Essential roles for calcium and calmodulin in G2/M progression in Aspergillus nidulans.
nimT encodes a protein in Aspergillus nidulans that is required for tyrosine dephosphorylation of p34cdc2 and has a strong homology to cdc25-type proteins. Conditional mutation of nimT (nimT23 mutation) arrests cells in G2 at the restrictive temperature. After release of the temperature-sensitive nimT23 block, p34cdc2 undergoes tyrosine dephosphorylation and we showed that as cells entered mitosis, a rapid increase in calmodulin was observed. The increase in calmodulin and progression into mitosis were prevented by reducing extracellular Ca2+ levels to 2 nM. The calmodulin gene of a nimT23-containing strain was replaced with a hybrid gene in which calmodulin transcription was regulated by the alcA promoter (AlcCaM/T23). This allowed experimental manipulation of the level of intracellular calmodulin by the carbon source in the medium. When either extracellular Ca2+ or intracellular calmodulin levels were reduced at the nimT23 G2 arrest point, p34cdc2 remained tyrosine phosphorylated but the mitotic NIMA kinase encoded by nimA was not activated. Release of the temperature sensitive nimT23 arrest when either extracellular Ca2+ or calmodulin concentrations were low blocked tyrosine dephosphorylation of p34cdc2, activation of NIMA and progression of cells into mitosis. However, reduced levels of either Ca2+ or calmodulin had no effect on the increase in histone H1 kinase activity associated with p13 beads or the degree of phosphorylation of the majority of MPM-2-reacting proteins following release of the nimT23 mutation. These results demonstrate that both Ca2+ and calmodulin are important for progression into mitosis from the nimT23 arrest point in a pathway involving activation of both NIMA and p34cdc2 protein kinases.


Antimicrobial and antiviral activities of polyphenolics from Cocos nucifera Linn. (Palmae) husk fiber extract.
The decoction of Cocos nucifera L. husk fiber has been used in northeastern Brazil traditional medicine for treatment of diarrhea and arthritis. Water extract obtained from coconut husk fiber and fractions from adsorption chromatography revealed antimicrobial activity against Staphylococcus aureus. The crude extract and one of the fractions rich in catechin also showed inhibitory activity against acyclovir-resistant herpes simplex virus type 1 (HSV-1-ACVr). All fractions were inactive against the fungi Candida albicans, Fonsecaea pedrosoi and Cryptococcus neoformans. Catechin and epicatechin together with condensed tannins (B-type procyanidins) were demonstrated to be the components of the water extract.


The PBDE metabolite 6-OH-BDE 47 affects melanin pigmentation and THRβ MRNA expression in the eye of zebrafish embryos.
Polybrominated diphenyl ethers and their hydroxyl-metabolites (OH-BDEs) are commonly detected contaminants in human serum in the US population. They are also considered to be endocrine disruptors, and are specifically known to affect thyroid hormone regulation. In this study, we investigated and compared the effects of a PBDE and its OH-BDE metabolite on developmental pathways regulated by thyroid hormones using zebrafish as a model. Exposure to 6-OHBDE 47 (10-100 nM), but not BDE 47 (1-50 μM), led to decreased melanin pigmentation and increased apoptosis in the retina of zebrafish embryos in a concentration-dependent manner in short-term exposures (4 - 30 hours). Six-OH-BDE 47 exposure also significantly decreased thyroid hormone receptor β (THRβ) mRNA expression, which was confirmed using both RT-PCR and in situ hybridization (whole mount and paraffin- section). Interestingly, exposure to the native thyroid hormone, triiodothyronine (T3) also led to similar responses: decreased THRβ mRNA expression, decreased melanin pigmentation and increased apoptosis, suggesting that 6-OH-BDE 47 may be acting as a T3 mimic. To further investigate short-term effects that may be regulated by THRβ, experiments using a morpholino gene knock down and THRβ mRNA over expression were conducted. Knock down of THRβ led to decreases in melanin pigmentation and increases in apoptotic cells in the eye of zebrafish embryos, similar to exposure to T3 and 6-OH-BDE 47, but THRβ mRNA overexpression rescued these effects. Histological analysis of eyes at 22 hpf from each group revealed that exposure to T3 or to 6-OH-BDE 47 was associated with a decrease of melanin and diminished proliferation of cells in layers of retina near the choroid. This study suggests that 6-OH-BDE 47 disrupts the activity of THRβ in early life stages of zebrafish, and warrants further studies on effects in developing humans.


Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice.
Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.


Integral rein control in physiology.
We propose that blood glucose is regulated by a principle which we call integral rein control, in which under most conditions both glucagon and insulin are produced and control is achieved by altering the balance between the two. Like other integral control systems, the mechanism achieves zero steady-state error, which explains how the blood glucose level can remain very nearly constant over a wide range of input and demand. In addition, the use of two hormones makes the system stable against relatively large perturbations in either direction. An important feature of the model is that the set point is not fixed by an external reference but arises out of the dynamics, in particular out of the relation between the rates of production of the two hormones. The model therefore predicts that the consequence of an inability to produce insulin will be not just that the control will be less effective but that the set point will be shifted. This allows us to explain why patients with untreated Type I diabetes mellitus have high blood glucose levels even under conditions of low glucose input, and why it is difficult to maintain the normal level of 5 mmol/1 in patients who are being treated with insulin. It also explains why Type II diabetes is easier to treat.


Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry.
Multiple major health organisations recommend the use of extracorporeal membrane oxygenation (ECMO) support for COVID-19-related acute hypoxaemic respiratory failure. However, initial reports of ECMO use in patients with COVID-19 described very high mortality and there have been no large, international cohort studies of ECMO for COVID-19 reported to date. We used data from the Extracorporeal Life Support Organization (ELSO) Registry to characterise the epidemiology, hospital course, and outcomes of patients aged 16 years or older with confirmed COVID-19 who had ECMO support initiated between Jan 16 and May 1, 2020, at 213 hospitals in 36 countries. The primary outcome was in-hospital death in a time-to-event analysis assessed at 90 days after ECMO initiation. We applied a multivariable Cox model to examine whether patient and hospital factors were associated with in-hospital mortality. Data for 1035 patients with COVID-19 who received ECMO support were included in this study. Of these, 67 (6%) remained hospitalised, 311 (30%) were discharged home or to an acute rehabilitation centre, 101 (10%) were discharged to a long-term acute care centre or unspecified location, 176 (17%) were discharged to another hospital, and 380 (37%) died. The estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 37·4% (95% CI 34·4-40·4). Mortality was 39% (380 of 968) in patients with a final disposition of death or hospital discharge. The use of ECMO for circulatory support was independently associated with higher in-hospital mortality (hazard ratio 1·89, 95% CI 1·20-2·97). In the subset of patients with COVID-19 receiving respiratory (venovenous) ECMO and characterised as having acute respiratory distress syndrome, the estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 38·0% (95% CI 34·6-41·5). In patients with COVID-19 who received ECMO, both estimated mortality 90 days after ECMO and mortality in those with a final disposition of death or discharge were less than 40%. These data from 213 hospitals worldwide provide a generalisable estimate of ECMO mortality in the setting of COVID-19. None.


Central nervous system pressor responses in rats susceptible and resistant to sodium chloride hypertension.
1. The pressor responses to hypertonic saline and angiotensin II introduced into the left lateral ventricle were both significantly greater in salt-sensitive (S) rats compared with salt-resistant (R) rats, with all rats on a low Na diet. 2. When S rats were given thiazide to nullify the pressor effect of dietary NaCl, their blood pressure averaged only 5 mmHg higher than that of the R rats; nevertheless, these S rats had significantly higher central nervous system pressor responses to angiotensin II and hypertonic saline. 3. Thus, if excessive dietary Na increases blood pressure by way of action on the central nervous system, these heightened pressor responses could partially account for the NaCl hypertension in S rats. Alternatively, depressed central nervous system pressor responses in R rats could partially explain the resistance of R rats to NaCl hypertension.


Performance of Zika Assays in the Context of Toxoplasma gondii, Parvovirus B19, Rubella Virus, and Cytomegalovirus (TORCH) Diagnostic Assays.
Infections during pregnancy that may cause congenital abnormalities have been recognized for decades, but their diagnosis is challenging. This was again illustrated with the emergence of Zika virus (ZIKV), highlighting the inherent difficulties in estimating the extent of pre- and postnatal ZIKV complications because of the difficulties in establishing definitive diagnoses. We reviewed the epidemiology, infection kinetics, and diagnostic methods used for Toxoplasma gondii, parvovirus B19, rubella virus, and cytomegalovirus (TORCH) infections and compared the results with current knowledge of ZIKV diagnostic assays to provide a basis for the inclusion of ZIKV in the TORCH complex evaluations. Similarities between TORCH pathogens and ZIKV support inclusion of ZIKV as an emerging TORCH infection. Our review evaluates the diagnostic performance of various TORCH diagnostic assays for maternal screening, fetal screening, and neonatal screening. We show that the sensitivity, specificity, and positive and negative predictive value of TORCH complex pathogens are widely variable, stressing the importance of confirmatory testing and the need for novel techniques for earlier and accurate diagnosis of maternal and congenital infections. In this context it is also important to acknowledge different needs and access to care for different geographic and resource settings.


The impact of emotional intelligence in health care professionals on caring behaviour towards patients in clinical and long-term care settings: Findings from an integrative review.
Over recent years there has been criticism within the United Kingdom's health service regarding a lack of care and compassion, resulting in adverse outcomes for patients. The impact of emotional intelligence in staff on patient health care outcomes has been recently highlighted. Many recruiters now assess emotional intelligence as part of their selection process for health care staff. However, it has been argued that the importance of emotional intelligence in health care has been overestimated. To explore relationships between emotional intelligence in health care professionals, and caring behaviour. To further explore any additional factors related to emotional intelligence that may impact upon caring behaviour. An integrative review design was used. Psychinfo, Medline, CINAHL Plus, Social Sciences Citation Index, Science Citation Index, and Scopus were searched for studies from 1995 to April 2017. Studies providing quantitative or qualitative exploration of how any healthcare professionals' emotional intelligence is linked to caring in healthcare settings were selected. Twenty two studies fulfilled the inclusion criteria. Three main types of health care professional were identified: nurses, nurse leaders, and physicians. Results indicated that the emotional intelligence of nurses was related to both physical and emotional caring, but emotional intelligence may be less relevant for nurse leaders and physicians. Age, experience, burnout, and job satisfaction may also be relevant factors for both caring and emotional intelligence. This review provides evidence that developing emotional intelligence in nurses may positively impact upon certain caring behaviours, and that there may be differences within groups that warrant further investigation. Understanding more about which aspects of emotional intelligence are most relevant for intervention is important, and directions for further large scale research have been identified.


