Molecular cytogenetic analysis of chromosomes 1 and 19 in glioma cell lines.
Deletions of chromosome 1p and 19q arms are frequent genetic abnormalities in primary human gliomas and are especially common in oligodendrogliomas. However, the chromosome 1p and 19q status of many glioma cell lines has not been established. Using homozygosity mapping, fluorescence in situ hybridization (FISH), and comparative genomic hybridization to arrayed BAC (CGHa), we screened 17 glioma cell lines for chromosome 1 and 19 deletions. Sequence tagged site polymorphisms were used to evaluate the cell lines for regions of chromosome 1p and 19q homozygosity. Cell lines A172, U251, TP265, U118, SW1088, U87, SW1783, and D32 contained significant regions of 19q homozygosity. In addition, A172, U87, TP483, D37, U118, MO67, and TP265 contained significant regions of 1p homozygosity. FISH probes localized to 1p36.32 and 19q13.33 as well as CGHa were used to determine which cell lines had deletions of 1p and/or 19q. Cell lines A172, U87, TP483, TP265, H4, U251, and D37 were deleted for portions of 1p. CGHa and homozygosity mapping of these cell lines define a 700-kilobase (Kb) common deletion region that is encompassed by a larger deletion region previously mapped in sporadic gliomas. This common deletion region is localized at 1p36.31 and includes CHD5, a putative tumor suppressor gene. Cell line A172 was observed to have a deletion between 19q13.33 and 19q13.41, while U87 was observed to have a smaller deletion of 19q13.33. Cell lines A172 and U87 contain 1p and 19q deletions similar to those found in sporadic gliomas and will be useful cellular reagents for evaluating the function of putative 1p and 19q glioma tumor suppressor genes.


A systematic review of selected musculoskeletal late effects in survivors of childhood cancer.
Survivors of childhood cancer are at risk for treatment-related musculoskeletal late effects. Early detection and orthopedic intervention can help ameliorate musculoskeletal late effects and prevent subsequent complications. This systematic review summarizes the literature describing associations between cancer, its treatment, and musculoskeletal late effects. We searched PubMed and Web of Science for English language articles published between January 1970 and December 2012. The search was limited to investigations with at least 15 participants and conducted at least 2 years after completion of therapy for childhood, adolescent, or young adult cancer. Some late skeletal effects, including low bone mineral density, osteonecrosis, slipped capital femoral epiphyses, oncogenic rickets, and hormonerelated growth disturbances have been previously reviewed and were excluded, as were outcomes following amputation and limb-salvage procedures. Of 2347 references identified, 30 met inclusion criteria and were retained. An additional 54 studies that met inclusion criteria were found in reference lists of retained studies. Of 84 studies, 60 focused on associations between radiotherapy, six between chemotherapy, and 18 between surgery and musculoskeletal late effects. We found that younger age, higher radiation dosage, and asymmetric or partial bone radiation volume influences the effects of radiation on the musculoskeletal system. Methotrexate and vincristine are associated with long-term muscular strength and flexibility deficits. Laminectomy and chest wall resection are associated with spinal malalignment, and enucleation is associated with orbital deformities among survivors. Radiotherapy, chemotherapy, and surgery are associated with musculoskeletal late effects independently and additively. Associations are additionally influenced by host and treatment characteristics.


MicroRNA-144 is a circulating effector of remote ischemic preconditioning.
Remote ischemic preconditioning (rIPC) induced by cycles of transient limb ischemia and reperfusion is a powerful cardioprotective strategy with additional pleiotropic effects. However, our understanding of its underlying mediators and mechanisms remains incomplete. We examined the role of miR-144 in the cardioprotection induced by rIPC. Microarray studies first established that rIPC increases, and IR injury decreases miR-144 levels in mouse myocardium, the latter being rescued by both rIPC and intravenous administration of miR-144. Going along with this systemic treatment with miR-144 increased P-Akt, P-GSK3β and P-p44/42 MAPK, decreased p-mTOR level and induced autophagy signaling, and induced early and delayed cardioprotection with improved functional recovery and reduction in infarct size similar to that achieved by rIPC. Conversely, systemic administration of a specific antisense oligonucleotide reduced myocardial levels of miR-144 and abrogated cardioprotection by rIPC. We then showed that rIPC increases plasma miR-144 levels in mice and humans, but there was no change in plasma microparticle (50-400 nM) numbers or their miR-144 content. However, there was an almost fourfold increase in miR-144 precursor in the exosome pellet, and a significant increase in miR-144 levels in exosome-poor serum which, in turn, was associated with increased levels of the miR carriage protein Argonaute-2. Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC. Future studies should assess the potential for plasma miR-144 as a biomarker of the effectiveness of rIPC induced by limb ischemia, and whether miR-144 itself may represent a novel therapy to reduce clinical ischemia-reperfusion injury.


Predicting prostate cancer biochemical recurrence using a panel of serum proteomic biomarkers.
The pathological state of the prostate may be reflected by serum proteome in a man. We hypothesized that biomarkers are present in preoperative serum, which may be used to predict the probability of biochemical recurrence following radical prostatectomy. Mass spectrometry analysis was used to compare 52 men who experienced biochemical recurrence with 52 who remained biochemical recurrence-free for approximately 5 years after radical retropubic prostatectomy. A total of 30 matched pairs of recurrent and nonrecurrent serum samples were randomly selected as a training set for biomarker discovery and model development. Selected mass spectrometry peaks were combined with pre-radical retropubic prostatectomy prostate specific antigen in a multivariate algorithm to predict recurrence. The algorithm was evaluated using the remaining 22 recurrent and 22 nonrecurrent subjects as test samples. Protein identities of the selected mass spectrometry peaks were investigated. Two serum biomarkers for recurrence, P1 and P2, were combined with preoperative prostate specific antigen to predict biochemical recurrence. The ROC AUC for prostate specific antigen and the predicted outcome was 0.606 and 0.691 in the testing data, respectively. Using a single cutoff the samples were divided into 2 groups that were predictive of biochemical recurrence (p = 0.026). In contrast, preoperative prostate specific antigen did not differ between recurrent and nonrecurrent cases (Wilcoxon matched pairs test p = 0.07). The protein identity of P1 was determined to be a truncated form of C4a (C4a des-Arg). Preliminary data indicated that P2 was an N-terminal fragment of protein C inhibitor. In the current study population, which was matched on Gleason score and TNM staging, pre-radical retropubic prostatectomy prostate specific antigen retained no independent power to predict recurrence. However, by adding 2 proteomic biomarkers to preoperative prostate specific antigen the combined model demonstrated statistically significant value for predicting prostate cancer recurrence in men who underwent radical retropubic prostatectomy.


Meeting report: batch-to-batch variability in estrogenic activity in commercial animal diets--importance and approaches for laboratory animal research.
We report information from two workshops sponsored by the National Institutes of Health that were held to a) assess whether dietary estrogens could significantly impact end points in experimental animals, and b) involve program participants and feed manufacturers to address the problems associated with measuring and eliminating batch-to-batch variability in rodent diets that may lead to conflicting findings in animal experiments within and between laboratories. Data were presented at the workshops showing that there is significant batch-to-batch variability in estrogenic content of commercial animal diets, and that this variability results in differences in experimental outcomes. A combination of methods were proposed to determine levels of total estrogenic activity and levels of specific estrogenic constituents in soy-containing, casein-containing, and other soy-free rodent diets. Workshop participants recommended that researchers pay greater attention to the type of diet being used in animal studies and choose a diet whose estrogenic activity (or lack thereof) is appropriate for the experimental model and end points of interest. Information about levels of specific phytoestrogens, as well as estrogenic activity caused by other contaminants and measured by bioassay, should be disclosed in scientific publications. This will require laboratory animal diet manufacturers to provide investigators with information regarding the phytoestrogen content and other estrogenic compounds in commercial diets used in animal research.


Local and regional processes in community assembly.
Controversy on whether local (deterministic) or regional (stochastic) factors control the structure of communities persists after decades of research. The main reason for why it has not been resolved may lie in the nature of evidence which largely comes from realized natural communities. In such communities assembly history leaves a mark that may support either set of factors. To avoid the confounding effects of assembly history we controlled for these effects experimentally. We created a null community by mixing 17 rock pool communities. We then divided the null community into replicates and distributed among treatments representing a gradient of factors from local to regional. We hypothesized that if deterministic factors dominate the assembly of communities, community structures should show a corresponding gradient from being very similar and convergent to dissimilar and divergent. In contrast, if local processes are predominantly stochastic in nature, such a gradient of community configurations should emerge even in the homogeneous setting. Our results appear to partially support both hypotheses and thus suggest that both deterministic and stochastic processes contribute to the assembly of communities. Furthermore, we found that to satisfactorily explain patterns observed in natural communities environmental heterogeneity and regional processes must also be considered. In conclusion, although deterministic mechanisms seem to be important in the assembly of communities, in natural systems their signal may be diluted and masked whenever other factors exert meaningful influence. Such factors increase the number of possible paths to the point that the number of paths equals the number of communities in a metacommunity.


