke, who additionally suffer from chronic diseases: diabetes, hypertension and/or obesity. The changes of resistin levels after 10 days from the onset of stroke and possible associations between resistin and pro-inflammatory cytokine TNFα were also evaluated. Material consisted of 41 women with ischemic stroke (aged 60-85 years) and 64 controls (aged 60-85 years). Circulating resistin and TNFα concentrations were measured using ELISA. Blood was taken twice in the stroke group, in the first and tenth day from the onset of clinical symptoms, and only once in the controls. Clinical and biochemical data (blood pressure, weight, height, glucose, insulin, lipid profile) were collected. Higher concentrations of resistin and TNFα were observed in ischemic stroke patients at the first day comparing to the controls. Second evaluation after 10 days in comparison with the first measurement revealed significantly higher TNFα levels and non-significant lower values of resistin. Resistin positively correlated with TNFα and stroke severity. Changes in resistin and TNFα concentrations were observed in the course of stroke. Further investigations are required to assess the implication of these findings. Higher resistin concentration might be associated with worse neurological deficits.


Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy.
Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV. After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.


Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous cycle: a comparison with ovariectomized females and intact males.
Variations in levels of estrogen receptor mRNA were investigated in the medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus throughout the phases of the female estrous cycle and compared with those in ovariectomized female and intact male rats. Female Wistar rats were killed during estrus, metestrus, diestrus, or proestrus or 72 h after ovariectomy as were a group of intact male rats. Brains were removed and frozen, and 20-microns cryostat sections were thaw-mounted onto slides and hybridized with a 35S-labeled antisense estrogen receptor probe. Section-mounted slides were processed, apposed to x-ray film, then dipped in liquid emulsion, and quantified. After exposure, estrogen receptor mRNA was detected in several brain regions, including the medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus. Estrogen receptor mRNA levels in the medial preoptic nucleus were highest during estrus and metestrus, attenuated at diestrus, and low during proestrus. In contrast, the hybridization signal in the arcuate and ventromedial nuclei was low during estrus and then gradually increased throughout the cycle until it peaked during proestrus. Ovariectomized females exhibited an elevated level of estrogen receptor mRNA in all brain regions investigated. Hybridization signal in male medial preoptic nucleus and ventromedial nucleus was reduced compared with those in both intact and ovariectomized females. Estrogen receptor mRNA levels in the arcuate nucleus were similar to those in intact females, but less than those in ovariectomized animals. The results of these studies demonstrate that estrogen receptor mRNA levels are sexually dimorphic, vary during the estrous cycle, and increase after ovariectomy. Furthermore, these results indicate that the magnitude and direction of change observed during the estrous cycle are region specific and suggest that factors other than endogenous estrogen levels differentially modulate estrogen receptor mRNA expression in the hypothalamus.


Pulmonary gas exchange in humans exercising at sea level and simulated altitude.
In a previous study of normal subjects exercising at sea level and simulated altitude, ventilation-perfusion (VA/Q) inequality and alveolar-end-capillary O2 diffusion limitation (DIFF) were found to increase on exercise at altitude, but at sea level the changes did not reach statistical significance. This paper reports additional measurements of VA/Q inequality and DIFF (at sea level and altitude) and also of pulmonary arterial pressure. This was to examine the hypothesis that VA/Q inequality is related to increased pulmonary arterial pressure. In a hypobaric chamber, eight normal subjects were exposed to barometric pressures of 752, 523, and 429 Torr (sea level, 10,000 ft, and 15,000 ft) in random order. At each altitude, inert and respiratory gas exchange and hemodynamic variables were studied at rest and during several levels of steady-state bicycle exercise. Multiple inert gas data from the previous and current studies were combined (after demonstrating no statistical difference between them) and showed increasing VA/Q inequality with sea level exercise (P = 0.02). Breathing 100% O2 did not reverse this increase. When O2 consumption exceeded about 2.7 1/min, evidence for DIFF at sea level was present (P = 0.01). VA/Q inequality and DIFF increased with exercise at altitude as found previously and was reversed by 100% O2 breathing. Indexes of VA/Q dispersion correlated well with mean pulmonary arterial pressure and also with minute ventilation. This study confirms the development of both VA/Q mismatch and DIFF in normal subjects during heavy exercise at sea level. However, the mechanism of increased VA/Q mismatch on exercise remains unclear due to the correlation with both ventilatory and circulatory variables and will require further study.


