A chemogenomic approach to identify personalized therapy for patients with relapse or refractory acute myeloid leukemia: results of a prospective feasibility study.
Targeted next-generation sequencing (tNGS) and ex vivo drug sensitivity/resistance profiling (DSRP) have laid foundations defining the functional genomic landscape of acute myeloid leukemia (AML) and premises of personalized medicine to guide treatment options for patients with aggressive and/or chemorefractory hematological malignancies. Here, we have assessed the feasibility of a tailored treatment strategy (TTS) guided by systematic parallel ex vivo DSRP and tNGS for patients with relapsed/refractory AML (number NCT02619071). A TTS issued by an institutional personalized committee could be achieved for 47/55 included patients (85%), 5 based on tNGS only, 6 on DSRP only, while 36 could be proposed on the basis of both, yielding more options and a better rationale. The TSS was available in <21 days for 28 patients (58.3%). On average, 3 to 4 potentially active drugs were selected per patient with only five patient samples being resistant to the entire drug panel. Seventeen patients received a TTS-guided treatment, resulting in four complete remissions, one partial remission, and five decreased peripheral blast counts. Our results show that chemogenomic combining tNGS with DSRP to determine a TTS is a promising approach to propose patient-specific treatment options within 21 days.


Musical experience modulates categorical perception of lexical tones in native Chinese speakers.
Although musical training has been shown to facilitate both native and non-native phonetic perception, it remains unclear whether and how musical experience affects native speakers' categorical perception (CP) of speech at the suprasegmental level. Using both identification and discrimination tasks, this study compared Chinese-speaking musicians and non-musicians in their CP of a lexical tone continuum (from the high level tone, Tone1 to the high falling tone, Tone4). While the identification functions showed similar steepness and boundary location between the two subject groups, the discrimination results revealed superior performance in the musicians for discriminating within-category stimuli pairs but not for between-category stimuli. These findings suggest that musical training can enhance sensitivity to subtle pitch differences between within-category sounds in the presence of robust mental representations in service of CP of lexical tonal contrasts.


Ready, aim, reform.
Now that President Clinton has finally submitted the details of his massive plan to overhaul the nation's health care system, the legislative and political challenges that confront Capitol Hill lawmakers--especially Democrats--seem steeper than ever before.


Arterial stiffness induced by carotid calcification leads to cerebral gliosis mediated by oxidative stress.
Arterial stiffness is a risk factor for cognitive decline and dementia. However, its precise effects on the brain remain unexplored. Using a mouse model of carotid stiffness, we investigated its effect on glial activation and oxidative stress. Arterial stiffness was induced by the application of calcium chloride to the adventitial region of the right carotid. Superoxide anion production, NADPH activity and levels, as well as glial activation were examined with immunohistochemical and biochemical approaches, 2-week postcalcification. Antioxidant treatment was done with Tempol (1 mmol/l) administered in the drinking water during 2 weeks. The current study revealed that arterial stiffness increases the levels of the microglial markers ionized calcium-binding adapter molecule 1 and cluster of differentiation 68 in hippocampus, and of the astrocyte marker, s100 calcium binding protein β in hippocampus and frontal cortex. The cerebral inflammatory effects of arterial stiffness were specific to the brain and not due to systemic inflammation. Treatment with Tempol prevented the increase in superoxide anion in mice with carotid stiffness and attenuated the activation of microglia and astrocytes in the hippocampus. To determine whether the increased oxidative stress derives from NADPH oxidase, superoxide anion production was assessed by incubating brain tissue in the presence of gp91ds-tat, a selective NADPH oxidase 2 inhibitor. This peptide inhibited superoxide anion production to a greater extent in the brains of mice with carotid calcification compared with controls. Carotid calcification leads to cerebral gliosis mediated by oxidative stress. Correcting arterial stiffness could offer a novel paradigm to protect the brain in populations where stiffness is prominent.


Water permeability of apical and basolateral cell membranes of rat inner medullary collecting duct.
To quantify the pathways for water permeation through the kidney medulla, knowledge of the water permeability (Posmol) of individual cell membranes in inner medullary collecting duct (IMCD) is required. Therefore IMCD segments from the inner two thirds of inner medulla of Sprague-Dawley rats were perfused in vitro using a setup devised for rapid bath and luminal fluid exchanges (half time, t1/2, of 55 and 41 ms). Differential interference contrast microscopy, coupled to video recording, was used to measure volume and approximate surface areas of single cells. Volume and volume-to-surface area ratio of IMCD cells were strongly correlated with their position along the inner medullary axis. Transmembrane water flow (Jv) was measured in response to a variety of osmotic gradients (delta II) presented on either basolateral or luminal side of the cells. The linear relation between Jv and delta II yielded the cell membrane Posmol, which was then corrected for membrane infoldings. Basolateral membrane Posmol was 126 +/- 3 microns/s. Apical membrane Posmol rose from a basal value of 26 +/- 3 microns/s to 99 +/- 5 microns/s in presence of antidiuretic hormone (ADH). Because of amplification of basolateral membrane, the ADH-stimulated apical membrane remained rate-limiting for transcellular osmotic water flow, and the IMCD cell did not swell significantly. Calculated transcellular Posmol, expressed in terms of smooth luminal surface, was 64 microns/s without ADH and 207 microns/s with ADH. IMCD cells in anisosmotic media displayed almost complete volume regulatory decrease but only partial volume regulatory increase.


Bi-component dictionary matching for MR fingerprinting for efficient quantification of fat fraction and water T1 in skeletal muscle.
To propose an efficient bi-component MR fingerprinting (MRF) fitting method using a Variable Projection (VARPRO) strategy, applied to the quantification of fat fraction (FF) and water T1 ( T 1 H 2 0 $$ \mathrm{T}{1}_{{\mathrm{H}}_20} $$ ) in skeletal muscle tissues. The MRF signals were analyzed in a two-step process by comparing them to the elements of separate water and fat dictionaries (bi-component dictionary matching). First, each pair of water and fat dictionary elements was fitted to the acquired signal to determine an optimal FF that was used to merge the fingerprints in a combined water/fat dictionary. Second, standard dictionary matching was applied to the combined dictionary for determining the remaining parameters. A clustering method was implemented to further accelerate the fitting. Accuracy, precision, and matching time of this approach were evaluated on both numerical and in vivo datasets, and compared to the reference dictionary-matching approach that includes FF as a dictionary parameter. In numerical phantoms, all MRF parameters showed high correlation with ground truth for the reference and the bi-component method (R2 > 0.98). In vivo, the estimated parameters from the proposed method were highly correlated with those from the reference approach (R2 > 0.997). The bi-component method achieved an acceleration factor of up to 360 compared to the reference dictionary matching. The proposed bi-component fitting approach enables a significant acceleration of the reconstruction of MRF parameter maps for fat-water imaging, while maintaining comparable precision and accuracy to the reference on FF and T 1 H 2 0 $$ \mathrm{T}{1}_{{\mathrm{H}}_20} $$ estimation.


Systematic review and meta-analysis of the utility of long non-coding RNA GAS5 as a diagnostic and prognostic cancer biomarker.
The growth arrest-specific 5 transcript (GAS5) is a long non-coding RNA (lncRNA) involved in the control of cell cycle progression and apoptosis in a wide variety of cells. To determine the clinical value of GAS5 expression in cancer patients, we performed a systematic review and meta-analysis exploring its association with the diagnosis, prognosis, and clinicopathological characteristics of cancer. Ten articles on prognosis, 15 on clinicopathology, and 5 on diagnosis were analyzed. Overall results showed that decreased GAS5 expression associated with unfavorable overall survival (OS) (HR = 2.50, 95%CI: 1.85-3.38, P < 0.001) and disease-free survival (DFS) (HR = 2.24, 95%CI: 1.58-3.18, P < 0.001) in several tumor types. Down-regulation of GAS5 correlated with poor recurrence-free survival (RFS) in hepatocellular carcinoma (HR = 2.40, 95%CI: 1.27-4.54, P = 0.007), and was associated with lymph node metastasis (OR = 1.92, 95% CI: 1.44-2.57, P < 0.001), distant metastasis (OR = 2.7, 95% CI: 1.05-6.97, P = 0.040), poor clinical stage (OR = 0.26, 95% CI: 0.18-0.38, P < 0.001), larger tumor size (OR = 3.21, 95% CI: 2.08-4.95, P < 0.001), and poor tumor differentiation (OR = 1.98, 95% CI: 1.40-2.80, P < 0.001). Pooled results of diagnostic data analysis showed that GAS5 exhibited a sensitivity of 0.76 and specificity of 0.64 for cancer diagnosis, and an area under the curve of 0.76 (95% CI: 0.72-0.80) indicated moderate diagnostic accuracy. This meta-analysis suggests GAS5 lncRNA may be a useful diagnostic and prognostic cancer biomarker, and may be especially useful for identifying patients prone to developing lymph node or distant metastasis.