The National Psychiatric Morbidity surveys of Great Britain--strategy and methods.
This paper describes the rationale and methodology of the first national psychiatric morbidity surveys to be carried out in Great Britain. The objectives of the surveys were to estimate the prevalence of psychiatric morbidity among adults aged 16-64 living in Great Britain; to identify the nature and extent of social disabilities associated with psychiatric morbidity; to describe the use of health and social services by people with psychiatric morbidity and to investigate the association between mental illness and potential environmental risk factors in a household sample. Four separate surveys were carried out in order to meet the objectives; a private household sample (N = 10108), a sample of institutions caring for the mentally ill (N = 1191), a sample of homeless people (N = 1166), and a supplementary sample of patients with psychosis living in private households (N = 350). A two-stage assessment procedure was used, in which all subjects were given the Revised Clinical Interview Schedule (CIS-R) administered by lay interviewers to assess neurotic symptoms and disorders and a psychosis screen, including the Psychosis Screening Questionnaire. Those who were positive on the psychosis screen were then interviewed by psychiatrists using the SCAN (incorporating the tenth edition of the Present State Examination). Large scale national surveys such as this augment the inadequate data on psychiatric morbidity that are routinely available and are, therefore, an important source of information upon which to base policy and generate aetiological hypotheses. These surveys provide a possible model for similar surveys in other countries.


Nusinersen injections in adults and children with spinal muscular atrophy: a single-center experience.
Nusinersen is a drug approved in December 2016 for treatment of spinal muscular atrophy (SMA). We want to share our initial experience with image-guided, non-image-guided, and port-delivered nusinersen injections in a large single-center SMA patient cohort, treating both pediatric and adult patients with focus on technical considerations and other patient concerns from a combined perspective of patient, neurologist, and radiologist. All nusinersen injections between February 2017 and September 2018 were retrospectively reviewed. We obtained age, sex, SMA type and technical details of the injections and postprocedure complications for each procedure. A total of 52 patients (24 women [46%]; 4 patients with SMA-1 [7.6%]; 30 patients with SMA-2 [57.8%]; 18 patients with SMA-3 [34.6%]; mean age, 25.5 years [7 months to 62 years]) with a total of 265 injections were included. Of the 265 injections, 206 (77.9%) were performed with local anesthetic, 25 (9.4%) with moderate sedation, and 23 (8.6%) under general anesthesia. We performed 65 CT-guided transforaminal injections in 13 patients, 106 fluoroscopy-guided lumbar punctures in 24 patients and 83 lumbar punctures in 16 patients using conventional technique. Only 6 of 265 injections (2.2%) ended up with a post-lumbar puncture headache (PLPH) requiring medical treatment. None required an epidural blood patch. Fourteen PLPH (5.2%) occurred and resolved at the same day without any treatment. After 6 of 265 injections (2.2%), patients reported soreness at the injection site which resolved spontaneously. Three elected to have an intrathecal reservoir placement (2 lumbar, 1 intraventricular) with a total of 11 injections. One patient with lumbar catheter developed infection after surgery with subsequent meningitis and treatment delay. After the resolution of meningitis, a new intraventricular reservoir was placed without any complication in the following injections. With the introduction of nusinersen treatment, neurologists and radiologists play an important role in treatment of SMA patients and therefore should be familiar with different techniques and complications of drug administration. Using good technique, it is possible to have very low complication rates even in this complex patient population, and various image-guided procedures can be a safe alternative to surgical approach, even in the most difficult cases.


Validation of methods for converting the original Disease Activity Score (DAS) to the DAS28.
The Disease Activity Score (DAS) is integral in tailoring the clinical management of rheumatoid arthritis (RA) patients and is an important measure in clinical research. Different versions have been developed over the years to improve reliability and ease of use. Combining the original DAS and the newer DAS28 data in both contemporary and historical studies is important for both primary and secondary data analyses. As such, a methodologically robust means of converting the old DAS to the new DAS28 measure would be invaluable. Using data from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28 data were used to develop new regression imputation formulas using the total DAS score (univariate), and using the separate components of the DAS score (multivariate). DAS were transformed to DAS28 using an existing formula quoted in the literature, and the newly developed formulas. Bland and Altman plots were used to compare the transformed DAS with the recorded DAS28 to ascertain levels of agreement. The current transformation formula tended to overestimate the true DAS28 score, particularly at the higher end of the scale. A formula which uses all separate components of the DAS was found to estimate the scores with a higher level of precision. A new formula is proposed that can be used by other early RA cohorts to convert the original DAS to DAS28.


The effects of transurethral resection and cystoprostatectomy on dissemination of epithelial cells in the circulation of patients with bladder cancer.
This study was undertaken to evaluate the risk of haematogenous dissemination of epithelial cells induced by endoscopic resection and/or cystoprostatectomy for transitional cell carcinoma of the bladder. Thirty-three patients were studied. Thirty-one had different stages and grades of bladder cancer and two patients had benign bladder conditions. Twenty-five cancer patients required transurethral resection of their bladder tumour. Of those, 20 had superficial disease (pTaG1-G2: n = 19; pT1G2: n = 1) and five had muscle invasive tumours (pT2G3: n = 2; pT3aG3: n = 1; pT4G3: n = 2). Five patients underwent radical cystoprostatectomy for muscle invasive cancers (pT2G3: n = 3; pT3bG3: n = 1; pT4G3: n = 1) and one man received chemotherapy for metastatic disease. Venous blood (10 ml) was obtained from the antecubital fossa in each patient, before and 1-2 h after completion of surgery, and prior to treatment in the metastatic patient. An indirect immunocytochemical technique was used to detect circulating epithelial cells after centrifugation on Ficoll gradient and fixation of mononuclear cells on slides, using a monoclonal antibody directed against three cytokeratins: CK8, CK18 and CK19. Circulating epithelial cells were detected only in the patient with metastatic disease. None of the other patients had evidence of epithelial circulating cells before or after surgery. The results suggest that irrespective of disease stage and grade, neither endoscopic nor open bladder surgery leads to detectable dissemination of urothelial cells in the peripheral circulation. These procedures are therefore unlikely to increase the risk of progression and metastasis in transitional cell carcinoma of the bladder.


Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis.
No adequate randomized trials have been reported for a comparison between hepatic resection (HR) versus radiofrequency ablation (RFA) for the treatment of patients with very early stage hepatocellular carcinoma (HCC), defined as an asymptomatic solitary HCC <2 cm. For compensated cirrhotic patients with very early stage HCC, a Markov model was created to simulate a randomized trial between HR (group I) versus primary percutaneous RFA followed by HR for cases of initial local failure (group II) versus percutaneous RFA monotherapy (group III); each arm was allocated with a hypothetical cohort of 10,000 patients. The primary endpoint was overall survival. The estimates of the variables were extracted from published articles after a systematic review. In the parameter estimations, we assumed the best scenario for HR and the worst scenario for RFA. The mean expected survival was 7.577 years, 7.564 years, and 7.356 years for group I, group II, and group III, respectively. One-way sensitivity analysis demonstrated that group II was the preferred strategy if the perioperative mortality rate was greater than 1.0%, if the probability of local recurrence following an initial complete ablation was <1.9% or if the positive microscopic resection margin rate was >0.3%. The 95% confidence intervals for the difference in overall survival were -0.18-0.18 years between group I and II, 0.06-0.36 years between group I and III, and 0.13-0.30 years between group II and III, respectively. Primary percutaneous RFA followed by HR for cases of initial local failure was nearly identical to HR for the overall survival of compensated cirrhotic patients with very early stage HCC.


Cerebral blood flow changes with acute cocaine intoxication: clinical correlations with SPECT, CT, and MRI.
In summary, these data suggest that widespread primary or secondary cerebral vasoconstriction is common in patients with neurological complications from cocaine. In most patients, SPECT showed wide-spread hypoperfusion in regions that had no clear clinical significance (e.g., the periventricular area). In many, the SPECT was performed more than 24 hours after the onset of neurological symptomatology. These findings raise several questions. It has been assumed that these SPECT changes in patients with acute neurological symptoms are temporary, although it will be important to determine whether these areas of hypoperfusion persist after symptoms have abated. Recently, Holman and colleagues (1991) found multifocal and deep areas of hypoperfusion with SPECT in 16 of 18 patients with a history of chronic cocaine abuse. Although most of the subjects tested positive for cocaine, several had abstained from cocaine use for weeks prior to the study. All 18 subjects had neuropsychological deficits, 13 mild and 5 moderate. Similarly, Pascual-Leone and colleagues (1991) have shown that CT scan atrophy strongly correlates with the duration of cocaine abuse, suggesting that brain injury may occur with continued use of cocaine. It is the authors' concern that cocaine abuse might produce permanent changes in cerebral perfusion. In conclusion, brain SPECT was found to be a useful procedure in the evaluation of acute cocaine intoxication. Brain SPECT revealed focal cortical lesions not seen on head CT or MRI, which corresponded to clinical deficits. In addition, [99mTc]HMPAO brain SPECT had a characteristic scalloped appearance, and this may be a marker for acute intoxication with cocaine. This study further supports the contention that cocaine causes neurological disease by its vasoconstrictive action.