Comparative chromosomal mapping of microsatellites in Leporinus species (Characiformes, Anostomidae): unequal accumulation on the W chromosomes.
Approximately 90 species in the genus Leporinus (Characiformes, Anostomidae) are known, and most of them do not present differentiated sex chromosomes. However, there is a group of 7 species that share a heteromorphic ZW sex system. In all of these species, the W chromosome is the largest one in the karyotype and is mostly heterochromatic. We investigated the distribution of several microsatellites in the genome of 4 Leporinus species that possess ZW chromosomes. Our results showed a very large accumulation of mostly microsatellites on the W chromosomes. This finding supports the presence of an interconnection between heterochromatinization and the accumulation of repetitive sequences, which has been proposed for sex chromosome evolution, and suggests that heterochromatinization is the earlier of the 2 processes. In spite of the common origin that has been proposed for W chromosomes in all of the studied species, the microsatellites followed different evolutionary trajectories in each species, which indicates a high plasticity for sex chromosome differentiation.


Prolonged Ocular Retention of Mucoadhesive Nanoparticle Eye Drop Formulation Enables Treatment of Eye Diseases Using Significantly Reduced Dosage.
Eye diseases, such as dry eye syndrome, are commonly treated with eye drop formulations. However, eye drop formulations require frequent dosing with high drug concentrations due to poor ocular surface retention, which leads to poor patient compliance and high risks of side effects. We developed a mucoadhesive nanoparticle eye drop delivery platform to prolong the ocular retention of topical drugs, thus enabling treatment of eye diseases using reduced dosage. Using fluorescent imaging on rabbit eyes, we showed ocular retention of the fluorescent dye delivered through these nanoparticles beyond 24 h while free dyes were mostly cleared from the ocular surface within 3 h after administration. Utilizing the prolonged retention of the nanoparticles, we demonstrated effective treatment of experimentally induced dry eye in mice by delivering cyclosporin A (CsA) bound to this delivery system. The once a week dosing of 0.005 to 0.01% CsA in NP eye drop formulation demonstrated both the elimination of the inflammation signs and the recovery of ocular surface goblet cells after a month. Thrice daily administration of RESTASIS on mice only showed elimination without recovering the ocular surface goblet cells. The mucoadhesive nanoparticle eye drop platform demonstrated prolonged ocular surface retention and effective treatment of dry eye conditions with up to 50- to 100-fold reduction in overall dosage of CsA compared to RESTASIS, which may significantly reduce side effects and, by extending the interdosing interval, improve patient compliance.


Thymosin beta4 and Ac-SDKP: tools to mend a broken heart.
Thymosin beta4 - an endogenously occurring 43 amino acid peptide - has recently been shown to possess cardioprotective properties in the setting of acute myocardial infarction. This review focuses on the reported mechanisms of action through which Thymosin beta4 might accomplish this effect and the clinical prospects for its use as a therapeutic agent.


Increase of ocular blood flow by some phytogenic compounds.
The effects of a number of phytogenic compounds on ocular blood flow were measured by the colored microsphere technique in rabbits. Methyltyramine and coumarin increased blood flow in all eye tissues tested. The blood flow of iris, ciliary body-iris root, retina and choroid was increased by methyltyramine for 255%, 322%, 189%, and 189%, respectively, and by coumarin for 375%, 193%, 139% and 299%, respectively, at 120 minutes after drug administration. Rescinnamine, apocynin and hesperetin also increased ocular blood flow in all eye tissues except retina. The blood flow of iris, ciliary body-iris root, and choroid was increased by rescinnamine for 344%, 234%, and 199%, respectively; by apocynin for 355%, 152%, and 414%, respectively; and by hesperetin for 265%, 136%, and 204%, respectively, at 120 minutes after drug instillation. These results indicate that these compounds could be used to treat ischemic eye diseases in the future.