Multi-omics analysis of synovial fluid: a promising approach in the study of osteoarthritis.
Osteoarthritis (OA), affecting 250 million individuals worldwide, is a significant social health problem. Therefore, the search for synovial fluid (SF) biomarkers that could anticipate the diagnosis of OA is gaining increasing importance in orthopaedics. This review summarizes the recent progresses preformed in the multi-omics approach to OA, mainly focusing on proteome and metabolome analysis of SF. Proteomics of the SF has shown the up-regulation of several components of the classic complement pathway in OA samples, including C1, C2, C3, C4A, C4B, C5 and C4 C4BPA, thus depicting that complement is involved in the pathogenesis of OA. Moreover, proteomics has displayed that some pro-inflammatory cytokines, namely IL-6, IL-8 and IL-18, have a role in OA. The metabolomic profiling of the SF in OA has identified some metabolites as potential biomarkers of OA and has shown the existence of metabolically different OA subgroups. However, further studies with larger samples sizes and matched-control groups are needed to identify SF biomarkers that could be useful in the diagnosis, treatment and follow-up of OA.


Nostopeptolide plays a governing role during cellular differentiation of the symbiotic cyanobacterium Nostoc punctiforme.
Nostoc punctiforme is a versatile cyanobacterium that can live either independently or in symbiosis with plants from distinct taxa. Chemical cues from plants and N. punctiforme were shown to stimulate or repress, respectively, the differentiation of infectious motile filaments known as hormogonia. We have used a polyketide synthase mutant that accumulates an elevated amount of hormogonia as a tool to understand the effect of secondary metabolites on cellular differentiation of N. punctiforme. Applying MALDI imaging to illustrate the reprogramming of the secondary metabolome, nostopeptolides were identified as the predominant difference in the pks2(-) mutant secretome. Subsequent differentiation assays and visualization of cell-type-specific expression of nostopeptolides via a transcriptional reporter strain provided evidence for a multifaceted role of nostopeptolides, either as an autogenic hormogonium-repressing factor or as a chemoattractant, depending on its extracellular concentration. Although nostopeptolide is constitutively expressed in the free-living state, secreted levels dynamically change before, during, and after the hormogonium differentiation phase. The metabolite was found to be strictly down-regulated in symbiosis with Gunnera manicata and Blasia pusilla, whereas other metabolites are up-regulated, as demonstrated via MALDI imaging, suggesting plants modulate the fine-balanced cross-talk network of secondary metabolites within N. punctiforme.


PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome.
We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 126.96.36.199)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 220.127.116.11) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.


Clinical and microbiological effects of root debridement in periodontal furcation pockets.
The aim of the present study was to investigate longitudinally over 52 weeks the clinical and microbiological effects of plaque control and root debridement at molar furcation sites. The results were compared with changes at non-molar sites. 24 non-molar sites and 31 grade II molar furcation sites with probing depth greater than or equal to 5.0 mm were monitored in 11 patients. Clinical measurements consisted of plaque scores, probing depths, and changes in probing attachment level. Microbiological monitoring was carried out with phase-contrast microscopy and anaerobic culturing. The debridement resulted in improvement in probing measurements and microbiological counts for both groups of sites. A slightly less favorable clinical response was noted for molar furcation sites. Higher post-operative microbiological counts were found throughout the 52-week observation period for molar furcation sites. Sites with probing attachment loss showed higher microbial counts and higher proportions of spirochetes, black pigmented colony forming units (CFU), and Bacteroides gingivalis CFU than sites with probing attachment gain. Individual site analysis, however, demonstrated marked variations of the microbiological counts at the different postoperative time points. In the few available sites undergoing probing attachment loss, no apparent association between target micro-organisms and periodontal deterioration was observed.


Stability of captopril in SyrSpend SF.
Captopril is an angiotensin-converting enzyme inhibitor available as a tablet. Patients who are unable to take tablets have led compounding pharmacies to seek alternative dosage forms including solutions and suspensions. The objective of this study was to determine the stability of captopril in sorbitol-free, alcohol-free SyrSpend SF suspending agent. The studied samples were compounded into a 0.8-mg/mL suspension and stored in low-actinic plastic bottles at temperatures between 2 degrees C to 8 degrees C. Six samples were assayed at each time point out to 32 days by a stability-indicating high-performance liquid chromatography method. The samples remained within 90% to 110% of the initial concentration throughout day 14 of the study. Based on the data collected, the beyond- use date of these preparations is 14 days when protected from light and refrigerated.


Screening of Coulomb interactions in liquid dielectrics.
The interaction of charges in dielectric materials is screened by the dielectric constant of the bulk dielectric. In dielectric theories, screening is assigned to surface charges appearing from preferential orientations of dipoles along the local field in the interface. For liquid dielectrics, such interfacial orientations are affected by the interfacial structure characterized by a separate interfacial dipolar susceptibility. We argue that dielectric properties of polar liquids should be characterized by two distinct susceptibilities responsible for local response (solvation) and long-range response (dielectric screening). A microscopic model for dipolar screening in polar liquids is developed here. It shows that the standard bulk dielectric constant is responsible for screening at large distances. The potential of mean force between ions in polar liquids becomes oscillatory at short distances. Oscillations arise from the coupling of collective longitudinal excitations (dipolarons) of the polar liquid with its interfacial density profile. Interfacial electrostatics demonstrates a crossover beyond the solute radius of ∼1 nm from the scaling laws roughly consistent with continuum expectations for small solutes to new scaling trends characterizing the much softer nano-scale solute-solvent interface. This crossover also marks the transition to a continuum-type electrostatic screening between ions, when short-distance oscillation of the potential of mean force become strongly damped. Screening oscillations are enhanced for more structured interfaces.


Identification of feature risk pathways of smoking-induced lung cancer based on SVM.
The present study aims to explore the role of smoking factors in the risk of lung cancer and screen the feature risk pathways of smoking-induced lung cancer. The expression profiles of the patient data from GEO database were standardized, and differentially expressed genes (DEGs) were analyzed by limma algorithm. Samples and genes were analyzed by Unsupervised hierarchical clustering method, while GO and KEGG enrichment analyses were performed on DEGs. The data of the protein-protein interaction (PPI) network were downloaded from the BioGrid and HPRD databases, and the DEGs were mapped into the PPI network to identify the interaction relationship. The enriched significant pathways were used to calculate the anomaly score and RFE method was used to optimize the feature sets. The model was trained using the support vector machine (SVM) and the predicted results were plotted into ROC curves. The AUC value was calculated to evaluate the predictive performance of the SVM model. A total of 1923 DEGs were obtained, of which 826 were down-regulated and 1097 were up-regulated. Unsupervised hierarchical clustering analysis showed that the diagnosis accuracy of lung cancer smokers was 74%, and that of non-lung cancer smokers was 75%. Five optimal feature pathway sets were obtained by screening, the clinical diagnostic ability of which was detected by SVM model with the accuracy improved to 84%. The diagnostic accuracy was 90% after combining clinical information. We verified that five signaling pathways combined with clinical information could be used as a feature risk pathway for identifying lung cancer smokers and non-lung cancer smokers and increased the diagnostic accuracy.


Epidemiology of hepatitis B in Sweden.
All the cases of clinical hepatitis B reported in Sweden since 1969 have been studied. The 10-year period 1976-1985 has been analysed intensively. For comparative purposes, the study also includes the hepatitis cases reported in 1962 and 1967. Serum hepatitis first affected young adults aged 15-24 years at the beginning of the 1960s. Cyclical outbreaks of hepatitis B due to transmission among drug abusers have been recognised since 1969. The disease was first observed in urban areas but later in rural parts of Sweden also. After 1976, a year in which outbreaks arose in various parts of Sweden, the numbers of hepatitis B cases decreased. In 1969, more than 50% of the cases reported as serum hepatitis concerned drug abusers. During the period 1976-1985, the main risk factor was drug abuse for between 20 and 52% of cases and sexual activity for between 8 and 28% of cases. Since 1969, 2-3% of cases annually have been related to blood-transfusion. In the last 5-year period, a total of 129 cases was reported among persons employed in the medical and dental fields. Of these, 59 had non-occupational exposure. During the same period, 33 patients reported contacts with infected persons, mostly household contacts. Seventy five persons had been travelling abroad.


In vivo analysis of the spontaneous firing of cerebellar Purkinje cells in awake transgenic mice that model spinocerebellar ataxia type 2.
Cerebellar Purkinje cells (PCs) fire spontaneously in a tonic mode, although the precision of this pacemaking activity is disturbed in many abnormal conditions involving cerebellar atrophy, such as many spinocerebellar ataxias (SCAs). In our previous studies we used the single-unit extracellular recording method to analyze spontaneous PC firing in vivo in the anesthetized SCA2-58Q transgenic mice. We realized that PCs from aging SCA2-58Q mice fire much less regularly compared to PCs from their wild type (WT) littermates and this abnormal activity can be reversed with an intraperitoneal (i. p.) injection of SK channel-positive modulator chlorzoxazone (CHZ). Here we used the same single-unit extracellular recording method to analyze the spontaneous firing in vivo in awake SCA2-58Q transgenic mice. For this purpose, we used the Mobile HomeCage (Neurotar, Finland) floating platform to immobilize the experimental animal's head during the recording sessions. We discovered that generally PCs from awake animals fired much more frequently and much less regularly than previously observed PCs from anesthetized animals. In vivo recordings from awake SCA2/WT mice revealed that complex spikes, which are generated by PCs in reply to the excitation coming by climbing fibers, as well as simple spikes, were much less frequent in SCA2 mice compared to their WT littermates. To test the effect of the SK channel positive modulation on the PCs firing activity in awake SCA2 mice and also the effect on their motor coordination, we started the CHZ trial in these mice. We discovered that the long-term i. p. injections of CHZ did not affect the spike generation in SCA2-58Q mice, however, they did recover the precision of this spontaneous pacemaking activity. Furthermore, we also showed that treatment with CHZ alleviated the age-dependent motor impairment in SCA2-58Q mice. We propose that the lack of precision in PC spike generation might be a key cause for the progression of ataxic symptoms in different SCAs and that the activation of calcium-activated potassium channels, including SK channels, can be used as a potential way to treat SCAs on the physiological level of the disease.