Single-Cell Characterization of in vitro Migration and Interaction Dynamics of T Cells Expanded with IL-2 and IL-7.
T cells are pivotal in the immune defense against cancers and infectious agents. To mount an effector response against cancer cells, T cells need to migrate to the cancer-site, engage in contacts with cancer cells, and perform their effector functions. Adoptive T cell therapy is an effective strategy as treatment of complications such as relapse or opportunistic infections after hematopoietic stem cell transplantations. This requires a sufficient amount of cells that are able to expand and respond to tumor or viral antigens. The cytokines interleukin (IL)-2 and IL-7 drive T cell differentiation, proliferation, and survival and are commonly used to expand T cells ex vivo. Here, we have used microchip-based live-cell imaging to follow the migration of individual T cells, their interactions with allogeneic monocytes, cell division, and apoptosis for extended periods of time; something that cannot be achieved by commonly used methods. Our data indicate that cells grown in IL-7 + IL-2 had similar migration and contact dynamics as cells grown in IL-2 alone. However, the addition of IL-7 decreased cell death creating a more viable cell population, which should be beneficial when preparing cells for immunotherapy.


Gray Matter Atrophy within the Default Mode Network of Fibromyalgia: A Meta-Analysis of Voxel-Based Morphometry Studies.
Over the years, studies have demonstrated morphological changes in the brain of fibromyalgia (FMS). We aimed to conduct a coordinate-based meta-analytic research through systemic review on voxel-based morphometry (VBM) imaging results to identify consistent gray matter (GM) difference between FMS patients and healthy subjects. We performed a comprehensive literature search in PubMed (January 2000-December 2015) and included six VBM publication on FMS. Stereotactic data were extracted from 180 patients of FMS and 123 healthy controls. By means of activation likelihood estimation (ALE) technique, regional GM reduction in left medial prefrontal cortex and right dorsal posterior cingulate cortex was identified. Both regions are within the default mode network. In conclusion, the gray matter deficit is related to the both affective and nonaffective components of pain processing. This result also provided the neuroanatomical correlates for emotional and cognitive symptoms in FMS.


Longitudinal tracking of recipient macrophages in a rat chronic cardiac allograft rejection model with noninvasive magnetic resonance imaging using micrometer-sized paramagnetic iron oxide particles.
Long-term survival of heart transplants is hampered by chronic rejection (CR). Studies indicate the involvement of host macrophages in the development of CR; however, the precise role of these cells in CR is unclear. Thus, it is important to develop noninvasive techniques to serially monitor the movement and distribution of recipient macrophages in chronic cardiac allograft rejection in vivo. We have employed a rat heterotopic working-heart CR model for a magnetic resonance imaging experiment. Twenty-one allograft (PVG.1U-->PVG.R8) and 9 isograft (PVG.R8-->PVG.R8) transplantations were performed. Recipient macrophages are labeled via intravenous injection of micron-sized paramagnetic iron oxide particles (0.9 microm in diameter) at a dose of 4.5 mg Fe per rat 1 day before transplantation. Serial in vivo magnetic resonance images were acquired for up to 16 weeks. The migration of labeled recipient cells in our CR model, in which cardiac CR is evident at 3 weeks and most extensive by 16 weeks after transplantation, can be assessed with the use of in vivo magnetic resonance imaging for >100 days after a single micron-sized paramagnetic iron oxide injection. The location and distribution of labeled recipient cells were confirmed with magnetic resonance microscopy and histology. This approach may improve our understanding of the immune cells involved in CR and the management of heart transplantation. Moreover, this study demonstrates the feasibility of noninvasively observing individual targeted cells over long time periods by serial in vivo magnetic resonance imaging.


A pleiotropic drug resistance transporter is involved in reduced sensitivity to multiple fungicide classes in Sclerotinia homoeocarpa (F.T. Bennett).
Dollar spot, caused by Sclerotinia homoeocarpa, is a prevalent turfgrass disease, and the fungus exhibits widespread fungicide resistance in North America. In a previous study, an ABC-G transporter, ShatrD, was associated with practical field resistance to demethylation inhibitor (DMI) fungicides. Mining of ABC-G transporters, also known as pleiotropic drug resistance (PDR) transporters, from RNA-Seq data gave an assortment of transcripts, several with high sequence similarity to functionally characterized transporters from Botrytis cinerea, and others with closest blastx hits from Aspergillus and Monilinia. In addition to ShatrD, another PDR transporter showed significant over-expression in replicated RNA-Seq data, and in a collection of field-resistant isolates, as measured by quantitative polymerase chain reaction. These isolates also showed reduced sensitivity to unrelated fungicide classes. Using a yeast complementation system, we sought to test the hypothesis that this PDR transporter effluxes DMI as well as chemically unrelated fungicides. The transporter (ShPDR1) was cloned into the Gal1 expression vector and transformed into a yeast PDR transporter deletion mutant, AD12345678. Complementation assays indicated that ShPDR1 complemented the mutant in the presence of propiconazole (DMI), iprodione (dicarboximide) and boscalid (SDHI, succinate dehydrogenase inhibitor). Our results indicate that the over-expression of ShPDR1 is correlated with practical field resistance to DMI fungicides and reduced sensitivity to dicarboximide and SDHI fungicides. These findings highlight the potential for the eventual development of a multidrug resistance phenotype in this pathogen. In addition, this study presents a pipeline for the discovery and validation of fungicide resistance genes using de novo next-generation sequencing and molecular biology techniques in an unsequenced plant pathogenic fungus.


BRCA1 haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cells.
Denosumab, a monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), might be a novel preventative therapy for BRCA1-mutation carriers at high risk of developing breast cancer. Beyond its well-recognized bone-targeted activity impeding osteoclastogenesis, denosumab has been proposed to interfere with the cross-talk between RANKL-producing sensor cells and cancer-initiating RANK+ responder cells that reside within premalignant tissues of BRCA1-mutation carriers. We herein tested the alternative but not mutually exclusive hypothesis that BRCA1 deficiency might cell-autonomously activate RANKL expression to generate cellular states with cancer stem cell (CSC)-like properties. Using isogenic pairs of normal-like human breast epithelial cells in which the inactivation of a single BRCA1 allele results in genomic instability, we assessed the impact of BRCA1 haploinsufficiency on the expression status of RANK and RANKL. RANK expression remained unaltered but RANKL was dramatically up-regulated in BRCA1mut/+ haploinsufficient cells relative to isogenic BRCA1+/+ parental cells. Neutralizing RANKL with denosumab significantly abrogated the ability of BRCA1 haploinsufficient cells to survive and proliferate as floating microtumors or "mammospheres" under non-adherent/non-differentiating conditions, an accepted surrogate of the relative proportion and survival of CSCs. Intriguingly, CSC-like states driven by epithelial-to-mesenchymal transition or HER2 overexpression traits responded to some extent to denosumab. We propose that breast epithelium-specific mono-allelic inactivation of BRCA1 might suffice to cell-autonomously generate RANKL-addicted, denosumab-responsive CSC-like states. The convergent addiction to a hyperactive RANKL/RANK axis of CSC-like states from genetically diverse breast cancer subtypes might inaugurate a new era of cancer prevention and treatment based on denosumab as a CSC-targeted agent.


Colocating health services: a way to improve coordination of children's health care?
Pediatric practices are faced with a growing demand that they address the healthy development of their patients. As pediatric practices strengthen their role as medical homes for their patients, they need either to provide expanded services or enhance their capacity to coordinate that care. One option for enhancing the existing capacity of pediatric practices is colocation with other providers and services in the same setting. This issue brief examines what is currently known about the use of colocation and its benefits. The literature and interviews used as information resources for the brief suggest that colocation of services is not a single strategy but rather a complex set of relationships, organizational structures, and other features meant to help practices deliver effective care. However, more thorough examination of current colocation approaches is needed before advice can be provided to practices considering this option.


The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group.
Only a few small trials have compared antithrombotic therapy (antiplatelet or anticoagulant agents) versus control in acute ischaemic stroke, and none has been large enough to provide reliable evidence on safety or efficacy. The International Stroke Trial (IST) was a large, randomised, open trial of up to 14 days of antithrombotic therapy started as soon as possible after stroke onset. The aim was to provide reliable evidence on the safety and efficacy of aspirin and of subcutaneous heparin. Half the patients were allocated unfractionated heparin (5000 or 12,500 IU bd [twice daily]), and half were allocated "avoid heparin"; and, in a factorial design, half were allocated aspirin 300 mg daily and half "avoid aspirin". The primary outcomes were death within 14 days and death or dependency at 6 months. 19,435 patients with suspected acute ischaemic stroke entering 467 hospitals in 36 countries were randomised within 48 hours of symptom onset. Among heparin-allocated patients, there were non-significantly fewer deaths within 14 days (876 [9.0%] heparin vs 905 [9.3%] no heparin), corresponding to 3 (SD 4) fewer deaths per 1000 patients. At 6 months the percentage dead or dependent was identical in both groups (62.9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 days (2.9% vs 3.8%) but this was offset by a similar-sized increase in haemorrhagic strokes (1.2% vs 0.4%), so the difference in death or non-fatal recurrent stroke (11.7% vs 12.0%) was not significant. Heparin was associated with a significant excess of 9 (SD 1) transfused or fatal extracranial bleeds per 1000. Compared with 5000 IU bd heparin, 12,500 IU bd heparin was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12.6% vs 10.8%). Among aspirin-allocated patients there were non-significantly fewer deaths within 14 days (872 [9.0%] vs 909 [9.4%]), corresponding to 4 (SD 4) fewer deaths per 1000 patients. At 6 months there was a non-significant trend towards a smaller percentage of the aspirin group being dead or dependent (62.2% vs 63.5%, 2p = 0.07), a difference of 13 (SD 7) per 1000; after adjustment for baseline prognosis the benefit from aspirin was significant (14 [SD 6] per 1000, 2p = 0.03). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2.8% vs 3.9%) with no significant excess of haemorrhagic strokes (0.9% vs 0.8%), so the reduction in death or non-fatal recurrent stroke with aspirin (11.3% vs 12.4%) was significant. Aspirin was associated with a significant excess of 5 (SD 1) transfused or fatal extracranial bleeds per 1000; in the absence of heparin the excess was 2 (SD 1) and was not significant. There was no interaction between aspirin and heparin in the main outcomes. Neither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term.