Evaluation of methods and timing in nail dynamisation for treating delayed healing femoral shaft fractures.
Dynamisation is a simple method for treating femoral shaft fractures (FSFs) in patients with delayed healing after intramedullary nailing. However, only around half of patients with a slow-healing FSF have been successfully treated with this strategy. Although it is thought that dynamisation with a screw preserved in the dynamic locking hole improves treatment outcome in these patients, to date, no studies have demonstrated empirical evidence supporting this technique. In this study, we investigated the effects of dynamisation with and without rotation and length control as well as timing of dynamisation on treatment outcomes in FSF patients with delayed healing. Thirty-nine consecutive acute FSF patients with static locking intramedullary nails who subsequently underwent dynamisation were recruited between January 2000 and June 2011. The indication for dynamisation was the presence of gap caused by bone absorption or over-traction at the fracture site when the locking screws were placed. Age, gender, dynamisation method, fracture classification, duration from nail insertion to dynamisation (i.e., timing of dynamisation) and dynamisation outcome were included in the statistical analysis. Patients whose nail was dynamised with a screw preserved in the dynamic locking hole had a significantly higher successful bone union rate (14/15 vs. 14/24, p=0.028) compared with those with all screws removed from one end of the nail. The patients treated in 10-24 weeks had a significantly increased chance of bone union than those treated after 24 weeks (p=0.027). A significantly higher bone union rate (p=0.036) was observed in 10-24 weeks (83.3%) than after 24 weeks (33.3%) in the group of dynamisation with all screws removed from one end of the nail. No statistical difference in bone union success rate was found between patients at 10-24 weeks and after 24 weeks in the group of dynamisation with a screw preserved in the dynamic locking hole. There were no significant differences in outcome based on other variables. (1) Dynamisation with a screw preserved in the dynamic locking hole was associated with a higher success rate in bone union than all screws removed from one end of the nail for patients with delayed healing FSFs. (2) Early dynamisation (10-24 weeks) had a better outcome than late dynamisation (>24 weeks). Late dynamisation with all screws removed from one end of the nails resulted in a poor success rate. Alternative treatment should be considered if the latter approach is to be adopted.


Low fractional excretion of urine sodium in acute renal failure due to sepsis.
A low fractional excretion of sodium (FENa) of less than 1% was present in two patients who had acute renal failure due to sepsis. Both patients had bacteremia and had undergone major abdominal and vascular surgery. Prerenal azotemia due to volume depletion was not present as adequate central filling pressures were maintained with a Swan-Ganz catheter. Interstitial nephritis and obstructive uropathy were carefully ruled out. Acute renal failure due to sepsis should be included among the other conditions recently reported with a low FENa. This is of great importance as errors in fluid management are possible in this high-risk patient population when much reliance is placed on the interpretation of a low FENa of less than 1%.


Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine.
A 32-year-old male developed neuropsychiatric symptoms 2 weeks after starting mefloquine 250 mg/week for malaria prophylaxis. He continued to take the medication for the next 4 months. Initial symptoms included vivid dreams and anxiety, as well as balance problems. These symptoms persisted and progressed over the next 4 years to include vertigo, emotional lability, and poor short-term memory, which have greatly affected his personal and professional life. An extensive evaluation revealed objective evidence supporting a central vestibulopathy. These symptoms have been unresponsive to pharmacologic therapy and psychotherapy. A Naranjo assessment score of 6 was obtained for his initial symptoms, indicating a probable adverse drug reaction to mefloquine given the relationship between the clinical picture and drug exposure.


Physiological and transcriptional approaches reveal connection between nitrogen and manganese cycles in Shewanella algae C6G3.
To explain anaerobic nitrite/nitrate production at the expense of ammonium mediated by manganese oxide (Mn(IV)) in sediment, nitrate and manganese respirations were investigated in a strain (Shewanella algae C6G3) presenting these features. In contrast to S. oneidensis MR-1, a biotic transitory nitrite accumulation at the expense of ammonium was observed in S. algae during anaerobic growth with Mn(IV) under condition of limiting electron acceptor, concomitantly, with a higher electron donor stoichiometry than expected. This low and reproducible transitory accumulation is the result of production and consumption since the strain is able to dissimilative reduce nitrate into ammonium. Nitrite production in Mn(IV) condition is strengthened by comparative expression of the nitrate/nitrite reductase genes (napA, nrfA, nrfA-2), and rates of the nitrate/nitrite reductase activities under Mn(IV), nitrate or fumarate conditions. Compared with S. oneidensis MR-1, S. algae contains additional genes that encode nitrate and nitrite reductases (napA-α and nrfA-2) and an Outer Membrane Cytochrome (OMC)(mtrH). Different patterns of expression of the OMC genes (omcA, mtrF, mtrH and mtrC) were observed depending on the electron acceptor and growth phase. Only gene mtrF-2 (SO1659 homolog) was specifically expressed under the Mn(IV) condition. Nitrate and Mn(IV) respirations seem connected at the physiological and transcriptional levels.