Protection of Animals during Transport: Analysis of the Infringements Reported from 2009 to 2013 during On-Road Inspections in Italy.
Council Regulation (EC) No 1/2005 requires that vehicles that are transporting animals be subjected to checks conducted by competent authorities. Yearly, each member state sends a report to the European government on the infringements that have been discovered during on-road inspections. The reports that were published by the Italian Ministry of Public Health from 2009 to 2013 were analyzed. Possible associations between the type of infringement (related to animal welfare (AW), vehicle (V) and accompanying documents (D)), year, season, transported species, place of inspection, and competent authorities were identified. A total of 985 infringements were analyzed, with some vehicles receiving more than one (mean: 1.58; max: 9). A score (from 1 to 3) that was related to the severity of the infringements was created. In 2009 and 2010, there was a 50% higher probability of encountering penalties of a lower severity (D or V) than in 2011 (p < 0.0001). Vehicles that were transporting pigs showed the highest probability of committing animal welfare-related infringements (odds ratio (OR) = 3.85, 95% confidence interval (95%CI) = 1.82-8.76, p < 0.0001). Vehicles were four times more likely to suffer animal welfare-related penalties when traffic police worked in synergy with veterinary services (OR = 4.12, 95%CI = 1.70-11.13, p = 0.0005). Vehicles that were transporting Equidae and "other species," including pets, for commercial purposes were more likely to be fined for a lack or incompleteness of the veterinary documents than those transporting cattle (p = 0.002 and p = 0.004, respectively). This study gives statistical evidence of the implementation of EC 1/2005. The training of transporters and drivers on how to manage transport in an animal welfare-friendly manner and a standardized method on how to conduct road inspections among competent authorities are recommended.


Prediction of caregiver burden in amyotrophic lateral sclerosis: a machine learning approach using random forests applied to a cohort study.
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that is characterised by the rapid degeneration of upper and lower motor neurons and has a fatal trajectory 3-4 years from symptom onset. Due to the nature of the condition patients with ALS require the assistance of informal caregivers whose task is demanding and can lead to high feelings of burden. This study aims to predict caregiver burden and identify related features using machine learning techniques. This included demographic and socioeconomic information, quality of life, anxiety and depression questionnaires, for patients and carers, resource use of patients and clinical information. The method used for prediction was the Random forest algorithm. This study investigates a cohort of 90 patients and their primary caregiver at three different time-points. The patients were attending the National ALS/Motor Neuron Disease Multidisciplinary Clinic at Beaumont Hospital, Dublin. The caregiver's quality of life and psychological distress were the most predictive features of burden (0.92 sensitivity and 0.78 specificity). The most predictive features for Clinical Decision Support model were associated with the weekly caregiving duties of the primary caregiver as well as their age and health and also the patient's physical functioning and age of onset. However, this model had a lower sensitivity and specificity score (0.84 and 0.72, respectively). The ability of patients without gastrostomy to cut food and handle utensils was also highly predictive of burden in this study. Generally, our models are better in predicting the high-risk category, and we suggest that information related to the caregiver's quality of life and psychological distress is required. This work demonstrates a proof of concept of an informatics solution to identifying caregivers at risk of burden that could be incorporated into future care pathways.


[The finding of Panstrongylus megistus in an artificial ecotope: taking up residence or merely visiting?].
As a first measure of Chagas' disease control in Brazil with chemical elimination of the most important vector of the disease, Triatoma infestans was removed. Attention is now being paid to Triatoma sordida and Panstrongylus megistus. That species can eventually be found inside houses, as happened with the specimens we examined from Bernardino de Campos and Sete Barras, all of them infected by Trypanosoma cruzi. These data suggest that a better knowledge about the behavior that species is needed to introduce changes in the control measures.


The BLOODSAFE program: Building the future of access to safe blood in Sub-Saharan Africa.
The supply of blood in many low- and middle-income nations in Sub-Saharan Africa (SSA) does not meet the patient care needs. Lack and delay of blood transfusion cause harm to patients and slow the rate of progress in other parts of the health system. Recognizing the power of implementation science, the BLOODSAFE Program was initiated which supports three SSA research study teams and one data coordinating center (DCC) with the goal to improve access to safe blood transfusion in SSA. The study team in Ghana is focusing on studying and decreasing iron deficiency in blood donors and evaluating social engagement of blood donors through different approaches. The study team in Kenya is building a "vein to vein" workflow model to elucidate and devise strategies to overcome barriers to blood donation and improve infrastructural components of blood product production and use. The Malawi team is studying the infectious disease ramifications of blood donation as well as blood donor retention strategies aimed at blood donors who commence their donation career in secondary schools. Together the project teams and the DCC work as a consortium to support each other through a shared study protocol that will study donor motivations, outcomes, and adverse events across all three countries. The BLOODSAFE Program has the potential to lead to generalizable improvement approaches for increasing access to safe blood in SSA as well as mentoring and building the research capacity and careers of many investigators.


Structured case reviews for organizational learning about diagnostic vulnerabilities: initial experiences from two medical centers.
Background An organization's ability to identify and learn from opportunities for improvement (OFI) is key to increasing diagnostic safety. Many lack effective processes required to capitalize on these learning opportunities. We describe two parallel attempts at creating such a process and identifying generalizable lessons and learn from them. Methods Triggered case review programs were created independently at two organizations, Site 1 (Regions Hospital, HealthPartners, Saint Paul, MN, USA) and site 2 (University of California, San Diego). Both used a five-step process to create the review system and provide feedback: (1) identify trigger criteria; (2) establish a review panel; (3) develop a system to conduct reviews; (4) perform reviews; and (5) provide feedback. Results Site 1 identified 112 OFI in 184 case reviews (61%), with 66 (59%) provider OFI and 46 (41%) system OFI. Site 2 focused mainly on systems OFI identifying 105 OFI in 346 cases (30%). Opportunities at both sites were variable; common themes included test result management and communication across teams in peri-procedural care and with consultants. Of provider-initiated reviews, 67% of cases had an OFI at site 1 and 87% at site 2. Conclusions Lessons learned include the following: (1) peer review of cases provides opportunities to learn and calibrate diagnostic and management decisions at an organizational level; (2) sharing cases in review groups supports a culture of open discussion of OFIs; (3) reviews focused on diagnostic safety identify opportunities that may complement other organization-wide review opportunities.


Survival of Staphylococcus aureus in intraperitoneal abscesses.
An examination of 10 strains of Staphylococcus aureus for survival within abscesses developing in the peritoneal cavity of mice revealed three distinct patterns of survival. Although non-haemolytic mutants were destroyed more rapidly than were their parent strains, this difference could not be attributed to any particular haemolysin. In abscesses generated with mixtures of non-haemolytic variants and their parent strains, the former were preferentially eliminated; this suggests that the non-haemolytic variants were inherently more sensitive to the conditions within these lesions. Subsequent studies confirmed that abscess homogenates were cidal for staphylococci and that this activity resided in the insoluble fraction of the homogenates. Staphylococci added to abscess homogenates were killed, but only after a lag. This lag could be shortened or eliminated by incubating homogenates before adding the test organism. After development of a suitable assay, it was found that the cidal activity in abscess homogenates could be increased 3-20-fold by pre-incubation. Staphylococcal strains differed in their relative sensitivities to the cidal material; those strains rapidly destroyed within abscesses were the most sensitive and strains capable of better survival were more resistant. The results support the concept that the cidal material is responsible for destruction of staphylococci within such lesions.


Decreased capacitance response with age in lower limbs of humans--a potential error in the study of cardiovascular reflexes in ageing.
The cardiovascular regulation in humans depends to a major extent on sympathetic reflexes originating from volume receptors in the arterial as well as the cardiopulmonary region. With experimental approaches, such as lower body negative pressure (LBNP) and tilting, signs of reduced efficiency with ageing have been shown. However, a confounding factor may be an age-related decline in venous capacitance response of the lower limbs, reducing the decrease in central blood volume and thus the deactivation of baro/cardiopulmonary receptors. This potential error was addressed in the present study. Central hypovolaemic stress was produced by LBNP 60 cmH2O in 10 young (mean age 23, range 20-25 years) and 10 old males (mean age 65, range 61-70 years). Changes in tissue volume of the calf were studied by strain gauge volumetric technique. Transmission of negative pressure to the calf muscle was studied in two young and two old volunteers. The haemodynamic response to hypovolaemic circulatory stress was attenuated in the old as compared with the young subjects, with a less marked increase in heart rate and peripheral resistance. Further, in the old subjects, the decrease in systolic blood pressure, pulse pressure and forearm blood flow was attenuated. Transmission of negative pressure to the calf was equal in both groups. The capacitance response was reduced with age from 2.27 +/- 0.14 to 1.64 +/- 0.13 mL 100 mL-1 (P < 0.005). However, the net capillary fluid filtration was unchanged. The reduced capacitance function might partly explain the declining reflex responses with age in humans, and thus seems to be of considerable importance when studying cardiovascular sympathetic reflex responses in ageing.