Mechanisms of action of rapamycin in gliomas.
Rapamycin has previously been shown to be efficacious against intracerebral glioma xenografts and to act in a cytostatic manner against gliomas. However, very little is known about the mechanism of action of rapamycin. The purpose of our study was to further investigate the in vitro and in vivo mechanisms of action of rapamycin, to elucidate molecular end points that may be applicable for investigation in a clinical trial, and to examine potential mechanisms of treatment failure. In the phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null glioma cell lines U-87 and D-54, but not the oligodendroglioma cell line HOG (PTEN null), doses of rapamycin at the IC50 resulted in accumulation of cells in G1, with a corresponding decrease in the fraction of cells traversing the S phase as early as 24 h after dosing. All glioma cell lines tested had markedly diminished production of vascular endothelial growth factor (VEGF) when cultured with rapamycin, even at doses below the IC50. After 48 h of exposure to rapamycin, the glioma cell lines (but not HOG cells) showed downregulation of the membrane type-1 matrix metalloproteinase (MMP) invasion molecule. In U-87 cells, MMP-2 was downregulated, and in D-54 cells, both MMP-2 and MMP-9 were downregulated after treatment with rapamycin. Treatment of established subcutaneous U-87 xenografts in vivo resulted in marked tumor regression (P < 0.05). Immunohistochemical studies of subcutaneous U-87 tumors demonstrated diminished production of VEGF in mice treated with rapamycin. Gelatin zymography showed marked reduction of MMP-2 in the mice with subcutaneous U-87 xenografts that were treated with rapamycin as compared with controls treated with phosphatebuffered saline. In contrast, treatment of established intracerebral U-87 xenografts did not result in increased median survival despite inhibition of the Akt pathway within the tumors. Also, in contrast with our findings for subcutaneous tumors, immunohistochemistry and quantitative Western blot analysis results for intracerebral U-87 xenografts indicated that there is not significant VEGF production, which suggests possible deferential regulation of the hypoxia-inducible factor 1alpha in the intracerebral compartment. These findings demonstrate that the complex operational mechanisms of rapamycin against gliomas include cytostasis, anti-VEGF, and anti-invasion activity, but these are dependent on the in vivo location of the tumor and have implications for the design of a clinical trial.


Assessment of iron status among preschool children (6 to 59 months) with and without malaria in Western Province, Kenya.
Iron deficiency is a major public health concern. Globally, iron deficiency ranks number 9 and is responsible for about 60% of all anemia cases among preschool children. In Africa iron deficiency is 43-52% while in Kenya, children under 5 years constitute the largest burden with 69% of them being deficient. There is limited iron deficiency data in Kenya. This study determined haemoglobin levels, serum ferritin levels, nutritional status and P.falciparum malaria infection in preschool children. A household cross sectional study was undertaken among 125 preschoolers in Western province, drawn from 37 clusters. Systematic random sampling was used for sample selection. Data was collected using pretested structured questionnaires, entered in Microsoft package. Data analysis was done in Statistical package for social science (SPSS) version 20 using bivariate and multivariate logistic regression and differences were considered significant at P < 0.05. The prevalence of iron deficiency (Serum ferritin <12mg/l), anaemia (Hb < 110g/l) and plasmodium falciparum malaria were 20.8%, 25% and 6.8% respectively. There was a significant association between iron deficiency and anaemia (OR = 3.43, 95% CI: 1.33-8.84, p = 0.008). A preschool child with anaemia was 3.43 times likely to be iron deficient compared to a preschool child who was not anaemic. Iron deficiency, anaemia and plasmodium falciparum malaria was prevalent among preschool children. The findings revealed a significant association between iron deficiency and anaemia. Therefore effective interventions to improve iron status will have large health benefits by greatly reducing anaemia in preschool children.


Strontium-85 scanning of suspected bone disease.
Strontium-85 scanning of suspected bone lesions in 81 patients has added to the criteria for the diagnosis of malignant and other lesions of bone. Of 46 patients with a previous history of malignant disease and skeletal symptoms negative radiological findings were recorded in 19, but nine of these had positive scans, eight of which when followed up over periods of up to four years proved to be metastatic. A similar prevalence of positive scans occurred in patients without a previous history of malignancy. Because of the anatomical localization of lesions made possible by this technique a tissue diagnosis was made in six patients, while fields of radiotherapy were altered in another seven. This technique can improve the management of patients with suspected bone disease.


Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation after clopidogrel.
The thienopyridine P2Y(12) receptor antagonist clopidogrel reduces the risk of arterial thrombosis and individual pharmacodynamic responses to clopidogrel are believed to reflect the levels of active metabolite (AM) generated. Rifampicin increases the inhibitory effect of clopidogrel on platelet aggregation (PA). We studied the response to clopidogrel before and during administration of rifampicin in order to study the relationship between individual AM levels and P2Y(12) blockade. Healthy volunteers received a 600-mg loading dose of clopidogrel followed by 75 mg daily for 7 days and, after a washout period and treatment with rifampicin [300 mg twice a day (b.i.d.)], received the same regimen of clopidogrel. Clopidogrel AM levels were determined over 4 h after the clopidogrel loading dose and unblocked P2Y(12) receptor number was assessed using a (33) P-2MeSADP binding assay. PA was measured by optical aggregometry with ADP and TRAP. Rifampicin enhanced clopidogrel AM production [area-under-the-curve (AUC): clopidogrel 89±22 ng h mL(-1) , clopidogrel+rifampicin 335±86 ng h mL(-1) , P<0.0001], and P2Y(12) blockade (unblocked receptors: clopidogrel 48±24, clopidogrel+rifampicin 4±2, P<0.0001) and reduced PA (5 μmol L(-1) ADP: clopidogrel 20±4, clopidogrel+rifampicin 5±2, P<0.01). Increasing numbers of unblocked receptors were required for an aggregation response with a decreasing concentration of ADP. PA induced by ADP 2 μmol L(-1) was particularly sensitive to low levels of receptor blockade. Potentiation of clopidogrel AM production by rifampicin leads to greater P2Y(12) blockade and consequently greater inhibition of PA. PA responses to low concentrations of ADP are more sensitive to P2Y(12) blockade.


Communal farming, climate change adaptation and the media in Zimbabwe.
Climate change is destroying Zimbabwean communal farmers' agricultural activities - a source of living for most people. As communal farmers struggle to adapt, the media is expected to assume a fundamental theoretical role of educating and informing them about the appropriate adaptation techniques. Located in Umguza District in Matabeleland North Province, the study explored how communal farmers created meaning out of climate change media content and its influence on their agricultural practices from October 2014 to April 2015. In doing so, the study used the Two-Step Flow theory and Hall's Encoding and Decoding Model. Entrenched in pragmatism, the study embedded quantitative techniques at different stages. Multistage sampling combining Simple Random Sampling (SRS), purposive and systematic sampling techniques was used to identify the 263 households for semi structured questionnaires, direct observations and in-depth interviews. The findings were analysed using Statistical Package for the Social Sciences (SPSS), thematic analysis and pattern matching. The results show that personal observations; print, broadcast and online media; and opinion leaders were the main sources of climate change information. The radio was the most used medium in communicating climate change adaptation though it was the second most accessed after mobile phones. Conservation Agriculture and planting of drought-resistant crops were some of the adaptation techniques communicated in the media. When interacting with media content, communal farmers create their own meaning influenced by their cultural values, resulting in some adopting, rejecting or modifying certain adaptation techniques. The study concludes that opinion leaders are fundamental in communal farmers' interaction with media but their influence must not be overestimated.


Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B.
The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B) is causative for frontotemporal dementia linked to chromosome 3 (FTD3). CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT) and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs) were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.


SARS-CoV-2 sample-to-answer nucleic acid testing in a tertiary care emergency department: evaluation and utility.
Rapid sample-to-answer tests for detection of SARS-CoV-2 are emerging and data on their relative performance is urgently needed. We evaluated the analytical performance of two rapid nucleic acid tests, Cepheid Xpert® Xpress SARS-CoV-2 and Mobidiag Novodiag® Covid-19, in comparison to a combination reference of three large-scale PCR tests. Moreover, utility of the Novodiag® test in tertiary care emergency departments was assessed. In the preliminary evaluation, analysis of 90 respiratory samples resulted in 100% specificity and sensitivity for Xpert®, whereas analysis of 107 samples resulted in 93.4% sensitivity and 100% specificity for Novodiag®. Rapid SARS-CoV-2 testing with Novodiag® was made available for four tertiary care emergency departments in Helsinki, Finland between 18 and 31 May, coinciding with a rapidly declining epidemic phase. Altogether 361 respiratory specimens, together with relevant clinical data, were analyzed with Novodiag® and reference tests: 355/361 of the specimens were negative with both methods, and 1/361 was positive in Novodiag® and negative by the reference method. Of the 5 remaining specimens, two were negative with Novodiag®, but positive with the reference method with late Ct values. On average, a test result using Novodiag® was available nearly 8 hours earlier than that obtained with the large-scale PCR tests. While the performance of novel sample-to-answer PCR tests need to be carefully evaluated, they may provide timely and reliable results in detection of SARS-CoV-2 and thus facilitate patient management including effective cohorting.