Effects of domestic violence policies, alcohol taxes and police staffing levels on intimate partner homicide in large US cities.
To assess the relationships between intimate partner homicide (IPH) and public policies including police staffing levels in large US cities. The research uses a multiple time-series design to examine the effects of statutes aimed at restricting access to firearms for perpetrators of domestic violence, allowing or mandating arrest for violators of domestic violence restraining orders (DVROs), beer excise taxes, and police staffing levels on IPH in 46 of the largest US cities from 1979 to 2003. Both total IPH and IPH committed with a firearm are analysed. Generalised estimating equations using a Poisson distribution are used to regress IPH on the policies and potential confounders. State statutes restricting those under DVROs from accessing firearms, and laws allowing the warrantless arrest of DVRO violators are associated with reductions in total and firearm IPH. Police staffing levels are also negatively associated with IPH and firearm IPH. There was no evidence that other policies to restrict firearm access to domestic violence offenders or alcohol taxes had a significant impact on IPH. Reducing access to firearms for DVRO defendants, increasing police staffing levels and allowing the warrantless arrest of DVRO violators may reduce the city-level risk of IPH. Future research should evaluate factors that may mediate the effect of these laws and increased police staffing levels on IPH to determine whether there are opportunities to increase their protective effect. Further research is needed on firearm law implementation to determine why the other tested laws were not found effective.


Gene therapy takes a cue from HAART: combinatorial antiviral therapeutics reach the clinic.
For the first time, scientists have tested a combination of three RNA-based gene therapies, delivered via a lentiviral vector, to target HIV in patients. This study not only demonstrates the safety and long-term viability of this approach, but also highlights areas in which focused improvements in gene therapy strategies may provide the most impact in increasingly translating promise in the laboratory to efficacy in the clinic.


Concerns about measuring "spirituality" in research.
Spirituality is increasingly being examined as a construct related to mental and physical health. The definition of spirituality, however, has been changing. Traditionally, spirituality was used to describe the deeply religious person, but it has now expanded to include the superficially religious person, the religious seeker, the seeker of well-being and happiness, and the completely secular person. Instruments used to measure spirituality reflect this trend. These measures are heavily contaminated with questions assessing positive character traits or mental health: optimism, forgiveness, gratitude, meaning and purpose in life, peacefulness, harmony, and general well-being. Spirituality, measured by indicators of good mental health, is found to be correlated with good mental health. This research has been reported in some of the world's top medical journals. Such associations are meaningless and tautological. Either spirituality should be defined and measured in traditional terms as a unique, uncontaminated construct, or it should be eliminated from use in academic research.


Thermal oxidative and ozone oxidative stabilization effect of hybridized functional graphene oxide in a silica-filled solution styrene butadiene elastomer.
Hybridization of modified functional graphene oxide (fGO) in silica-filled solution styrene butadiene rubber (SSBR) endows preferable tensile and dynamic properties before and after thermal oxidative aging, and similar mechanical hysteresis performance compared with the composites without fGO. The preventing mechanism of fGO is attributed to its intrinsic peroxy radical scavenging and gas barrier abilities, which significantly reduces the peroxy radical concentration and oxygen permeability of nanocomposites and then prolongs oxidative induction time (OIT), characterized by differential scanning calorimetry (DSC). The ozone resisting effect of different loadings of fGO on nanocomposites have also been investigated by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) after ozonization under 50 ppm ozone concentration. As a result, incorporation of fGO apparently suppresses both the formation of oxygenic groups of the olefinic elastomer and crack morphology extension upon ozonization. We propose that fGO protects the SSBR elastomer from ozone attack through the conjugated delocalized π-bonds of the fGO instead of the C[double bond, length as m-dash]C bonds of the elastomer matrix being attacked, and the compared experiments, characterized by X-ray photoelectron spectroscopy (XPS), confirm that this presumption is perhaps reasonable. Moreover, more than 3 phr incorporation of fGO in nanocomposites deteriorates the chemical and mechanical properties of the elastomer during the thermal oxidation and ozonization because of the cleavage influence of oxygenic groups on peroxy radicals.


The emerging role for rituximab in the treatment of nodular lymphocyte predominant Hodgkin lymphoma.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma that is distinct from classical Hodgkin lymphoma (cHL). The unique malignant 'popcorn' cells express the B-cell antigen CD20 and lack expression of the cHL markers CD15 and CD30. Traditionally, NLPHL has been included with cHL in clinical trials with excellent prognosis reported in several series. The reliable expression of CD20 has led to the evaluation of the chimeric monoclonal anti-CD20 antibody rituximab in several recent trials. Three series have reported the efficacy of 4 weekly doses of rituximab in all stages of NLPHL, both in the treatment-naive and relapsed settings. Emerging data also suggest that longer courses of antibody therapy may improve the duration of response. Rituximab appears to offer a nonchemotherapy-based effective treatment option, which is well tolerated. Ongoing studies are required to further define the optimal patient population who may benefit from rituximab and evaluate its role in maintenance as well as in combination with radiotherapy and chemotherapy.