Combination of Fenton oxidation and composting for the treatment of the olive solid residue and the olive mile wastewater from the olive oil industry in Cyprus.
Co-composting of olive oil solid residue (OOSR) and treated wastewaters (with Fenton) from the olive oil production process has been studied as an alternative method for the treatment of wastewater containing high organic and toxic pollutants in small olive oil industry in Cyprus. The experimental results indicated that the olive mill wastewater (OMW) is detoxified at the end of Fenton Process and the COD is reduced up to 70%. The final co-composted material of OOSR with the treated olive mile wastewater (TOMW) is presented with optimum characteristics and is suitable for agricultural purpose. The final product coming out from an in-Vessel reactor seems to mature faster than the product from the windrow system and is presented with a better soil conditioner.


When should we define the response rates in the treatment of bone metastases by palliative radiotherapy?
It is well established that palliative radiotherapy provides effective pain relief for symptomatic bone metastases, but controversy remains regarding the optimal dose fractionation. Several meta-analyses and systematic reviews of trials comparing the efficacy of single vs multiple fractionated radiotherapy schedules noted that it is difficult to reach a consensus when inconsistent response end point definitions are used. The purpose of this study was to determine when the most appropriate time to evaluate a response is. Patients with symptomatic bone metastases treated with palliative radiotherapy between May 2003 and June 2005 were enrolled in the study. They were assessed with the Brief Pain Inventory at baseline, 1, 2 and 3 months after radiotherapy. Analgesic consumption during the preceding 24h was recorded and converted into an equivalent total daily dose of oral morphine. The response to radiotherapy was assessed using the International Bone Metastases Consensus end point definitions at 1, 2 and 3 months of follow-up. One hundred and ninety-nine patients were treated with palliative radiotherapy. All pain scores and functional interference items improved after radiotherapy. The proportion of evaluable patients with a complete response or a partial response increased between 1 month (58%) and 3 months of follow-up (67%). However, when considering intention-to-treat percentages, which take attrition into consideration, overall response rates dropped from 35% at 1 month, to 32% at 2 months, and finally 24% at 3 months. We conclude that 2 months after radiotherapy is the most appropriate time point to measure response rates for two reasons: (i) the maximum pain relief for some patients may take more than 4 weeks to achieve and (ii) attrition poses a major problem when response rates are measured at a later date. Future trials should use standardised criteria for end points to facilitate comparison and analysis across clinical trials. Given the limitations of this study, however, further investigations are needed to confirm the response time points for palliative cancer patients.


Cerebral alveolar echinococcosis. A case report with MRI and review of the literature.
Alveolar echinococcosis is an important zoonotic infection caused by the larval stage of the Echinococcus multilocularis. It is endemic to North America, Central Europa, Russia, China and Turkey. The liver and the lung are the organs most commonly involved. Cerebral alveolar echinococcosis is rare accounting for only 1% of cases. We present a 55-year-old patient with a right frontal mass. T2-weighted MRI series revealed a grape like multilobular, heterogeneous mass with low density. A diagnosis of glial tumor was made. The mass was totally removed. The histopathological examination showed a diffuse growth composed of compartments that are filled with a gelatinous matrix and many brood capsules and protoscolices filled with necrotic tissue. Histopathological findings were consistent with the diagnosis of alveolar echinococcosis. No postoperative complications were observed. There were no lesions in the liver and lungs. The patient was started on albendazole (ABZ) at a daily dosage of 800 mg for 3 months. The patient has remained free of any mass lesion for 5 years. Hypointense grape-like mass with calcification and surrounding white matter edema in T2-weighted MRI should suggest cerebral alveolar echinococcosis. Radical surgery and an adjuvant therapy with ABZ provides useful prolongation of life.


[Multislice helical CT (MSCT) for mid-facial trauma: Optimization of parameters for scanning and reconstruction].
To determine the optimal scan parameters in multislice helical CT (MSCT) of the facial bone complex for both axial scanning and multiplanar reconstructions. An anthropomorphic skull phantom was examined with a MSCT. Axial scans were performed with continuously increasing collimations (4 x 1.25 - 4 x 2.5 mm), tube current (20 - 200 mA) and table speeds (3.75 mm/rot. and 7.5 mm/rot.). Multiplanar reconstructions in coronal and parasagittal planes with different reconstruction increment and slice thickness were evaluated in terms of image noise, contour artifacts and visualisation of anatomical structures. The best image quality was obtained with a collimation of 4 x 1.25 mm and a table speed of 3.75 mm/rot. A reconstruction increment of 0.6 mm achieved the best time to image quality relation. With these parameters the bone structures were depicted in an optimal way without artifacts. The tube current could be reduced to 50 mA without significant loss of image quality. The optimized protocol was used for regular routine examinations in patients with facial trauma (n = 66). Low-dose MSCT using thin collimation, low table speed and small reconstruction increments provides excellent data for both axial images and multiplanar reconstructions in patients with facial trauma. An additional examination in coronal orientation is therefore no longer necessary.


Hallux adductus as a surgical complication.
The authors correlate pertinent literature with their experience in discussing hallux adductus as a postoperative complication. Presented is the accurate terminology of hallux adductus to describe the transverse plane abnormality. Hallux adductovarus is utilized if there is an additional frontal plane rotation. In presenting 10 cases of hallux adductus, the authors found that 9 were sequelae of a McBride modification. Their incidence of slightly over 1% agrees with past reports. Detailed measurements of cases taken from pre- and postoperative radiographs are presented to attempt to gain better understanding of the factors involved with the deformity. Also introduced is the hallux adductus angle. A review of the treatments is discussed.


Text Classification to Inform Suicide Risk Assessment in Electronic Health Records.
Assessing a patient's risk of an impending suicide attempt has been hampered by limited information about dynamic factors that change rapidly in the days leading up to an attempt. The storage of patient data in electronic health records (EHRs) has facilitated population-level risk assessment studies using machine learning techniques. Until recently, most such work has used only structured EHR data and excluded the unstructured text of clinical notes. In this article, we describe our experiments on suicide risk assessment, modelling the problem as a classification task. Given the wealth of text data in mental health EHRs, we aimed to assess the impact of using this data in distinguishing periods prior to a suicide attempt from those not preceding such an attempt. We compare three different feature sets, one structured and two text-based, and show that inclusion of text features significantly improves classification accuracy in suicide risk assessment.


Inhibition of Drp1-mediated mitochondrial fission improves mitochondrial dynamics and bioenergetics stimulating neurogenesis in hippocampal progenitor cells from a Down syndrome mouse model.
Functional and structural damages to mitochondria have been critically associated with the pathogenesis of Down syndrome (DS), a human multifactorial disease caused by trisomy of chromosome 21 and associated with neurodevelopmental delay, intellectual disability and early neurodegeneration. Recently, we demonstrated in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice -a widely used model of DS - a severe impairment of mitochondrial bioenergetics and biogenesis and reduced NPC proliferation. Here we further investigated the origin of mitochondrial dysfunction in DS and explored a possible mechanistic link among alteration of mitochondrial dynamics, mitochondrial dysfunctions and defective neurogenesis in DS. We first analyzed mitochondrial network and structure by both confocal and transmission electron microscopy as well as by evaluating the levels of key proteins involved in the fission and fusion machinery. We found a fragmentation of mitochondria due to an increase in mitochondrial fission associated with an up-regulation of dynamin-related protein 1 (Drp1), and a decrease in mitochondrial fusion associated with a down-regulation of mitofusin 2 (Mnf2) and increased proteolysis of optic atrophy 1 (Opa1). Next, using the well-known neuroprotective agent mitochondrial division inhibitor 1 (Mdivi-1), we assessed whether the inhibition of mitochondrial fission might reverse alteration of mitochondrial dynamics and mitochondrial dysfunctions in DS neural progenitors cells. We demonstrate here for the first time, that Mdivi-1 restores mitochondrial network organization, mitochondrial energy production and ultimately improves proliferation and neuronal differentiation of NPCs. This research paves the way for the discovery of new therapeutic tools in managing some DS-associated clinical manifestations.