Post-Traumatic Stress Disorder and Associated Factors during the Early Stage of the COVID-19 Pandemic in Norway.
The COVID-19 outbreak and the sudden lockdown of society in March 2020 had a large impact on people's daily life and gave rise to concerns for the mental health in the general population. The aim of the study was to examine post-traumatic stress reactions related to the COVID-19 pandemic, the prevalence of symptom-defined post-traumatic stress disorder (PTSD), and factors associated with post-traumatic stress in the Norwegian population during the early stages of the COVID-19 outbreak. A survey was administered via social media channels, to which a sample of 4527 adults (≥18 years) responded. Symptom-defined PTSD was measured with the PTSD Checklist for the DSM-5. The items were specifically linked to the COVID-19 pandemic. We used the DSM-5 diagnostic guidelines to categorize participants as fulfilling the PTSD symptom criteria or not. Associations with PTSD were examined with single and multiple logistic regression analyses. The prevalence of symptom-defined PTSD was 12.5% for men and 19.5% for women. PTSD was associated with lower age, female gender, lack of social support, and a range of pandemic-related variables such as economic concerns, expecting economic loss, having been in quarantine or isolation, being at high risk for complications from COVID-19 infection, and having concern for family and close friends. In conclusion, post-traumatic stress reactions appear to be common in the Norwegian population in the early stages of the COVID-19 outbreak. Concerns about finances, health, and family and friends seem to matter.


Synthesis and characterization of 4-(2-aminoethyl)aniline imprinted polymer as a highly effective sorbent of dopamine.
The aim of the study was to develop an efficient sorbent for the separation of dopamine. 4-(2-Aminoethyl)aniline was chosen as a pseudo-template to produce the imprinted polymers from seven different functional monomers in the presence of ethylene glycol dimethacrylate as a cross-linker. The binding capacity showed that the highest binding specificity towards dopamine was achieved when methacrylic acid was used as the monomer in methanol solution to form a polymer matrix. The imprinting factor value was equal to 22.96. Other biogenic amines were bound much more weakly. A simple theoretical model was used to give an insight into the imprinting process and the selectivity of polymer matrix. Two artificial urine samples were used as the complex matrices to show the usefulness of the new sorbent for bioanalysis.


The barriers to smoking cessation in Swiss methadone and buprenorphine-maintained patients.
Smoking rates in methadone-maintained patients are almost three times higher than in the general population and remain elevated and stable. Due to the various negative health effects of smoking, nicotine dependence contributes to the high mortality in this patient group. The purpose of the current study was to investigate Swiss methadone and buprenorphine-maintained patients' willingness to stop smoking and to clarify further smoking cessation procedures. Substance abuse history, nicotine dependence, and readiness to stop smoking were assessed in a sample of 103 opiate-dependent patients in the metropolitan area of Zurich, Switzerland. Patients were asked to document their smoking patterns and readiness to quit. Only a small number of patients were willing to quit smoking cigarettes (10.7%) and, even though bupropione or nicotine replacement therapy was included in the fixed daily treatment care, only one patient received nicotine replacement therapy for smoking cessation. A diagnosis of depression in patients' clinical records was associated with readiness to stop smoking. No significant associations were found between readiness to quit smoking and age, methadone treatment characteristics, and presence of co-dependencies. The current prescription level of best medicine for nicotine dependence in Swiss methadone and buprenorphine-maintained patients is far from adequate. Possible explanations and treatment-relevant implications are discussed.


An Early Viral Response Predicts the Virological Response to Ribavirin in Hepatitis E Virus Organ Transplant Patients.
Ribavirin is efficient at treating chronic hepatitis E virus infection in solid-organ transplant patients. However, the early kinetics of viral replication under therapy and the impact of immunosuppressant regimens on viral replication are unknown: thus, determining the aim of our study. Thirty-five patients with a solid-organ transplant and chronic hepatitis E virus infection were given ribavirin for 3 months. The hepatitis E virus (HEV) RNA concentrations were determined before treatment, at days 7, 15, and 21 and at months 1, 2, and 3 during therapy and after ribavirin cessation. A sustained virological response (SVR) occurred in 63%. Decreased viral concentration within the first week post-ribavirin therapy was an independent predictive factor for SVR, and a decreased HEV concentration of 0.5 log copies/mL or greater had an 88% positive predictive value. No correlation between ribavirin trough level on day 7 or at month 2 with a virological response or an SVR was observed. Before therapy, HEV RNA concentration was significantly greater in patients receiving mechanistic target of rapamycin inhibitor-based immunosuppression compared to patients given calcineurin inhibitors. The use of mycophenolic acid did not impact on the response to ribavirin. An early response to ribavirin can be used to define the optimal duration of therapy in the setting of HEV infection.


Lipid membrane domain formation and alamethicin aggregation studied by calorimetry, sound velocity measurements, and atomic force microscopy.
An experimental study of phosphocholine membranes made from one lipid, from mixtures of DPPC and DLPC, and also from lipids and small amounts of alamethicin is presented. We used atomic force microscopy to investigate the spatial organization and structure of lipid domains and also of the defects induced by the peptide. Alamethicin was found to alter the state of lipids in the gel state in a way that domains of fluid lipids are formed close to the defects. Differential calorimetry revealed phase characteristics of the lipid mixtures and the effect of small amounts of alamethicin on the phase behavior. It was also shown that the sound velocity profiles of the membranes suspensions can be well calculated from the heat capacity traces of the samples. This result confirms the correlation between the mechanical properties and the specific heat of membrane systems.


Is all asthenopia the same?
Any of several conditions can cause asthenopia. The purpose of this study was to determine whether the particular sensations or their location vary dependent on the symptom-inducing condition. Twenty subjects with good vision performed eight reading tasks in random order during different conditions. Each condition used different stimuli to induce asthenopia. The eight conditions were mixed astigmatism, close viewing distance, upward gaze, dry eyes, lens flipper, small font, glare, and flickering light. Subjects were asked to read until attaining a level of discomfort self-defined as "barely tolerable." After each task, subjects rated the magnitude of several symptom descriptors (burning, ache, strain, irritation, tearing, blurred vision, double vision, dryness, and headache) and their location. Analysis of variance with repeated measures was used to determine that all of the individual symptom sensation measures (except blur) were significantly related (p values ranged from 0.003 to <0.0001) to the inducing condition. Principal factor analysis with orthogonal varimax rotation was used to test symptom by condition relationships and determined two latent factors, designated external and internal symptom factors (ESF and ISF), that related symptoms to inducing condition. The ESF pattern comprises burning, irritation, tearing, and dryness located in the front and bottom of the eye. ESF is caused by holding the eyelid open, glare, up gaze, small font, and flickering. ESF seems highly related to dry-eye symptoms. The ISF pattern comprises ache, strain, and headache located behind the eyes. ISF is caused by the close viewing distance, lens flipper, and mixed astigmatism conditions and is likely related to accommodative and vergence stress. Symptom descriptors and locations were able to distinguish discomfort on the basis of causative condition. Results support two different symptom constellations and, hence, at least two different afferent pathways for symptoms of asthenopia.


Evidence that natural murine soluble interleukin 4 receptors may act as transport proteins.
The present studies were undertaken to determine whether the interleukin 4 binding proteins (IL-4BPs) previously identified in the biological fluids of mice are soluble forms of IL-4Rs. We also studied the binding properties of IL-4BPs in order to gain insight into their physiological role in vivo. Affinity-purified IL-4BPs and recombinant soluble IL-4Rs generated similar one-dimensional (Cleveland) peptide maps after digestion with either Staphylococcus aureus V8 protease or trypsin, indicating structural similarities. Furthermore, a rat mAb directed against the murine IL-4Rs immunoprecipitated the IL-4BPs and completely inhibited binding of 125I-IL-4 to a purified preparation of IL-4BPs. Taken together these data indicate that the IL-4BPs are soluble IL-4Rs. At 4 degrees C the IL-4BPs competitively inhibited the binding of IL-4 to membrane IL-4Rs but their ability to prevent binding of IL-4 to cells at 37 degrees C, at the same concentrations, was significantly reduced. Kinetic binding studies of soluble IL-4BPs vs. membrane IL-4Rs disclosed important differences in their rates of dissociation from IL-4. Whereas dissociation at 4 degrees C was slow for both, dissociation of IL-4 from IL-BPs at 37 degrees C was considerably faster (t 1/2 of 2 min) than dissociation of IL-4 from membrane IL-4Rs (t 1/2 of approximately 69 min). Temperature-dependent changes in dissociation kinetics were reversible, and could not be accounted for by either inactivation of the IL-4BPs at 37 degrees C or receptor internalization. Additional experiments also demonstrated that when IL-4BPs bind to IL-4 at 37 degrees C, the IL-4/IL-4BPs complex can rapidly dissociate, allowing IL-4 to bind to membrane IL-4Rs. In addition, binding of IL-4 by the IL-4BPs protects IL-4 from proteolytic degradation. Taken together, these results suggest that the IL-4BPs are naturally occurring forms of soluble IL-4Rs and that some of their properties (fast dissociation kinetics and protection of IL-4 from proteolysis) are consistent with a potential role as carrier proteins for IL-4 in the circulation.