Glypicans shield the Wnt lipid moiety to enable signalling at a distance.
A relatively small number of proteins have been suggested to act as morphogens-signalling molecules that spread within tissues to organize tissue repair and the specification of cell fate during development. Among them are Wnt proteins, which carry a palmitoleate moiety that is essential for signalling activity1-3. How a hydrophobic lipoprotein can spread in the aqueous extracellular space is unknown. Several mechanisms, such as those involving lipoprotein particles, exosomes or a specific chaperone, have been proposed to overcome this so-called Wnt solubility problem4-6. Here we provide evidence against these models and show that the Wnt lipid is shielded by the core domain of a subclass of glypicans defined by the Dally-like protein (Dlp). Structural analysis shows that, in the presence of palmitoleoylated peptides, these glypicans change conformation to create a hydrophobic space. Thus, glypicans of the Dlp family protect the lipid of Wnt proteins from the aqueous environment and serve as a reservoir from which Wnt proteins can be handed over to signalling receptors.


Role of CO2 in the formation of gold deposits.
Much of global gold production has come from deposits with uneconomic concentrations of base metals, such as copper, lead and zinc. These 'gold-only' deposits are thought to have formed from hot, aqueous fluids rich in carbon dioxide, but only minor significance has been attached to the role of the CO2 in the process of gold transport. This is because chemical bonding between gold ions and CO2 species is not strong, and so it is unlikely that CO2 has a direct role in gold transport. An alternative indirect role for CO2 as a weak acid that buffers pH has also appeared unlikely, because previously inferred pH values for such gold-bearing fluids are variable. Here we show that such calculated pH values are unlikely to record conditions of gold transport, and propose that CO2 may play a critical role during gold transport by buffering the fluid in a pH range where elevated gold concentration can be maintained by complexation with reduced sulphur. Our conclusions, which are supported by geochemical modelling, may provide a platform for new gold exploration methods.


Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.
To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung carcinoma (NSCLC), we conducted a consistency meta-analysis study using genome-wide association approaches for overall survival in 327 never smoker patients with NSCLC from The University of Texas MD Anderson Cancer Center (Houston, TX) and 293 cases from the Mayo Clinic (Rochester, MN). We then conducted a two-pronged validation of the top 25 variants that included additional validation in 1,256 patients with NSCLC from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a P value of 10(-6). Two variants of these 25 were also significant in the Taiwanese population: rs6901416 [HR, 1.44; 95% confidence interval (CI), 1.01-2.06] and rs10766739 (HR, 1.23; 95%CI, 1.00-1.51). These loci resulted in a reduction of median survival time of at least eight and five months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung tissue. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biologic mechanism for a subset of these observed associations.


Combined bacterial and fungal targeted amplicon sequencing of respiratory samples: Does the DNA extraction method matter?
High-throughput sequencing techniques are used to analyse the diversity of the respiratory microbiota in health and disease. Although extensive data are available regarding bacterial respiratory microbiota, its fungal component remains poorly studied. This is partly due to the technical issues associated with fungal metagenomics analyses. In this study, we compared two DNA extraction protocols and two fungal amplification targets for combined bacterial and fungal targeted amplicon sequencing analyses of the respiratory microbiota. Six sputa, randomly selected from routine samples in Mondor Hospital (Creteil, France) and treated anonymously, were tested after bacterial and fungal routine culture. Two of which were spiked with Aspergillus Fumigati and Aspergillus Nigri (105 conidia/mL). After mechanical lysis, DNA was extracted using automated QIAsymphony® extraction (AQE) or manual PowerSoil® MoBio extraction (MPE). DNA yield and purity were compared. DNA extracted from spiked sputa was subjected to (i) real-time PCR for Aspergillus DNA detection and (ii) combined metagenomic analyses targeting barcoded primers for fungal ITS1 and ITS2, and bacterial V1-V2 and V3-V4 16S regions. Amplicon libraries were prepared using MiSeq Reagent V3 kit on Illumina platform. Data were analysed using PyroMIC© and SHAMAN software, and compared with culture results. AQE extraction provided a higher yield of DNA (AQE/MPE DNA ratio = 4.5 [1.3-11]) in a shorter time. The yield of Aspergillus DNA detected by qPCR was similar for spiked sputa regardless of extraction protocol. The extraction moderately impacted the diversity or relative abundances of bacterial communities using targeted amplicon sequencing (2/43 taxa impacted). For fungi, the relative abundances of 4/11 major taxa were impacted and AQE results were closer to culture results. The V1-V2 or V3-V4 and ITS1 or ITS2 targets assessed similarly the diversity of bacterial and fungal major taxa, but ITS2 and V3-V4 detected more minor taxa. Our results showed the importance of DNA extraction for combined bacterial and fungal targeted metagenomics of respiratory samples. The extraction protocol can affect DNA yield and the relative abundances of few bacterial but more fungal taxa. For fungal analysis, ITS2 allowed the detection of a greater number of minor taxa compared with ITS1.