MiR-126 promotes coxsackievirus replication by mediating cross-talk of ERK1/2 and Wnt/β-catenin signal pathways.
Coxsackievirus B3 (CVB3) is one of the most prevalent causes of viral myocarditis and is associated with many other pathological conditions. CVB3 replication relies on host cellular machineries and causes direct damage to host cells. MicroRNAs have been found to regulate viral infections but their roles in CVB3 infection are still poorly understood. Here we describe a novel mechanism by which miR-126 regulates two signal pathways essential for CVB3 replication. We found that CVB3-induced ERK1/2 activation triggered the phosphorylation of ETS-1 and ETS-2 transcription factors, which induced miR-126 upregulation. By using both microRNA mimics and inhibitors, we proved that the upregulated miR-126 suppressed sprouty-related, EVH1 domain containing 1 (SPRED1) and in turn enhanced ERK1/2 activation. This positive feedback loop of ERK1/2-miR-126-ERK1/2 promoted CVB3 replication. Meanwhile, miR-126 expression stimulated GSK-3β activity and induced degradation of β-catenin through suppressing LRP6 and WRCH1, two newly identified targets in the Wnt/β-catenin pathway, which sensitized the cells to virus-induced cell death and increased viral progeny release to initiate new infections. Our results demonstrate that upregulated miR-126 upon CVB3 infection targets SPRED1, LRP6, and WRCH1 genes, mediating cross-talk between ERK1/2 and Wnt/β-catenin pathways, and thus promoting viral replication and contributes to the viral cytopathogenicity.


Human Herpesvirus 6 Infection in Pediatric Liver Transplantation: Single-Center Study of Incidence, Outcomes, and Management.
Distinctions between HHV-6 primary infection in seronegative patients and HHV-6 reactivation in seropositive patients remains largely undescribed in pediatric liver transplant (LT) recipients. We implemented pretransplant serology testing of HHV-6 in a large pediatric hospital and retrospectively assessed the incidence, manifestations and outcomes of HHV-6 infections over a 3-year period. Among 101 pediatric LT recipients, 96 had pretransplant HHV-6 serologies; 34 (35.4%) were seronegative and 62 (64.6%) seropositive. Posttransplantation, 8/25 (32%) seronegative patients had HHV-6 DNAemia (primary infection) compared to 2/48 (4%) seropositive patients (p=0.002). Compared to seropositive patients, seronegative patients with HHV-6 DNAemia were younger, and had symptoms of fever and/or elevated aminotransferases in association with higher viral loads, in the first month post-transplant. More than 90% of seronegative patients and 77.8% of seropositive patients had HHV-6 detected by PCR in liver biopsy obtained for concerns of allograft rejection, but most had no detectable concomitant DNAemia. Active replication of virus in the liver was confirmed by in situ hybridization in select cases. While HHV-6 infection occurred among patients on prophylaxis doses of antivirals for CMV, HHV-6 DNAemia and presenting symptoms resolved on treatment doses. HHV-6 DNA-emia occurred more frequently in seronegative pediatric LT recipients, usually in the early posttransplant period, and was subsequently detected in allograft biopsies. HHV-6 cannot be ruled out as a cause of hepatitis in the absence of allograft tissue testing and specialized virological assays, as HHV-6 may disrupt local allograft immune homeostasis while evading traditional screening methods using blood or plasma. The assessment of pre-transplant HHV-6 serological status may be important for risk stratification and post-transplant management of pediatric LT recipients.


Isolation of complement-fragment-iC3b-binding proteins by affinity chromatography. The identification of p150,95 as an iC3b-binding protein.
The proteins from labelled human spleen membranes and polymorphonuclear leucocytes which bind to the iC3b fragment of complement component C3 were prepared by iC3b-Sepharose chromatography in the presence of bivalent cations. Complement receptor type 3(CR3) was eluted from iC3b-Sepharose by removal of bivalent cations. Complement receptors type 1 and 2 (present in spleen but not in polymorphonuclear leucocytes) were sequentially eluted by an NaCl gradient. An additional protein of Mr 135 000 was eluted from iC3b-Sepharose under the same conditions as those used to elute CR3. Preabsorption of the starting material on an anti-(CR3 beta-subunit) antibody column before iC3b-Sepharose chromatography removed the alpha- and beta-chains of CR3 and the 135 000-Mr protein. Preabsorption with iC3b-Sepharose before the anti-(CR3 beta-subunit) antibody column showed that iC3b binds CR3 and p150,95, the smallest member of the group of three homologous proteins that share the same beta-subunit.


Racial Disparities and Surgical Outcomes After Anterior Cervical Discectomy and Fusion: National Surgical Quality Improvement Program Analysis 2015-2020.
Our objective was to assess the effect of race on outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF). We identified 57,913 adult patients who underwent elective ACDF spine surgery from 2015 to 2020. Data were extracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Demographics, comorbidities, perioperative course, and 30-day postoperative outcomes were stratified by race. A total of 57,913 patients, white (n = 49,016), African American (AA; n = 7200), Native American (NA; n = 565), and Asian (n = 1132) underwent ACDF fusion surgery. AA patients had higher comorbidities, including diabetes (24.7%), dyspnea (5.9%), and hypertension (61.6%) compared with the other groups (P < 0.001). NA and AA were higher tobacco users, (33.1%) and (28.7%), respectively (P < 0.001). Most of the patients reported in this dataset had single-level surgeries. AAs had a longer average hospital stay (2.51±7.31 days) and operative time (144.13±82.26 min) (P < 0.001). Lower risk of superficial surgical site infection (adjusted odds ratio [ORadj], 0.41; 95% confidence interval [CI], 0.22-0.77; P = 0.005) and greater risk of reintubation (ORadj, 1.65; 95% CI, 1.25-2.17; P < 0.001), pulmonary embolism (ORadj, 1.88; 95% CI, 1.27-2.79; P = 0.001), renal insufficiency (ORadj, 3.15; 95% CI, 1.38-7.20; P = 0.006), and return to the operating room (ORadj, 1.41; 95% CI, 1.18-1.65; P < 0.001 were reported in AAs compared with whites. NAs showed an increased risk of superficial surgical site infection compared with whites (ORadj, 2.59; 95% CI, 1.05-6.36; P = 0.037). Racial disparities were found to independently affect rates of complications after surgery for ACDF.


Enhanced image detail using continuity in the MIP Z-buffer: applications to magnetic resonance angiography.
In this paper a new algorithm is presented for the segmentation and display of blood vessels from images obtained with magnetic resonance angiography (MRA) and other three-dimensional (3D) angiographic imaging techniques. The algorithm developed is based on the observation that vessels are strongly evident in the maximum intensity projection (MIP) Z-buffer as regions of high continuity and low local roughness. Roughness is measured here by the minimum chi2 value of a low-order local least-squares fit in the principal directions through each point in the MIP Z-buffer. Although some background pixels in the Z-buffer exhibit low local roughness, the size of the connected region is nearly always much smaller than even the very smallest vessels that appear in the MIP image. It is shown that by applying connectivity to the regions of low roughness, there is nearly complete separation between vascular detail and background. When connectivity is further applied in the original 3D image, vascular bed segmentation becomes nearly complete. The algorithm consists of three basic steps: a) determination of the minimum local roughness at each point in the MIP Z-buffer; b) connection of all neighboring points of low local roughness; and c) connection of all points in the original 3D image matrix that are connected to the points determined in the MIP Z-buffer and that are above an intensity threshold. The algorithm as presented is not optimized but demonstrates a very strong potential for improved portrayal of vascular detail.


Increased Opportunities for Transplantation for Women in the New Heart Allocation System.
Historically, women have had less access to advanced heart failure therapies, including temporary and permanent mechanical circulatory support and heart transplantation (HT), with worse waitlist and post-transplant survival compared with men. This study evaluated for improvement in sex differences across all phases of HT in the 2018 allocation system. The United Network for Organ Sharing registry was queried to identify adult patients (≥18 years) listed for HT from October 18, 2016, to October 17, 2018 (old allocation), and from October 18, 2018, to October 18, 2020 (new allocation). The outcomes of interest included waitlist survival, pretransplant use of temporary and durable mechanical circulatory support, rates of HT, and post-transplant survival. There were 15,629 patients who were listed for HT and included in this analysis; 7745 (2039 women, 26.3%) in the new and 7875 patients (2074 women, 26.3%) in the old allocation system. When compared with men in the new allocation system, women were more likely to have lower priority United Network for Organ Sharing status at time of transplant, and less likely to be supported by an intra-aortic balloon pump (27.1% vs 32.2%, P < .001), with no difference in the use of venoarterial extracorporeal membrane oxygenation (5.5% vs 6.3%, P = .28). Despite these findings, when transplantation was viewed in the context of risk for death or delisting, the cumulative incidence of transplant within 6 months of listing was higher in women than men in the new allocation system (62.4% vs 54.9%, P < .001) with no differences in post-transplant survival. When comparing women in the old with the new allocation system, the distance traveled for organ procurement was 187.5 ± 207.0 miles vs 272.8 ± 233.7 miles (P < .001). Although the use of temporary mechanical circulatory support in women remains lower than in men in the new allocation system, more women are being transplanted with comparable waitlist and post-transplant outcomes as men. Broader sharing may be making its greatest impact on improving transplant opportunities for women.