The association between exaggeration in health related science news and academic press releases: retrospective observational study.
To identify the source (press releases or news) of distortions, exaggerations, or changes to the main conclusions drawn from research that could potentially influence a reader's health related behaviour. Retrospective quantitative content analysis. Journal articles, press releases, and related news, with accompanying simulations. Press releases (n = 462) on biomedical and health related science issued by 20 leading UK universities in 2011, alongside their associated peer reviewed research papers and news stories (n = 668). Advice to readers to change behaviour, causal statements drawn from correlational research, and inference to humans from animal research that went beyond those in the associated peer reviewed papers. 40% (95% confidence interval 33% to 46%) of the press releases contained exaggerated advice, 33% (26% to 40%) contained exaggerated causal claims, and 36% (28% to 46%) contained exaggerated inference to humans from animal research. When press releases contained such exaggeration, 58% (95% confidence interval 48% to 68%), 81% (70% to 93%), and 86% (77% to 95%) of news stories, respectively, contained similar exaggeration, compared with exaggeration rates of 17% (10% to 24%), 18% (9% to 27%), and 10% (0% to 19%) in news when the press releases were not exaggerated. Odds ratios for each category of analysis were 6.5 (95% confidence interval 3.5 to 12), 20 (7.6 to 51), and 56 (15 to 211). At the same time, there was little evidence that exaggeration in press releases increased the uptake of news. Exaggeration in news is strongly associated with exaggeration in press releases. Improving the accuracy of academic press releases could represent a key opportunity for reducing misleading health related news.


Modeling macropore flow effects on pesticide leaching: inverse parameter estimation using microlysimeters.
Macropore flow is a key factor determining pesticide fate, but models accounting for this process need parameters that cannot be easily measured. This study was conducted to investigate the use of inverse techniques to estimate parameters controlling macropore flow and pesticide fate in the dual-permeability model MACRO. Undisturbed columns were sampled at three landscape positions (hilltop, slope, hollow) with contrasting texture and organic carbon content. Transient leaching experiments were performed for an anionic tracer and the herbicide MCPA (4-chloro-2methylphenoxy acetic acid) during a 4-mo period, first under natural rainfall, and then under controlled irrigation in the laboratory. The tracer breakthrough for the liner-textured soil from the hilltop showed strong evidence of macropore flow, resulting in a rapid leaching of MCPA, while leaching was minimal from the organic-rich hollow soil, since macropore flow was weaker and adsorption stronger. The MACRO model was linked to the inverse modeling program SUFI (Sequential Uncertainty Fitting) to enable calibration of nine key model parameters. Based on calculated model efficiencies, MACRO-SUFI gave generally good predictions of water movement and tracer and pesticide transport, although some errors were attributed to difficulties in simulating the effects of soil moisture on degradation and the timing of water outflows. Even after calibration, significant uncertainties remained for some key parameters controlling macropore flow. Nevertheless, the parameter estimates were significantly different between landscape positions and could also be related to basic soil properties. The posterior uncertainty ranges could probably be reduced with a more exhaustive sampling of the parameter space and improved experimental designs.


Using automated flight mills to manipulate fat reserves in Douglas-fir beetles (Coleoptera: Curculionidae).
Because current techniques for quantifying fat, the main fuel used for flight in insects, are destructive, researchers are limited to only one direct measure of fat per specimen. This limitation is problematic for studies aimed at assessing whether fat loss through flight influences subsequent behavioral activity. To overcome this problem, we used body volume, body mass, emergence day, and brood density as parameters in a multiple regression model to predict initial fat levels in female Douglas-fir beetles, Dendroctonus pseudotsugae Hopkins, on emergence from the host. The model explained 54% of the variation in fat reserves as determined by Soxhlet extraction with petroleum ether. Treatments of 30-1,380 min of flight on rotary flight mills were used to establish the relationship between flight and fat reserves. Using a model that incorporated estimated initial fat levels, as well as time spent in flight and time in nonflight activities on the flight mills, we found that 6 h of flight decreased fat by approximately 50%. Flight activity and nonflight activity did not differ significantly in terms of their effect on fat reserves. Individual beetles with high initial fat content flew longer and faster on flight mills than beetles with low initial fat reserves. Our study shows how researchers can manipulate fat levels in bark beetles and other insects through flight, thereby opening the door to using these manipulations in behavioral studies.


Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.
Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d). Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.


Comparative proteomics-network analysis of proteins responsible for ursolic acid-induced cytotoxicity in colorectal cancer cells.
Ursolic acid is a key active compound present in many medicinal herbs that have been widely used in traditional Chinese medicine for the clinical treatment of various cancers. However, the precise mechanisms of its antitumor activity have been poorly understood. To identify the cellular targets of ursolic acid, two-dimensional gel electrophoresis combined with mass spectrometry was performed in this study, which identified 15 proteins with significantly altered levels in protein expression. This demonstrated that ursolic acid-induced cytotoxicity in colorectal cancer cells involves dysregulation in protein folding, signal transduction, cell proliferation, cell cycle, and apoptosis. Corresponding protein regulation was also confirmed by Western blotting. Furthermore, the study of functional association between these 15 proteins revealed that 10 were closely related in a protein-protein interaction network, whereby the proteins either had a direct interaction with each other or were associated via only one intermediary protein. In this instance, the ATP5B/CALR/HSP90B1/HSPB1/HSPD1-signaling network was revealed as the predominant target which was associated with the majority of the observed protein-protein interactions. As a result, the identified targets may be useful in explaining the anticancer mechanisms of ursolic acid and as potential targets for colorectal cancer therapy.


Individual differences in prefrontal cortex activity during perception of bitter taste using fNIRS methodology.
Although bitter taste has a crucial role in nutrition by preventing the ingestion of toxic foods, there are few studies on bitter taste neuroimaging. To identify cortical areas involved in bitter taste perception and to determine if individual differences in taste sensitivity to 6-n-propylthiouracil (PROP) are represented in the brain by different cortical activation patterns, we examined 48 healthy volunteers using functional near-infrared spectroscopy. Participants rated the perceived intensity of filter paper disks impregnated with PROP and NaCl during the imaging procedure and were then classified as PROP tasters and nontasters. We monitored cortical activity in both the anterior and posterior regions of the dorsolateral prefrontal cortex (DLPFC) and in the ventrolateral prefrontal cortex (VLPFC). No activity was detected in the anterior DLPFC in any of the participants. However, during the administration of PROP, significant cortical activation was detected in the more posterior regions of the left DLPFC and in the left and right VLPFC but only in PROP tasters. PROP nontasters showed no cortical activity in these areas. These data suggest that the prefrontal cortex is involved in the conscious perception of the bitter taste of PROP and that the pattern of activity is consistent with individual differences in the ability to taste this compound. Thus, the PROP phenotype is associated with fundamental differences in cortical taste processing.


'Whose failure counts?' A critical reflection on definitions of failure for community health volunteers providing HIV self-testing in a community-based HIV/TB intervention study in urban Malawi.
The category of community health worker applied within the context of health intervention trials has been promoted as a cost-effective approach to meeting study objectives across large populations, relying on the promotion of the concept of 'community belonging' to encourage altruistic volunteerism from community members to promote health. This community-based category of individuals is recruited to facilitate externally driven priorities defined by large research teams, outside of the target research environment. An externally defined intervention is then 'brought to' the community through locally recruited community volunteers who form a bridge between the researchers and participants. The specific role of these workers is context-driven and responsive to the needs of the intervention. This paper is based on the findings from an annual evaluation of community health worker performance employed as community counsellors to deliver semi-supervised HIV self-testing (HIVST) at community level of a large HIV/TB intervention trial conducted in urban Blantyre, Malawi. A performance evaluation was conducted to appraise individual service delivery and assess achievements in meeting pre-defined targets for uptake of HIVST with the aim of improving overall uptake of HIVST. Through an empirical 'evaluation of the evaluation' this paper critically reflects on the position of the community volunteer through the analytical lens of 'failure', exploring the tensions in communication and interpretation of intervention delivery between researchers and community volunteers and the differing perspectives on defining failure. It is concluded that community interventions should be developed in collaboration with the population and that information guiding success should be clearly defined.


Could kinesiology taping help mitigate pain, breathlessness and abdominal-related symptoms in cancer?
We present the case of a woman who was an amateur athlete diagnosed with primary breast cancer, and 10 years later with terminal metastatic cancer. This case report was prepared posthumously in co-operation with her next of kin (husband). The patient first presented to a sports physiotherapist (AR) for her pain-management and to help maintain physical fitness so that she could continue with sports and an active lifestyle. The patient continued with physiotherapy for several months to enable her to be active. However, when her health deteriorated significantly due to advancing cancer, the treatment was modified and aimed at improving the patient's general well-being. The physiotherapist applied kinesiology tape over the patient's lower rib cage, diaphragm and abdomen in an attempt to manage pain, breathlessness and abdominal bloating. The patient reported alleviation of pain, breathlessness, abdominal discomfort and nausea, accompanied by improvements in eating, drinking, energy levels and physical function.