Expression of transcobalamin II receptors by human leukemia K562 and HL-60 cells.
Plasma membrane receptors for the serum cobalamin-binding protein transcobalamin II (TCII) were identified on human leukemia K562 and HL-60 cells using immunoaffinity-purified human TCII labeled with [57Co]cyanocobalamin. The Bmax values for TCII receptors on proliferating K562 and HL-60 cells were 4,500 and 2,700 per cell, respectively. Corresponding dissociation constants (kd) were 8.0 x 10(-11) mol/L and 9.0 x 10(-11) mol/L. Rabbit TCII also bound to K562 and HL-60 cells but with slightly reduced affinities. Calcium was required for the binding of transcobalamin II to K562 cells. Brief treatment of these cells with trypsin resulted in almost total loss of surface binding activity. After removal of trypsin, surface receptors for TCII slowly reappeared, reaching pretrypsin treatment densities only after 24 hours. Reappearance of receptors was blocked by cycloheximide. TCII receptor densities on K562 and HL-60 cells correlated inversely with the concentration of cobalamin in the culture medium. This suggests that intracellular stores of cobalamin may affect the expression of transcobalamin receptors. Nonproliferating stationary-phase K562 cells had low TCII receptor densities (less than 1,200 receptors/cell). However, the density of TCII receptors increased substantially when cells were subcultured in fresh medium. Up-regulation of receptor expression coincided with increased 3H-thymidine incorporation, which preceded the resumption of cellular proliferation as measured by cell density. In the presence of cytosine arabinoside, which induces erythroid differentiation, K562 cells down-regulated expression of TCII receptors. When HL-60 cells were subcultured in fresh medium containing dimethysulfoxide to induce granulocytic differentiation, the up-regulation of TCII receptors was suppressed. This event occurred well before a diminution of 3H-thymidine incorporation and cessation of proliferation. Thus, changes in the regulation of expression of TCII receptors correlate with both the proliferative and differentiation status of cells.


A highly stable N-heterocyclic carbene complex of trichloro-oxo-vanadium(V) displaying novel Cl-Ccarbene bonding interactions.
Reaction of 1,3-dimesitylimidazol-2-ylidene and trichloro-oxo-vanadium(V) yields an air stable 1:1 adduct, which demonstrates the utility of N-heterocyclic carbenes to stabilize metal complexes in high oxidation states. The molecular structure of this compound reveals that the chloride ligands cis to the carbene are oriented toward the Ccarbene atom. Density functional theory calculations show that a bonding interaction occurs between lone pairs of these chlorides and the formally unoccupied p-orbital of the carbene. Previous studies indicated that this orbital was not involved in the bonding of N-heterocyclic carbenes to transition metals. The observed interaction therefore represents a new bonding mode for these widely used ligands.


Specificity of facial expression labeling deficits in childhood psychopathology.
We examined whether face-emotion labeling deficits are illness-specific or an epiphenomenon of generalized impairment in pediatric psychiatric disorders involving mood and behavioral dysregulation. Two hundred fifty-two youths (7-18 years old) completed child and adult facial expression recognition subtests from the Diagnostic Analysis of Nonverbal Accuracy (DANVA) instrument. Forty-two participants had bipolar disorder (BD), 39 had severe mood dysregulation (SMD; i.e., chronic irritability, hyperarousal without manic episodes), 44 had anxiety and/or major depressive disorders (ANX/MDD), 35 had attention-deficit/hyperactivity and/or conduct disorder (ADHD/CD), and 92 were controls. Dependent measures were number of errors labeling happy, angry, sad, or fearful emotions. BD and SMD patients made more errors than ANX/MDD, ADHD/CD, or controls when labeling adult or child emotional expressions. BD and SMD patients did not differ in their emotion-labeling deficits. Face-emotion labeling deficits differentiate BD and SMD patients from patients with ANX/MDD or ADHD/CD and controls. The extent to which such deficits cause vs. result from emotional dysregulation requires further study.