Ecological interventions to prevent and manage zoonotic pathogen spillover.
Spillover of a pathogen from a wildlife reservoir into a human or livestock host requires the pathogen to overcome a hierarchical series of barriers. Interventions aimed at one or more of these barriers may be able to prevent the occurrence of spillover. Here, we demonstrate how interventions that target the ecological context in which spillover occurs (i.e. ecological interventions) can complement conventional approaches like vaccination, treatment, disinfection and chemical control. Accelerating spillover owing to environmental change requires effective, affordable, durable and scalable solutions that fully harness the complex processes involved in cross-species pathogen spillover. This article is part of the theme issue 'Dynamic and integrative approaches to understanding pathogen spillover'.


Paradoxical antagonism of neuromuscular block by vecuronium metabolites.
Vecuronium is hydrolyzed in the body to 3-deacetyl (ORG 7268), 17-deacetyl (ORG NC58), and 3, 17-bis-deacetyl (ORG 7402) derivatives. Interactions of vecuronium and these metabolites were studied in phrenic nerve-hemidiaphragm preparations of rats. As already reported, ORG 7268 had a potent neuromuscular blocking action, and ORG NC58 and ORG 7402 had a weak neuromuscular blocking action. As expected, ORG 7268 increased the degree of neuromuscular block by vecuronium. However, a low concentration (10 microM) of ORG NC58 and ORG 7402 reversed the block by vecuronium. At a high concentration (50 microM), ORG NC58 and ORG 7402 increased the degree of block by vecuronium. Although we do not have enough data to explain these paradoxical reversal of neuromuscular block at this moment, we postulate that these results reflect the interaction between "slow" and "fast" competitive antagonists. Regardless of the mechanism, it should be emphasized that the concentrations of ORG NC58 and ORG 7402 which are necessary to reverse the block are much lower than those which facilitate the block. It is conceivable that this paradoxical reversal of the block occurs in experimental and clinical situations. Therefore, in determining the neuromuscular blocking action of a compound, the "antagonistic" effect of its metabolites should also be considered.


Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.
The authors evaluated the safety, tolerability, and efficacy of treatment using lonafarnib, a novel farnesyltransferase inhibitor (FTI), in combination with paclitaxel in patients with metastatic (Stage IIIB/V), taxane-refractory/resistant nonsmall cell lung carcinoma (NSCLC). Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m(2) intravenously over 3 hours on Day 8 of each 21-day cycle. A total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%). Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted.


Improved serodiagnosis of whooping cough caused by Bordetella pertussis by determination of IgG anti-LPF antibody levels.
The enzyme-linked immunosorbent assay (ELISA) has been used for the determination of the isotype and the specificity of Bordetella pertussis serum antibodies induced by natural infection and by vaccination. In a previous study (J. Med. Microbiol., 16, 417-426 (1984)) it was shown that the presence of pertussis serum IgA antibodies could be used as an indicator of infection: IgA antibodies were not induced by vaccination nor transported from the mother to the serum of the child. In the present study ELISA was used for the determination of IgA, IgM and IgG antibodies. From the results obtained with sera from suspected pertussis cases, it was concluded that antibodies against FHA are hardly induced by infection, in contrast to anti-LPF (determined in a fetuin sandwich ELISA) and anti-LPS antibodies. In view of the lower standard deviation of the mean anti-LPF antibody titer these antibodies were studied more extensively. From a number of bacteriologically proved pertussis cases, it was shown that high levels of IgG anti-LPF antibodies were found before IgA antibodies could be detected. On the other hand, we had the impression that IgG antibodies declined more rapidly than IgA antibodies. One has, however, to take into account that IgG antibodies are transferred from mother to child. From assay of sera from infants prior to, during and two months after vaccination (ages of vaccination: 3, 4, 5 and 12 months) it was concluded that IgG anti-LPF antibodies were induced to a much lower level by DTP-polio vaccination (10 O.U. per dose) than by natural infection.(ABSTRACT TRUNCATED AT 250 WORDS)


An evaluation of near infrared spectroscopy and cryospectrophotometry estimates of haemoglobin oxygen saturation in a rodent mammary tumour model.
Haemoglobin oxygen saturation in subcutaneous rat mammary tumours was measured using near infrared spectroscopy (NIRS) in vivo and in rapidly frozen sections from the same tumours using cryospectrophotometry, which reports oxygen saturation in individual blood vessels to depths of 4 mm from the tissue surface. Measurements were performed on tumours while animals breathed either room air or carbogen. In five of nine tumours, the average saturation calculated from cryospectrophotometric measurements agreed with that determined from NIRS to within 13%, and in four of these five tumours agreement was 5% or better. In the remaining four of nine tumours, where agreement was poor, the volume-averaged saturations estimated from NIRS were consistently higher than those calculated from cryospectrophotometry. Monte Carlo simulations demonstrated that the depth of tissue probed by NIRS was significantly greater than that sampled by cryospectrophotometry. Analysis of the frequency of severely hypoxic vessels showed that when NIRS reported a saturation of approximately 70% or higher, the fraction of tumour vessels with saturations less than 10% was limited to 0.06 or less. Sensitivity and specificity analysis suggests that NIRS and NIRS imaging may identify clinically relevant hypoxia, even when its spatial extent is below the resolution limit of the NIRS technique.


Toward Understanding Non-coding RNA Roles in Intracranial Aneurysms and Subarachnoid Hemorrhage.
Subarachnoid hemorrhage (SAH) is a common and frequently life-threatening cerebrovascular disease, which is mostly related with a ruptured intracranial aneurysm. Its complications include rebleeding, early brain injury, cerebral vasospasm, delayed cerebral ischemia, chronic hydrocephalus, and also non neurological problems. Non-coding RNAs (ncRNAs), comprising of microRNAs (miRNAs), small interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs), play an important role in intracranial aneurysms and SAH. Here, we review the non-coding RNAs expression profile and their related mechanisms in intracranial aneurysms and SAH. Moreover, we suggest that these non-coding RNAs function as novel molecular biomarkers to predict intracranial aneurysms and SAH, and may yield new therapies after SAH in the future.


[A Case of Lung Metastases from Rectal Cancer Treated for Quite Long with FOLFIRI plus Ramucirumab as a Late Line of Therapy].
We herein report a case of lung metastases from rectal cancer treated with FOLFIRI plus ramucirumab(Ram)therapy after salvage for a long time. A 44-year-old woman underwent low anterior resection for rectal cancer. Fifteen months after the surgery, mFOLFOX6 plus bevacizumab(BV)therapy was initiated for left obturator lymph node metastases. Although the target lesion shrunk, left lung metastasis was found 36 months after the surgery. Partial resection of the lung metastasis was performed, and carbon-ion radiotherapy for pelvic recurrence was administered. Following these treatments, mFOLFOX6 plus BV therapy was administered again for multiple lung metastases 42 months after the surgery. FOLFIRI plus BV therapy, TAS- 102 plus BV therapy, and regorafenib were then administered because of the disease progression. Although the best supportive care was provided after disease progression, FOLFIRI plus Ram therapy was initiated owing to the patient's wish. Although Grade 3 hematological toxicity was observed, severe digestive symptoms were not noted. Long-term administration(approximately 1 year, 21 courses)of the drugs was possible with withdrawal. The patient died due to disease progression 66 months after recurrence. We experienced a case in which FOLFIRI plus Ram therapy after salvage line could be administered for a quite long time. It has been suggested that anti-VEGF drugs with different targets may improve the prognosis even as a late line of therapy if it is tolerable.


[Histochemical observations of oral mucosa in the non-smoking cirrhotic patient (author's transl)].
Buccal mucosa samples from non-smoking cirrhotic patients were studied with the help of histochemical methods and compared with biopsies from smoking cirrhotic and healthy subjects. Very few differences were observed between the two cirrhotic groups, except for the following which were noted in the epithelium of the non smoking group: an increase of acid phosphatase, an increase of SS and SH contents of the surface keratin, and an increase of the DNA in the active cellular layers. The basal cells mitochondria were almost always reactive. The vascular walls showed enzymatic changes with a decrease of thiamine pyrophosphatase and alkaline phosphatase activity. These observations do not allow us to draw any conclusions regarding the pathogenesis of oral cancer in cirrhotic patients.


Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study.
There is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy. To develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive Candida infection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models. Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis. Ninety-six UK adult general critical care units. Consecutive admissions to participating critical care units. None. Invasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasive Candida infection, defined as IFD-positive for Candida species. Systematic review: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection. Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive for Candida species. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions. Statistical modelling: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample. Economic decision model: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small compared with the incremental costs. Incremental net benefits of each prophylaxis strategy compared with current practice were all negative. Cost-effectiveness acceptability curves showed that current practice was the strategy most likely to be cost-effective. Across all parameters in the decision model, results indicated that the value of further research for the whole population of interest might be high relative to the research costs. The results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at 'high risk' of invasive Candida infection. Results of the economic model suggested that the current most cost-effective treatment strategy for prophylactic use of systemic antifungal agents among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of no risk assessment and no antifungal prophylaxis. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.