STAT3 expression by myeloid cells is detrimental for the T- cell-mediated control of infection with Mycobacterium tuberculosis.
STAT3 is a master regulator of the immune responses. Here we show that M. tuberculosis-infected stat3fl/fl lysm cre mice, defective for STAT3 in myeloid cells, contained lower bacterial load in lungs and spleens, reduced granuloma extension but higher levels of pulmonary neutrophils. STAT3-deficient macrophages showed no improved control of intracellular mycobacterial growth. Instead, protection associated to elevated ability of stat3fl/fl lysm cre antigen-presenting cells (APCs) to release IL-6 and IL-23 and to stimulate IL-17 secretion by mycobacteria-specific T cells. The increased IL-17 secretion accounted for the improved control of infection since neutralization of IL-17 receptor A in stat3fl/fl lysm cre mice hampered bacterial control. APCs lacking SOCS3, which inhibits STAT3 activation via several cytokine receptors, were poor inducers of priming and of the IL-17 production by mycobacteria-specific T cells. In agreement, socs3fl/fl cd11c cre mice deficient of SOCS3 in DCs showed increased susceptibility to M. tuberculosis infection. While STAT3 in APCs hampered IL-17 responses, STAT3 in mycobacteria-specific T cells was critical for IL-17 secretion, while SOCS3 in T cells impeded IL-17 secretion. Altogether, STAT3 signalling in myeloid cells is deleterious in the control of infection with M. tuberculosis.


Beneficial effect of resveratrol on bovine oocyte maturation and subsequent embryonic development after in vitro fertilization.
To analyze the potential beneficial effects and mechanisms of action of resveratrol on the maturation of bovine oocytes that were incubated in different concentrations of resveratrol (0.1, 1.0, or 10.0 μM) as germinal vesicle-stage oocytes. In vitro prospective study. University research laboratory. Animal models for human studies. In vitro culture in the presence of various concentrations of the antioxidant resveratrol. Parameters of hormone levels, oocyte nuclear maturation, cumulus expansion, levels of intracellular glutathione and reactive oxygen species, embryonic cleavage, blastocyst formation, gene expression associated with mature bovine oocytes and cumulus cells, and level of sirtuin 1 gene expression. Resveratrol statistically significantly increased progesterone secretion and decreased estradiol-17β secretion by cumulus cells. The elevated levels of progesterone activated the Mos/MEK/p42 mitogen-activated protein kinase (MAPK) cascade in the oocytes. At a concentration of 1.0 μM, resveratrol statistically significantly improved cumulus expansion, polar body formation, the (hatched) blastocyst rate, and the mean number of cells/blastocysts. Meanwhile, resveratrol statistically significantly reduced the level of reactive oxygen species (ROS) and increased the level of glutathione (GSH). For the first time, the expression of the sirtuin-1 gene was identified in granulosa cells, cumulus cells, oocytes, and blastocysts. Further studies revealed that resveratrol promoted sirtuin-1 gene expression. Resveratrol promoted bovine oocyte maturation and subsequent post-in vitro fertilization embryonic development by inducing progesterone secretion and an antioxidant effect, probably in a manner dependent on sirtuin-1.


Effects of fatigue on kinematics and kinetics during overground running: a systematic review.
Understanding kinematic and kinetic changes with fatigue during running is important to assess changes that may influence performance and injury. The aim of this systematic review was to identify, critique and summarize literature about the effects of fatigue on kinematics and kinetics during a fatiguing overground run and present the reported influence on performance and injury. An electronic search was conducted of MEDLINE, SPORTDiscus, CINAHL and PubMed databases. Two reviewers assessed articles for inclusion, and evaluated the quality of articles included using a modified version of the Downs and Black Quality Index. A total of twelve articles were identified for review. The mean quality assessment score was seven out of a possible 12. Kinematic and kinetic changes reported to affect performance included decreased speed, step or stride frequency and length, increased trunk flexion, lower leg position at heel strike, mediolateral acceleration, changes in hip and knee ranges, and decreased stride regularity, heel lift, maximum knee rotation and backward ankle velocity. Alterations reported to increase risk of injury included decreased step frequency, increased upper body rotation and lower leg position at heel strike, and decreased knee flexion during stance. Reduced risk of injury has been linked to decreased step length and hip ranges, and increased trunk flexion. This review found limited evidence regarding changes in kinematic and kinetic during a fatiguing run in relation to performance and injury. Higher quality studies are warranted, with a larger sample of homogenous runners, and type of run carefully selected to provide quality information for runners, coaches and clinicians.


Taxon abundance, diversity, co-occurrence and network analysis of the ruminal microbiota in response to dietary changes in dairy cows.
The ruminal microbiome, comprising large numbers of bacteria, ciliate protozoa, archaea and fungi, responds to diet and dietary additives in a complex way. The aim of this study was to investigate the benefits of increasing the depth of the community analysis in describing and explaining responses to dietary changes. Quantitative PCR, ssu rRNA amplicon based taxa composition, diversity and co-occurrence network analyses were applied to ruminal digesta samples obtained from four multiparous Nordic Red dairy cows fitted with rumen cannulae. The cows received diets with forage:concentrate ratio either 35:65 (diet H) or 65:35 (L), supplemented or not with sunflower oil (SO) (0 or 50 g/kg diet dry matter), supplied in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments and four 35-day periods. Digesta samples were collected on days 22 and 24 and combined. QPCR provided a broad picture in which a large fall in the abundance of fungi was seen with SO in the H but not the L diet. Amplicon sequencing showed higher community diversity indices in L as compared to H diets and revealed diet specific taxa abundance changes, highlighting large differences in protozoal and fungal composition. Methanobrevibacter ruminantium and Mbb. gottschalkii dominated archaeal communities, and their abundance correlated negatively with each other. Co-occurrence network analysis provided evidence that no microbial domain played a more central role in network formation, that some minor-abundance taxa were at nodes of highest centrality, and that microbial interactions were diet specific. Networks added new dimensions to our understanding of the diet effect on rumen microbial community interactions.


Nail gun injuries to the head with minimal neurological consequences: a case series.
An estimated 3700 individuals are seen annually in US emergency departments for nail gun-related injuries. Approximately 45 cases have been reported in the literature concerning nail gun injuries penetrating the cranium. These cases pose a challenge for the neurosurgeon because of the uniqueness of each case, the dynamics of high pressure nail gun injuries, and the surgical planning to remove the foreign body without further vascular injury or uncontrolled intracranial hemorrhage. Here we present four cases of penetrating nail gun injuries with variable presentations. Case 1 is of a 33-year-old white man who sustained 10 nail gunshot injuries to his head. Case 2 is of a 51-year-old white man who sustained bi-temporal nail gun injuries to his head. Cases 3 and 4 are of two white men aged 22 years and 49 years with a single nail gun injury to the head. In the context of these individual cases and a review of similar cases in the literature we present surgical approaches and considerations in the management of nail gun injuries to the cranium. Case 1 presented with cranial nerve deficits, Case 2 required intubation for low Glasgow Coma Scale, while Cases 3 and 4 were neurologically intact on presentation. Three patients underwent angiography for assessment of vascular injury and all patients underwent surgical removal of foreign objects using a vice-grip. No neurological deficits were found in these patients on follow-up. Nail gun injuries can present with variable clinical status; mortality and morbidity is low for surgically managed isolated nail gun-related injuries to the head. The current case series describes the surgical use of a vice-grip for a good grip of the nail head and controlled extraction, and these patients appear to have a good postoperative prognosis with minimal neurological deficits postoperatively and on follow-up.


Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, so-called statins, reduce the relative risk of a major coronary event by lowering the serum cholesterol level. In addition, statins may confer beneficial effects by cholesterol-lowering independent mechanisms, which are incompletely characterized. Because angiotensin II (Ang II) plays crucial roles in the pathogenesis of cardiovascular diseases, we examined the effect of statins on the expression of the Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs). Cerivastatin and fluvastatin reduced the AT(1)-R mRNA and the AT(1)-R protein levels; however, pravastatin lacked this effect. Cerivastatin and fluvastatin suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. Coincubation of VSMCs with mevalonate or geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate reversed the cerivastatin-induced AT(1)-R downregulation. Overexpression of dominant-negative Rho A also suppressed AT(1)-R mRNA expression. Treatment with cerivastatin for 24 hours reduced the calcium response of VSMCs to Ang II. Taken together, statins downregulate AT(1)-R expression through a mevalonate-dependent, geranylgeranyl pyrophosphate-dependent, and Rho A-dependent manner and attenuate the biological function of Ang II. Downregulation of AT(1)-R may contribute to the cholesterol-independent beneficial effect of statins on the cardiovascular system.