Salivary nitrite production is elevated in individuals with a higher abundance of oral nitrate-reducing bacteria.
Nitric oxide (NO) can be generated endogenously via NO synthases or via the diet following the action of symbiotic nitrate-reducing bacteria in the oral cavity. Given the important role of NO in smooth muscle control there is an intriguing suggestion that cardiovascular homeostasis may be intertwined with the presence of these bacteria. Here, we measured the abundance of nitrate-reducing bacteria in the oral cavity of 25 healthy humans using 16S rRNA sequencing and observed, for 3.5 h, the physiological responses to dietary nitrate ingestion via measurement of blood pressure, and salivary and plasma NO metabolites. We identified 7 species of bacteria previously known to contribute to nitrate-reduction, the most prevalent of which were Prevotella melaninogenica and Veillonella dispar. Following dietary nitrate supplementation, blood pressure was reduced and salivary and plasma nitrate and nitrite increased substantially. We found that the abundance of nitrate-reducing bacteria was associated with the generation of salivary nitrite but not with any other measured variable. To examine the impact of bacterial abundance on pharmacokinetics we also categorised our participants into two groups; those with a higher abundance of nitrate reducing bacteria (> 50%), and those with a lower abundance (< 50%). Salivary nitrite production was lower in participants with lower abundance of bacteria and these individuals also exhibited slower salivary nitrite pharmacokinetics. We therefore show that the rate of nitrate to nitrite reduction in the oral cavity is associated with the abundance of nitrate-reducing bacteria. Nevertheless, higher abundance of these bacteria did not result in an exaggerated plasma nitrite response, the best known marker of NO bioavailability. These data from healthy young adults suggest that the abundance of oral nitrate-reducing bacteria does not influence the generation of NO through the diet, at least when the host has a functional minimum threshold of these microorganisms.


pubmed.mineR: an R package with text-mining algorithms to analyse PubMed abstracts.
The PubMed literature database is a valuable source of information for scientific research. It is rich in biomedical literature with more than 24 million citations. Data-mining of voluminous literature is a challenging task. Although several text-mining algorithms have been developed in recent years with focus on data visualization, they have limitations such as speed, are rigid and are not available in the open source. We have developed an R package, pubmed.mineR, wherein we have combined the advantages of existing algorithms, overcome their limitations, and offer user flexibility and link with other packages in Bioconductor and the Comprehensive R Network (CRAN) in order to expand the user capabilities for executing multifaceted approaches. Three case studies are presented, namely, 'Evolving role of diabetes educators', 'Cancer risk assessment' and 'Dynamic concepts on disease and comorbidity' to illustrate the use of pubmed.mineR. The package generally runs fast with small elapsed times in regular workstations even on large corpus sizes and with compute intensive functions. The pubmed.mineR is available at http://cran.rproject. org/web/packages/pubmed.mineR.


Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer.
Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).


Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma.
Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their use in pediatric brain cancers is lacking. Here we investigated the potential role for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in medulloblastoma and ependymoma. Dose-dependent cytotoxicity of medulloblastoma and ependymoma cells was induced by THC and CBD in vitro, and a synergistic reduction in viability was observed when both drugs were combined. Mechanistically, cannabinoids induced cell cycle arrest, in part by the production of reactive oxygen species, autophagy, and apoptosis; however, this did not translate to increased survival in orthotopic transplant models despite being well tolerated. We also tested the combination of cannabinoids with the medulloblastoma drug cyclophosphamide, and despite some in vitro synergism, no survival advantage was observed in vivo. Consequently, clinical benefit from the use of cannabinoids in the treatment of high-grade medulloblastoma and ependymoma is expected to be limited. This study emphasizes the importance of preclinical models in validating therapeutic agent efficacy prior to clinical trials, ensuring that enrolled patients are afforded the most promising therapies available.