Acute brucellosis treated with trimethoprim and sulphamethoxazole.
Four patients with acute brucellosis are described, none of whom had any connexion with farming or milk industry, the source of infection being different in each case. The diagnosis was made by serological tests, and in three of the four cases was confirmed by positive cultures from bone marrow (one case) and liver biopsy (two cases). Treatment with the combination of trimethoprim/sulphamethoxazole was successful in three out of four cases, and in the fourth case failure may have been due to the development of trimethoprim resistance.


Massive open online courses on health and medicine: review.
Massive open online courses (MOOCs) have become immensely popular in a short span of time. However, there is very little research exploring MOOCs in the discipline of health and medicine. We aim to provide a review of MOOCs related to health and medicine offered by various MOOC platforms in 2013, by analyzing and comparing the various offerings, their target audience, typical length of course, and credentials offered. We also discuss opportunities and challenges presented by MOOCs in health and medicine. Health and medicine-related MOOCs were gathered using several methods to ensure the richness and completeness of data. Identified MOOC platform websites were used to gather the lists of offerings. In parallel, these MOOC platforms were contacted to access official data on their offerings. Two MOOC aggregator sites (Class Central and MOOC List) were also consulted to gather data on MOOC offerings. Eligibility criteria were defined to concentrate on the courses that were offered in 2013 and primarily on the subject of health and medicine. All language translations in this paper were done using Google Translate. The search identified 225 courses, of which 98 were eligible for the review. Over half (58%, 57/98) of the MOOCs considered were offered on the Coursera platform, and 94% (92/98) of all the MOOCs were offered in English. Universities offered 90 MOOCs, and the John Hopkins University offered the largest number of MOOCs (12/90). Only three MOOCs were offered by developing countries (China, West Indies, and Saudi Arabia). The duration of MOOCs varied from 3-20 weeks with an average length of 6.7 weeks. On average, MOOCs expected a participant to work on the material for 4.2 hours a week. Verified certificates were offered by 14 MOOCs, while three others offered other professional recognition. The review presents evidence to suggest that MOOCs can be used as a way to provide continuous medical education. It also shows the potential of MOOCs as a means of increasing health literacy among the public.


Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis.
Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.


Burn trauma in skeletal muscle results in oxidative stress as assessed by in vivo electron paramagnetic resonance.
Using a mouse model, we tested the hypotheses that severe burn trauma causes metabolic disturbances in skeletal muscle, and that these can be measured and repeatedly followed by in vivo electron paramagnetic resonance (EPR). We used a 1.2-GHz (L-band) EPR spectrometer to measure partial pressure of oxygen (pO(2)) levels, redox status and oxidative stress following a non-lethal burn trauma model to the left hind limbs of mice. Results obtained in the burned mouse gastrocnemius muscle indicated a significant decrease in tissue pO(2) immediately (P=0.032) and at 6 h post burn (P=0.004), compared to the gastrocnemius of the unburned hind limb. The redox status of the skeletal muscle also peaked at 6 h post burn (P=0.027) in burned mice. In addition, there was an increase in the EPR signal of the nitroxide produced by oxidation of the hydroxylamine (CP-H) probe at 12 h post burn injury, indicating a burn-induced increase in mitochondrial reactive oxygen species (ROS). The nitroxide signal continued to increase between 12 and 24 h, suggesting a further increase in ROS generation post burn. These results confirm genomic results, which indicate a downregulation of antioxidant genes and therefore strongly suggest the dysfunction of the mitochondrial oxidative system. We believe that the direct measurement of tissue parameters such as pO(2), redox and ROS by EPR may be used to complement measurements by nuclear magnetic resonance (NMR) in order to assess tissue damage and the therapeutic effectiveness of antioxidant agents in severe burn trauma.


Multiple cholecystokinin (CCK) receptors and CCK-monoamine interactions are instrumental in the control of feeding.
Almost two decades ago, exogenous cholecystokinin (CCK) was shown to suppress food consumption in rats. Since then, CCK has been detected not only in peripheral tissue but extensively throughout the central nervous system. Furthermore, specific CCK receptors have been described, and a distinction drawn between CCK-A and CCK-B receptors. Recently, potent, orally active CCK antagonists, which show a high degree of selectivity for either CCK-A or CCK-B receptors, have been introduced. The present report reviews recent evidence obtained in studies using devazepide (a selective CCK-A receptor antagonist) and L-365,260 (a selective CCK-B/gastrin receptor antagonist). Both compounds increased food consumption and postponed the onset of satiety in well-satiated rats. L-365,260 was more potent, suggesting that central CCK-B type receptors may mediate the satiety effects of endogenously released CCK. Only devazepide was effective in blocking the feeding-suppressant effect of exogenous CCK, indicating that CCK-A type receptors mediate this effect. In a second series of studies, devazepide but not L-365,260 antagonized the anorectic effect of either d-fenfluramine or systemically administered 5-HT. Hence, CCK-A type receptors appear to be involved in the anorectic effects of these serotonergic drugs. We propose that CCK and 5-HT mechanisms involved in mediating satiety are mutually interdependent. Possible interactions between CCK and catecholaminergic mechanisms are also briefly considered.