Rapid reactions of platelets studied by a quenched-flow approach: aggregation kinetics.
Understanding the nature and regulation of very early events in the platelet activation sequence is an important goal. A general approach based on quenched-flow principles has therefore been developed. Platelet reactions are initiated by mixing inducing agent with whole blood, PRP, or washed platelets and pumping the mixture through narrow-bore tubing with quenching (stopping the reaction) at the outlet. Reaction times less than 1 sec are feasible. The quenched-flow system has been combined with a continuous-flow modification of resistive-particle counters to follow aggregation kinetics of "single" particles. Aggregation at 37 degrees is extremely rapid: after a lag period of about 1 sec, between 20% and 50% of platelets then aggregate per second (10 micro M ADP). Although the kinetics are second order, data can be expressed as the percent of "single" platelets aggregating per second and treated as pseudo-first order. This enables derivation of apparent maximal velocities of aggregation and inducer activation constants, for characterizing platelet reactivity.


Dolasetron for the prevention of postoperative nausea and vomiting following outpatient surgery with general anaesthesia: a randomized, placebo-controlled study. The Dolasetron PONV Prevention Study Group.
In a multicentre, randomized, double-blind, placebo-controlled dose-ranging study, 1030 patients undergoing outpatient surgery with general anaesthesia received i.v. dolasetron mesylate (12.5, 25, 50, or 100 mg) or placebo. The principal outcome measure was the proportion of patients who were free of emesis or rescue medication for the 24-h period after the study drug was given; the subsidiary outcome measure was survival time without rescue medication. Effects on nausea were quantified using a visual analogue scale. Compared with placebo, a complete response was significantly higher when all four dolasetron doses were combined (49% vs. 58%, P =0.025). In females, dolasetron, 12.5-mg, dolasetron provided maximum clinical benefit (effectiveness compared with adverse events), with no additional benefit in complete response rates or nausea visual analogue scale scores at higher doses. No significant differences were observed in complete response for any dolasetron dose in males compared with placebo. The majority of adverse events reported were mild or moderate. Dolasetron provided well-tolerated, safe, and effective prophylaxis for post-operative nausea and vomiting with maximum effectiveness observed at a dose of 12.5 mg.


A method for named entity normalization in biomedical articles: application to diseases and plants.
In biomedical articles, a named entity recognition (NER) technique that identifies entity names from texts is an important element for extracting biological knowledge from articles. After NER is applied to articles, the next step is to normalize the identified names into standard concepts (i.e., disease names are mapped to the National Library of Medicine's Medical Subject Headings disease terms). In biomedical articles, many entity normalization methods rely on domain-specific dictionaries for resolving synonyms and abbreviations. However, the dictionaries are not comprehensive except for some entities such as genes. In recent years, biomedical articles have accumulated rapidly, and neural network-based algorithms that incorporate a large amount of unlabeled data have shown considerable success in several natural language processing problems. In this study, we propose an approach for normalizing biological entities, such as disease names and plant names, by using word embeddings to represent semantic spaces. For diseases, training data from the National Center for Biotechnology Information (NCBI) disease corpus and unlabeled data from PubMed abstracts were used to construct word representations. For plants, a training corpus that we manually constructed and unlabeled PubMed abstracts were used to represent word vectors. We showed that the proposed approach performed better than the use of only the training corpus or only the unlabeled data and showed that the normalization accuracy was improved by using our model even when the dictionaries were not comprehensive. We obtained F-scores of 0.808 and 0.690 for normalizing the NCBI disease corpus and manually constructed plant corpus, respectively. We further evaluated our approach using a data set in the disease normalization task of the BioCreative V challenge. When only the disease corpus was used as a dictionary, our approach significantly outperformed the best system of the task. The proposed approach shows robust performance for normalizing biological entities. The manually constructed plant corpus and the proposed model are available at http://gcancer.org/plant and http://gcancer.org/normalization , respectively.


The Functional Characterization of Podosphaera xanthii Candidate Effector Genes Reveals Novel Target Functions for Fungal Pathogenicity.
Podosphaera xanthii is the main causal agent of powdery mildew disease in cucurbits. In a previous study, we determined that P. xanthii expresses approximately 50 Podosphaera effector candidates (PECs), identified based on the presence of a predicted signal peptide and the absence of functional annotation. In this work, we used host-induced gene silencing (HIGS), employing Agrobacterium tumefaciens as a vector for the delivery of the silencing constructs (ATM-HIGS), to identify genes involved in early plant-pathogen interaction. The analysis of seven selected PEC-encoding genes showed that six of them, PEC007, PEC009, PEC019, PEC032, PEC034, and PEC054, are required for P. xanthii pathogenesis, as revealed by reduced fungal growth and increased production of hydrogen peroxide by host cells. In addition, protein models and protein-ligand predictions allowed us to identify putative functions for these candidates. The biochemical activities of PEC019, PEC032, and PEC054 were elucidated using their corresponding proteins expressed in Escherichia coli. These proteins were confirmed as phospholipid-binding protein, α-mannosidase, and cellulose-binding protein. Further, BLAST searches showed that these three effectors are widely distributed in phytopathogenic fungi. These results suggest novel targets for fungal effectors, such as host-cell plasma membrane, host-cell glycosylation, and damage-associated molecular pattern-triggered immunity.


Screening and confirmation of human immunodeficiency virus type 1 infection solely by detection of RNA.
Diagnosis of human immunodeficiency virus (HIV) infection by antibody-based testing allows for some recently infected individuals to be falsely assessed as non-infected. Since such individuals often have high viral loads and are capable of transmitting HIV, it is an imperative public health need to identify these individuals. We investigated the feasibility and capability of a diagnostic algorithm which included screening and confirmation of HIV infection using only nucleic-acid-based tests. This investigation involved screening 1361 prospectively collected specimens using antibody-based methods in parallel to simultaneously testing the same specimens by a qualitative HIV RNA detection method (APTIMA HIV-1). Specimens that were positive by antibody screening were confirmed by either immunofluorescent assay or Western blotting, while specimens positive by RNA screening were confirmed by real-time RT-PCR. In the course of the study, 27 specimens were found to contain either HIV antibody or HIV RNA. Twenty-six of the 27 specimens were HIV RNA positive, while 23 of the 27 specimens were antibody positive. One specimen was found which possessed HIV antibody but was assessed as negative by the HIV RNA screening test. Four specimens were found to contain detectable HIV RNA but were negative by the antibody screening test. Three of these four patients were negative at point-of-care by rapid test, while one was negative by enzyme immunoassay. These data indicate that screening and confirmation of HIV infection by RNA methods alone, if affordable, may constitute an effective alternative HIV diagnostic algorithm in certain settings.


Unmet Supportive Care Needs Survey among Male Partners of Gynecological Cancer Survivors in Indonesia.
The number of gynecological cancer survivors is increasing in Indonesia, and these women often require physical and emotional support from their male partners as primary caregivers. However, the male caregiver's need for biological, psychological, and social support is often neglected. This study aims to assess the demographic and clinical determinants affecting the unmet supportive care needs of the gynecological cancer survivors' husbands in Indonesia. This cross-sectional survey involved 152 husbands of survivors who were recruited by a consecutive sampling method in two national referral hospitals. A self-administered Cancer Survivors' Partners Unmet Needs Questionnaire was used for data collection. Multiple linear regression was performed to analyze the data. The majority of participants (97.4%) reported at least one unmet need. The primary unmet needs were legal services (71.1%), financial support (70.4%), cancer recurrence concerns (69.7%), and ongoing health support (66.4%). These needs were significantly associated with the wife's radio-chemotherapy and lower household income (P < 0.01) and also related to the husband's education level, duration of caregiving, and wife's cancer stage. Husbands of gynecological cancer survivors in Indonesia reported a need for legal, financial, and health-care information and assistance. Multidisciplinary professionals should be involved in developing policy and interventions which facilitate the social-economic protection of survivors and their husbands, as well as comprehensive care needs to enhance the women's survival rate.


Extracorporeal life support for cardiac assist in pediatric patients. Review of ELSO Registry data.
The collected data on extracorporeal membrane oxygenation (ECMO), now referred to as extracorporeal life support (ECLS), for pediatric cardiac support has not been analyzed. The purpose of this study was to review the Extracorporeal Life Support (ELSO) Registry data to evaluate the results, identify possible predictors of outcome, and attempt to establish criteria. From 1981 to June of 1990, 189 patients were placed on ECLS for cardiac assist. The age range was 0-204 months (median, 7 months). Mean time on ECLS was 115 +/- 75 hours. Fourteen patients were placed on ECLS as a bridge to transplant or for management of transplant rejection. All of the remaining 175 patients were treated in the postoperative period. The causes of mortality included lack of improvement in cardiovascular function in 69 (37%) of the patients, major central nervous system damage in 28 (15%), uncontrollable hemorrhage in three (2%), sepsis in three (2%), and pulmonary interstitial disease in two (1%). The Registry data were examined for predictors of outcome. There was no significant difference between survivors and nonsurvivors when compared for duration of ECLS, mechanical complications, arterial or venous blood gases, ventilation settings, or hemodynamics. Forty-three percent of 189 pediatric patients treated with ECLS for cardiac failure survived. The highest survival, 61%, occurred in right-sided lesions and the lowest, 18%, in post-Fontan. Mediastinal bleeding, cardiac arrest, renal failure, and prolonged intubation were all associated with a poor outcome. Most deaths were attributed to irreversible cardiac or brain injury, suggesting that results could be improved by earlier identification of high-risk patients and earlier institution of ECLS.