Eccentric hip muscle function in females with and without patellofemoral pain syndrome.
Patellofemoral pain syndrome (PFPS) is a common knee condition in athletes. Recently, researchers have indicated that factors proximal to the knee, including hip muscle weakness and motor control impairment, contribute to the development of PFPS. However, no investigators have evaluated eccentric hip muscle function in people with PFPS. To compare the eccentric hip muscle function between females with PFPS and a female control group. Cross-sectional study. Musculoskeletal laboratory. two groups of females were studied: a group with PFPS (n = 10) and a group with no history of lower extremity injury or surgery (n = 10). Eccentric torque of the hip musculature was evaluated on an isokinetic dynamometer. Eccentric hip abduction, adduction, and external and internal rotation peak torque were measured and expressed as a percentage of body mass (Nm/kg x 100). We also evaluated eccentric hip adduction to abduction and internal to external rotation torque ratios. The peak torque value of 5 maximal eccentric contractions was used for calculation. Two-tailed, independent-samples t tests were used to compare torque results between groups. Participants with PFPS exhibited much lower eccentric hip abduction (t(18) = -2.917, P = .008) and adduction (t(18) = -2.764, P = .009) peak torque values than did their healthy counterparts. No differences in eccentric hip external (t(18) = 0.45, P = .96) or internal (t(18) = -0.742, P = .47) rotation peak torque values were detected between the groups. The eccentric hip adduction to abduction torque ratio was much higher in the PFPS group than in the control group (t(18) = 2.113, P = .04), but we found no difference in the eccentric hip internal to external rotation torque ratios between the 2 groups (t(18) = -0.932, P = .36). Participants with PFPS demonstrated lower eccentric hip abduction and adduction peak torque and higher eccentric adduction to abduction torque ratios when compared with control participants. Thus, clinicians should consider eccentric hip abduction strengthening exercises when developing rehabilitation programs for females with PFPS.


Modelling the initial spread of foot-and-mouth disease through animal movements.
Livestock movements in Great Britain (GB) are well recorded and are a unique record of the network of connections among livestock-holding locations. These connections can be critical for disease spread, as in the 2001 epidemic of foot-and-mouth disease (FMD) in the UK. Here, the movement data are used to construct an individual-farm-based model of the initial spread of FMD in GB and determine the susceptibility of the GB livestock industry to future outbreaks under the current legislative requirements. Transmission through movements is modelled, with additional local spread unrelated to the known movements. Simulations show that movements can result in a large nationwide epidemic, but only if cattle are heavily involved, or the epidemic occurs in late summer or early autumn. Inclusion of random local spread can considerably increase epidemic size, but has only a small impact on the spatial extent of the disease. There is a geographical bias in the epidemic size reached, with larger epidemics originating in Scotland and the north of England than elsewhere.


Spatial variation of epoxyscillirosidine concentrations in Moraea pallida (yellow tulp) in South Africa.
Moraea pallida (yellow tulp) poisoning is economically the most important intoxication of livestock in South Africa. Poisoning varies according to locality, climatic conditions and growth stage of the plant. The primary objective of this study was to determine the concentration of the toxic principle, epoxyscillirosidine, in yellow tulp leaves and to ascertain the variability of epoxyscillirosidine concentrations within and between different locations. A secondary objective was to utilise Geographic Information Systems in an attempt to explain the variability in toxicity. Flowering yellow tulp plants were collected at 26 sampling points across 20 districts of South Africa. The leaves of five plants per sampling point were extracted and submitted for liquid chromatography/mass spectrometry analysis. A large variation in mean epoxyscillirosidine concentrations, ranging from 3.32 μg/g - 238.27 μg/g, occurred between different geographical regions. The epoxyscillirosidine concentrations also varied tremendously between individual plants (n = 5) collected at the same sampling point, with up to a 24 times difference between the lowest and highest concentration detected. No generalised correlation between epoxyscillirosidine concentrations and soil elemental concentrations could be established. However, samples obtained from the north-eastern part of the sampling region tended to have higher epoxyscillirosidine concentrations compared to samples obtained from the south-western part of the sampling region. Higher toxin concentrations in the north-east were associated with statistically significant higher soil concentrations of iron, bismuth, bromide, cadmium, chromium, rubidium, tellurium, thallium, titanium and zinc, whilst soil concentrations of strontium and soil pH, were significantly lower. This study corroborated the contention that epoxyscillirosidine concentration in yellow tulp fluctuates and may explain the variability in toxicity.