Expression of CLDN1 in colorectal cancer: a novel marker for prognosis.
Claudin1 (CLDN1) plays an important role not only in the intercellular barrier function of tight junctions (TJs) but also in migration and invasiveness of cancer cells. Previous reports show that CLDN1 overexpression is significantly related to the malignant behavior in several cancer types whereas its significance in colorectal cancer (CRC) is not fully understood. The present study comprised 119 patients who underwent surgery for CRC, as well as 3 cell lines derived from human CRC. The correlation of gene expression with clinical parameters in patients was assessed by knockdown experiments using 3 cell lines. Patients with high CLDN1 expression were statistically shown to have a relatively better prognosis, and those with low CLDN1 expression showed poorer overall survival and disease-free survival than those with high expression. The assessment of CLDN1 knockdown in the 3 cell lines demonstrated that the siRNA inhibition resulted in a statistically significant increase in cell invasiveness. In conclusion, the present data strongly suggest that CLDN1 expression is a prognostic factor in CRC patients.


Primary psoas sarcoma causing malignant psoas syndrome: favourable response to radiotherapy.
Malignant psoas syndrome (MPS) is an uncommon condition first described by Stevens et al. MPS is caused by malignant infiltration of the psoas muscle and adjacent nerves and is characterised by (fixed) flexion deformity of the ipsilateral hip and proximal lumbosacral plexopathy. It has previously been described in relation to metastatic carcinoma, melanoma and liposarcoma, as well as non-Hodgkins lymphoma. We present the case of a 68-year-old woman with a sarcoma arising in the left psoas muscle at the level of L4 who presented with symptoms of MPS. To the authors' knowledge this is the first case of MPS arising from a primary sarcoma of the iliopsoas compartment. The patient underwent presurgical radiotherapy, with a significant improvement in pain control without an increase in analgesic medications. We discuss the aetiology of MPS and the role of radiotherapy in the treatment of this rare syndrome.


Alpha-particle activity of apollo 11 samples.
Nine polishled thin sectionis have been exposed to nulclear track plates, three have been counted by alplia-particle spectrometry, and one has been examined by electron mocroprobe. Interpretation of the results is in a preliminary stage. Alpha track distribiutioni in the autoradiograph of a breccia forms a network that appears related to the rims of accretionary lapilli comiiposinig the breccia. Thorium in a coarse-grained crystalline rock is concenitrated in micron-sized, zirconium-rich crystals. Alplia count rates agree with what would be predicted from previously reported thorium and uranium contents of the same rocks, suggesting secular equilibriunm for the thorium and uranium decay series.


Genetic variation in aldosterone synthase predicts plasma glucose levels.
The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms--one in the putative promoter (T-344C) and another resulting in a lysine/arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population--were associated with fasting plasma glucose levels (P = 0.000017) and those 60 (P = 0.017) and 120 (P = 0.0019) min after an oral glucose challenge. A C/T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39-3.92; P = 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02-5.5; P = 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.


Does the Delivery System Matter? The Scaling-Out of a School-Based Resilience Curriculum to the Social Services Sector.
Background: The context is highly relevant to the implementation of new health-related programs and is an implicit or explicit part of the major implementation models in the literature. The Resilience Curriculum (RESCUR) program was developed to foster the psychosocial development of children in early and primary education. RESCUR seeks specifically to decrease children's vulnerability. It aims to promote the emotional and social learning of children who may be at risk of leaving school pre-maturely, social exclusion and mental-health problems. The program is taught using a teachers' manual to support consistency of delivery, a parents' guide, and a resource package. This study aimed to examine the scaling-out of RESCUR to social services, and specifically to test if implementation differs between the school and social services sectors. Methods: RESCUR was implemented in schools and social services in Sweden 2017-2019. Data were collected via group leaders' self-reports and observation protocols for 3 months after implementation started. There were 34 self-reports from schools, and 12 from the social services sector; 30 observation protocols were collected from schools, and 10 from social services. We examined whether there were differences in implementation outcomes (in, for example, dosage, duration, fidelity, adaptation, quality of delivery) between the two delivery systems. Descriptive statistics were prepared and non-parametric tests of significance conducted to compare implementation-related factors across the two settings. Results: Analyses of both the observation protocols and group leaders' self-reports revealed that RESCUR was well-implemented in both schools and social services. The results showed a few significant differences in the outcomes of implementation between the sectors. First, regarding observations, school staff more often adapted the pace of RESCUR lessons to ensure that the children could understand than did social services staff (p < 0.01). Second, social services staff demonstrated greater interest in students and sensitivity to the needs of individual students than did school staff (p = 0.02). Regarding self-reports, social services staff reported having delivered more (p = 0.4) and longer (p < 0.01) lessons than did school staff. Second, school staff reported greater fidelity to (p = 0.02) and less adaptation of (p < 0.01) the intervention than did social services staff. Both observations and self-reports, however, indicated a high fidelity of implementation. Conclusions: Overall, the findings suggest that the resilience program, designed for delivery in schools, can be scaled-out to social services with its implementation outcomes retained. Further research is needed to test the effectiveness of the program regarding child health-related outcomes. Clinical Trial Registration: National Institute of Health, ClinicalTrials.gov, identifier: NCT03655418. Registered August 31, 2018.


Antigen receptor engagement delivers a stop signal to migrating T lymphocytes.
We investigated the role of the T cell antigen receptor (TcR) in control of T cell migration in an in vitro system. We used T cells from transgenic mice bearing a TcR for the lysozyme peptide 48-62 bound to I-A(k) (3A9). T cells from the 3A9 TcR transgenic mice crawled on purified intercellular adhesion molecule-1 substrates, but strikingly, stopped upon interaction with the physiological ligand, i.e., the mouse I-A(k) with covalently attached hen egg white lysozyme peptide residues 48-62 complex. TcR-triggered stopping was reversible by treatment with adhesion-strengthening phorbol esters. The microtubule organizing center of stopped cells was positioned adjacent to the site of stable cell anchorage. Direct conversion of lymphocyte function associated-1 to the high-affinity conformation with antibodies also stopped T cells in a similar manner to antigen. Thus, physiological TcR engagement triggers a stop signal through lymphocyte function associated-1. We propose that the stop signal is an early and essential event in T cell activation that also will play an important role in control of T cell migration.


Drosophila Myc.
Myc genes play a major role in human cancer, and they are important regulators of growth and proliferation during normal development. Despite intense study over the last three decades, many aspects of Myc function remain poorly understood. The identification of a single Myc homolog in the model organism Drosophila melanogaster more than 10 years ago has opened new possibilities for addressing these issues. This review summarizes what the last decade has taught us about Myc biology in the fruit fly.


Investments in social capital--implications of social interactions for the production of health.
This paper develops a theoretical model of the family as producer of health- and social capital. There are both direct and indirect returns on the production and accumulation of health- and social capital. Direct returns (the consumption motives) result since health and social capital both enhance individual welfare per se. Indirect returns (the investment motives) result since health capital increases the amount of productive time, and social capital improves the efficiency of the production technology used for producing health capital. The main prediction of the theoretical model is that the amount of social capital is positively related to the level of health; individuals with high levels of social capital are healthier than individuals with lower levels of social capital, ceteris paribus. An empirical model is estimated, using a set of individual panel data from three different time periods in Sweden. We find that social capital is positively related to the level of health capital, which supports the theoretical model. Further, we find that the level of social capital (1) declines with age, (2) is lower for those married or cohabiting, and (3) is lower for men than for women.


Design of functional electrospun nanofibers for cancer cell capture applications.
Electrospun nanofibers possess an extremely large surface area to volume ratio, good biocompatibility, ability to mimic native extracellular matrix, and the advantages of easy preparation and surface functionalization. These properties enable them to be used as an ideal platform for cancer cell capture applications. This review reports some recent advances in the use of nanofibers for cancer cell capture applications, in particular, preparation and surface functionalization of nanofibers with targeting molecules, static capture of cancer cells using nanofibrous substrates, dynamic capture of cancer cells and circulating tumor cells using fiber-integrated microfluidic platforms, and strategies used to release the captured cancer cells. Some of the key developments are introduced and summarized in detail; future perspectives are also briefly discussed.


Streptococcus bovis infection of total hip arthroplasty in association with carcinoma of colon.
Streptococcus bovis is normally found in the gastrointestinal tract of the human population. The association between Streptococcus bovis and bowel neoplasia has been frequently reported. This report presents two cases of total hip arthroplasty with Streptococcus Bovis infection at 18 and 11 years after arthroplasty. The diagnosis was made with the help of clinical findings, standard radiographs, and laboratory tests (complete blood count, C-reactive protein, sedimentation rate, and the hip aspiration). Infections were treated by implant removal and antibiotic spacer implantation. Intravenous antibiotics were administered for 12 weeks. Revision arthroplasty was performed when laboratory tests (complete blood count, C-reactive protein, sedimentation rate) were within normal limits. Streptococcus bovis infection prompted the authors to investigate for any bowel malignancy. Colonoscopy and transrectal biopsy revealed adenocarcinoma in case 1, while case 2 had prior diagnosis of flat polyps in the colon. There are a limited number of reports in the literature reporting the presence of Streptococcus bovis infection concurrent with arthroplasty and bowel malignancy. These two case reports highlight the possibility of hematogenous seeding of arthroplasty components by Streptococcus bovis in patients with colonic neoplasia. Streptococcus bovis infection of hip arthroplasty may provide an opportunity for diagnosis of colonic neoplasia. Acute hip pain in patients with hip endoprostheses and simultaneous bowel malignancy should be evaluated promptly for hematogenous infection by standard radiograph, complete blood count, C-reactive protein, sedimentation rate, and hip aspiration.