Ionic switch controls the DNA state in phage λ.
We have recently found that DNA packaged in phage λ undergoes a disordering transition triggered by temperature, which results in increased genome mobility. This solid-to-fluid like DNA transition markedly increases the number of infectious λ particles facilitating infection. However, the structural transition strongly depends on temperature and ionic conditions in the surrounding medium. Using titration microcalorimetry combined with solution X-ray scattering, we mapped both energetic and structural changes associated with transition of the encapsidated λ-DNA. Packaged DNA needs to reach a critical stress level in order for transition to occur. We varied the stress on DNA in the capsid by changing the temperature, packaged DNA length and ionic conditions. We found striking evidence that the intracapsid DNA transition is 'switched on' at the ionic conditions mimicking those in vivo and also at the physiologic temperature of infection at 37°C. This ion regulated on-off switch of packaged DNA mobility in turn affects viral replication. These results suggest a remarkable adaptation of phage λ to the environment of its host bacteria in the human gut. The metastable DNA state in the capsid provides a new paradigm for the physical evolution of viruses.


Optical fluorescent imaging to monitor temporal effects of microbubble-mediated ultrasound therapy.
Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p <0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors.


Differential temperature dependence of taste nerve responses to various taste stimuli in dogs and rats.
The temperature dependence of the canine and rat chorda tympani nerve responses to various taste stimuli was examined. The temperature dependence greatly varied with species of stimuli. In the dog, the tonic responses to fructose, sucrose, acetic acid, and guanosine 5'-monophosphate (GMP) and the response induced by the synergism between monosodium glutamate (MSG) and GMP showed peaks at approximately 30 degrees C, whereas those to NaCl, NH4Cl, and MSG showed peaks between 10 and 20 degrees C. In the rat, the tonic response to NH4Cl increased with an increase in temperature up to 45 degrees C, whereas the responses to other stimuli examined showed peaks at approximately 30 degrees C. The responses to glycine, sucrose, and quinine showed sharp temperature dependence, and the responses to acids (HCl and acetic acid) and salts (NaCl and KCl) showed relatively flat dependence. The effects of the temperature change on dose-response curves for fructose, NH4Cl, and GMP were examined using dogs. The temperature change did not practically affect the thresholds for these stimuli and affected the magnitude of the responses to higher concentrations of stimuli. The origins of the temperature dependence were discussed in terms of taste receptor mechanisms.


AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease.
Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD, but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3-kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD; however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here, we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.


Cholinergic drugs as therapeutic tools in inflammatory diseases: participation of neuronal and non-neuronal cholinergic systems.
Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) from acetylcoenzime A and choline. This reaction occurs not only in pre-ganglionic fibers of the autonomic nervous system and post-ganglionic parasympathetic nervous fibers but also in non neuronal cells. This knowledge led to expand the role of ACh as a neurotransmitter and to consider it as a "cytotransmitter" and also to evaluate the existence of a non-neuronal cholinergic system comprising ACh, ChAT, acetylcholinesterase, and the nicotinic and muscarinic ACh receptors, outside the nervous system. This review analyzes the participation of cholinergic system in inflammation and discusses the role of different muscarinic and nicotinic drugs that are being used to treat skin inflammatory disorders, asthma, and chronic obstructive pulmonary disease as well as, intestinal inflammation and systemic inflammatory diseases, among others, to assess the potential application of these compounds as therapeutic tools.


Biology of lung cancer with implications for new therapies.
To provide an overview of the biology of lung cancer with respect to genetic carcinogenesis and specific mutations and to discuss new therapies being developed to target lung cancer's biologic processes. Published articles, abstracts, book chapters, lectures, and personal experiences with experimental agents. Lung cancer is the number one cause of cancer deaths for men and women in the United States, with minimal changes in the five-year survival rate during the past decade. New understanding of the biologic process of lung cancer is providing potential new therapies that many hope will lead to increased survival for patients with lung cancer. Exciting new therapies for lung cancer are being developed that target specific biologic processes of lung cancer. When nurses are familiar with the rationale behind biologic therapies, they can understand the drugs, assess toxicities, and help patients make educated decisions about therapeutic alternatives.


[Afrikaanse Reseptiewe Woordeskattoets (ARW) : Suitability for a group of non-standard Afrikaans speaking children].
The need for culturally appropriate language tests served as motivation for this study. The aim of the study was to evaluate the suitability and adaptability of the Afrikaanse Reseptiewe Woordeskattoets (ARW) (Buitendag, 1994) for a group of seven and ten year old non-standard Afrikaans speaking children from the coloured community in Gauteng, North West, Mpumalanga and Northern Province. In order to achieve this goal the ARW (Buitendag, 1994), and a questionnaire regarding socio-economic deprivation, were administered to a proportionally stratified randomized sample of 960 children. Test bias was evaluated by comparing the psychometric characteristics of the test for the research group to those of the normative group. Various test adaptation procedures were considered, namely adaptations to the rank order of item difficulty, test starting points and test procedures. The results indicated the same degree of confidence in the test results of the two groups. It demonstrated that the original rank order of item difficulty does not need to be changed and that corresponding increase in ARW scores is evident with an increase in age in both groups. The findings imply that the test measures the same ability in the two groups. Although comparison of the psychometric characteristics of the test for the research group to those for the normative group failed to identify test bias, intra-group comparison indicated that the test may be linguistically biased against the socio-economically deprived sub-group. Significant differences in individual ARW scores occurred when a shift in the child's basal or ceiling item occurred as a result of the biased items. The test's cultural validity for the group may be increased by lowering the test starting points, in order to prevent reversed testing. Culturally appropriate responses should be accepted as correct, in order to award equal credit to standard and non-standard language responses and to take intra-group differences into consideration. This research is an important contribution towards the expansion of the speech-language therapist's skills and resources, vitally needed to provide culturally relevant services in South Africa to all individuals with communication disorders.


Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production.
Although proinflammatory cytokine-induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER) and paracellular permeability were measured. Production levels and localization of tight junction (TJ) proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC) and MLC kinase (MLCK) mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation.


Long-term condition management in adults with intellectual disability in primary care: a systematic review.
Adults with intellectual disabilities have higher morbidity and earlier mortality than the general population. Access to primary health care is lower, despite a higher prevalence of many long-term conditions. To synthesise the evidence for the management of long-term conditions in adults with intellectual disabilities and identify barriers and facilitators to management in primary care. Mixed-methods systematic review. Seven electronic databases were searched to identify both quantitative and qualitative studies concerning identification and management of long-term conditions in adults with intellectual disability in primary care. Both the screening of titles, abstracts, and full texts, and the quality assessment were carried out in duplicate. Findings were combined in a narrative synthesis. Fifty-two studies were identified. Adults with intellectual disabilities are less likely than the general population to receive screening and health promotion interventions. Annual health checks may improve screening, identification of health needs, and management of long-term conditions. Health checks have been implemented in various primary care contexts, but the long-term impact on outcomes has not been investigated. Qualitative findings highlighted barriers and facilitators to primary care access, communication, and disease management. Accounts of experiences of adults with intellectual disabilities reveal a dilemma between promoting self-care and ensuring access to services, while avoiding paternalistic care. Adults with intellectual disabilities face numerous barriers to managing long-term conditions. Reasonable adjustments, based on the experience of adults with intellectual disability, in addition to intervention such as health checks, may improve access and management, but longer-term evaluation of their effectiveness is required.


Adipose stem cell microbeads as production sources for chondrogenic growth factors.
Microencapsulating stem cells in injectable microbeads can enhance delivery and localization, but their ability to act as growth factor production sources is still unknown. To address this concern, growth factor mRNA levels and production from alginate microbeads with encapsulated human adipose stem cells (ASC microbeads) cultured in both growth and chondrogenic media (GM and CM) were measured over a two week period. Human ASCs in microbeads were either commercially purchased (Lonza) or isolated from six human donors and compared to human ASCs on tissue culture polystyrene (TCPS). The effects of crosslinking and alginate compositions on growth factor mRNA levels and production were also determined. Secretion profiles of IGF-I, TGF-β3 and VEGF-A from commercial human ASC microbeads were linear and at a significantly higher rate than TCPS cultures over two weeks. For human ASCs derived from different donors, microencapsulation increased pthlh and both IGF-I and TGF-β3 secretion. CM decreased fgf2 and VEGF-A secretion from ASC microbeads derived from the same donor population. Crosslinking microbeads in BaCl2 instead of CaCl2 did not eliminate microencapsulation's beneficial effects, but did decrease IGF-I production. Increasing the guluronate content of the alginate microbead increased IGF-I retention. Decreasing alginate molecular weight eliminated the effects microencapsulation had on increasing IGF-I secretion. This study demonstrated that microencapsulation can enhance chondrogenic growth factor production and that chondrogenic medium treatment can decrease angiogenic growth factor production from ASCs, making these cells a potential source for paracrine factors that can stimulate cartilage regeneration.