Child delinquency and intelligence testing at Santiago's Juvenile Court, Chile, 1929-1942.
This article deals with intelligence testing conducted at Santiago's Juvenile Court, in Chile, between 1929 and 1942. It is based on an analysis of 56 court records containing psychological or psychopedagogical reports filed by the Section for Observation and Classification at Santiago's House of Juveniles, an institution created in 1929 as part of the Juvenile Protection Law. To understand the purposes for juvenile intelligence testing in this field, several articles published at the time by the key actors involved in these institutions will also be analyzed. The results of this research signal, first, that psychology did indeed play a role in the juvenile justice system by laying the groundwork for the idea that it was necessary to measure and diagnose intelligence. The Binet-Simon Intelligence Scale, developed in France between 1904 and 1911 and adapted for Chile between 1922 and 1925, was systematically administered to juveniles in Santiago's Juvenile Court; the results were deployed as technical-scientific recommendations at the service of the presiding juvenile judge. On the one hand, this instrument, supposedly scientific and objective, helped legitimize the nascent field of psychology. On the other, it emerged as a useful tool in its own right to assess children. Second, the notions of intelligence underpinning these practices, while certainly in debt to the American approaches from which they were appropriated, managed to forge a more balanced stance between nature and nurture, positioning intelligence testing as a way of conceiving of and planning to prevent crime and reeducate juveniles. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


From Environmental Sequences to Morphology: Observation and Characterisation of a Paulinellid Testate Amoeba (Micropyxidiella edaphonis gen. nov. sp. nov. Euglyphida, Paulinellidae) from Soil using Fluorescent in situ Hybridization.
High microbial diversity is revealed by environmental DNA surveys. However, nothing is known about the morphology and function of these potentially new organisms. In the course of an environmental soil diversity study, we found for the first time environmental sequences that reveal the presence of Paulinellidae (a mostly marine and marginally freshwater family of euglyphid testate amoebae) in samples of forest litter from different geographic origins. The new sequences form a basal, robust clade in the family. We used fluorescent in situ hybridization (FISH) to detect the organisms from which these sequences derived. We isolated the cells and documented them with light and scanning electron microscopy. Based on these observations, we described these organisms as Micropyxidiella edaphonis gen. nov. sp. nov. The organisms were very small testate amoebae (generally less than 10μm) with an irregular proteinaceous test. This suggests an unknown diversity in testate amoebae, and calls for extending this type of investigations to other protist groups which are known only as environmental DNA sequences.


Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors.
The activin type II receptorgene (ACTRII) is mutated in 58.1% of microsatellite-unstable (MSI-H) colorectal cancers and is a close relative of the TGFbeta-1 type II receptor, which is known to be involved in both MSI-H and non-MSI-H colorectal carcinogenesis. We therefore sought to determine whether ACTRII was involved in non-MSI-H colorectal cancers. We evaluated ACTRII inactivation by allelic deletion, loss of mRNA expression, or somatic mutation in 51 non-MSI-H colon cancers. Loss of heterozygosity (LOH) at the ACTRII locus (2q23.1) was found in 9 (17.6%) of 51 primary tumors. Loss of ACTRII mRNA expression was seen in one (14.3%) of the seven LOH-positive primary tumors from which total RNA was available. We also performed DNA sequencing analysis of tumors showing LOH. One LOH-positive primary tumor exhibited a novel germline missense sequence alteration (amino acid substitution, 117 Ile to Phe) that was not found in 23 additional normal individuals, implying that this alteration is not a frequent polymorphism. We conclude that ACTRII is probably involved in both non-MSI-H and MSI-H colorectal carcinogenesis, but more frequently in the latter subgroup.


The impact of diabetes on the short- to mid-term outcome of total ankle replacement.
We compared the clinical and radiographic results of total ankle replacement (TAR) performed in non-diabetic and diabetic patients. We identified 173 patients who underwent unilateral TAR between 2004 and 2011 with a minimum of two years' follow-up. There were 88 male (50.9%) and 85 female (49.1%) patients with a mean age of 66 years (sd 7.9, 43 to 84). There were 43 diabetic patients, including 25 with controlled diabetes and 18 with uncontrolled diabetes, and 130 non-diabetic patients. The clinical data which were analysed included the Ankle Osteoarthritis Scale (AOS) and the American Orthopaedic Foot and Ankle Society (AOFAS) scores, as well the incidence of peri-operative complications. The mean AOS and AOFAS scores were significantly better in the non-diabetic group (p = 0.018 and p = 0.038, respectively). In all, nine TARs (21%) in the diabetic group had clinical failure at a mean follow-up of five years (24 to 109), which was significantly higher than the rate of failure of 15 (11.6%) in the non-diabetic group (p = 0.004). The uncontrolled diabetic subgroup had a significantly poorer outcome than the non-diabetic group (p = 0.02), and a higher rate of delayed wound healing. The incidence of early-onset osteolysis was higher in the diabetic group than in the non-diabetic group (p = 0.02). These results suggest that diabetes mellitus, especially with poor glycaemic control, negatively affects the short- to mid-term outcome after TAR.


Disengaging the Smc3/kleisin interface releases cohesin from Drosophila chromosomes during interphase and mitosis.
Cohesin's Smc1, Smc3, and kleisin subunits create a tripartite ring within which sister DNAs are entrapped. Evidence suggests that DNA enters through a gate created by transient dissociation of the Smc1/3 interface. Release at the onset of anaphase is triggered by proteolytic cleavage of kleisin. Less well understood is the mechanism of release at other stages of the cell cycle, in particular during prophase when most cohesin dissociates from chromosome arms in a process dependent on the regulatory subunit Wapl. We show here that Wapl-dependent release from salivary gland polytene chromosomes during interphase and from neuroblast chromosome arms during prophase is blocked by translational fusion of Smc3's C-terminus to kleisin's N-terminus. Our findings imply that proteolysis-independent release of cohesin from chromatin is mediated by Wapl-dependent escape of DNAs through a gate created by transient dissociation of the Smc3/kleisin interface. Thus, cohesin's DNA entry and exit gates are distinct.


Metal-VO2 hybrid grating structure for a terahertz active switchable linear polarizer.
An active terahertz (THz) wave hybrid grating structure of Au/Ti metallic grating on VO2/Al2O3 (0001) was fabricated and evaluated. In our structure, it is shown that the metallic gratings on the VO2 layer strengthen the metallic characteristics to enhance the contrast of the metallic and dielectric phases of a VO2-based device. Especially, the metal grating-induced optical conductivity of the device is greatly enhanced, three times more than that of a metallic phase of bare VO2 films in the 0.1-2.0 THz spectral range. As an illustrative example, we fabricated an actively on/off switchable THz linear polarizer. The fabricated device has shown commercially comparable values in degree of polarization (DOP) and extinction ratio (ER). A high value of 0.89 in the modulation depth (MD) for the transmission field amplitude, superior to other THz wave modulators, is achieved. The experimental results show that the fabricated device can be highly useful in many applications, including active THz linear polarizers, THz wave modulators and variable THz attenuators.


Raising awareness of antimicrobial resistance in rural aquaculture practice in Bangladesh through digital communications: a pilot study.
One of the key strategic objectives of the World Health Organisation's global antimicrobial resistance (AMR) action plan is to improve public awareness and understanding of this issue. Very few AMR awareness campaigns have targeted the animal production sector, particularly in low- and middle-income countries (LMICs) where rural communities can be geographically difficult to access via traditional face-to-face community engagement methods. Aquaculture is a major food production industry in Bangladesh and across Asia, an area which poses a significant risk to global AMR dissemination. In this pilot study, we sought to investigate the potential for digital communication materials to rapidly and effectively communicate AMR messages to rural aquaculture farmers in Bangladesh. Working with stakeholders from the Bangladesh aquaculture industry, we developed a 4-minute digital animation designed specifically for this audience and assessed its capacity to engage and communicate AMR messages to farmers. We then conducted a small-scale social media campaign, to determine the potential for rapidly disseminating AMR awareness materials to a large audience across Bangladesh, where there is an extensive 4 G internet network and an ever-increasing proportion of the population (57% as of December 2019) have mobile internet access. Thirty-six farmers were surveyed: all of them liked this method of communication and 97% said it would change the way they use antibiotics in the future. Through the social media campaign, the animation received 9,100 views in the first 2 weeks alone. Although preliminary, these results demonstrate the huge potential for digital communication methods for the rapid and widespread communication of AMR awareness materials to rural aquaculture communities in Bangladesh and across Asia. Our results support the need for more research into the most appropriate and effective content of AMR awareness campaigns for aquaculture communities and question the need for explaining the science underlying AMR in such communication materials.


A nearly planar water sheet sandwiched between strontium-imidazolium carboxylate coordination polymers.
The crystal structure of a strontium-imidazolium polymeric material obtained from the reaction of zwitterionic 1,3-bis(carboxymethyl)imidazolium with SrCO(3) (2:1) in water is reported. The compound crystallized in the orthorhombic space group Pcc2 with a = 14.545(3) A, b = 8.514(5) A, c = 8.5619(14) A, V = 1060.2(6) A(3), and Z = 2. The macromolecular structure is constructed from 8-coordinate strontium, which binds to six different imidazolium carboxylate molecules. The two-dimensional polymer is separated by water sheets in which the water molecules form near-planar hexagons.


Microbiota around root-form endosseous implants: a review of the literature.
Although high success rates for root-form endosseous implants have been reported, failures occasionally occur, and these implants must be removed. At least 10% of the failures have been suggested to be the result of peri-implantitis. There is some evidence that periodontal pathogens, mainly those belonging to the group of gram-negative anaerobic rods, play a role in the etiology of peri-implantitis. This article provides an overview of the literature associated with common peri-implant microbiology and an assessment as to whether bacteria associated with periodontitis exert a possible risk for peri-implant tissue breakdown. The peri-implant area is colonized by a large variety of oral microbial complexes. The microflora of the oral cavity prior to implant placement determines the composition of the microflora in the peri-implant area. Implants involved in peri-implantitis are colonized with large amounts of gram-negative anaerobic bacteria, including Fusobacteria, spirochetes, Bacteroides forsythus, and "black-pigmented bacteria" such as Prevotella intermedia, Prevotella nigrescens, and Porphyromonas gingivalis. Also, Actinobacillus actinomycetemcomitans can be isolated from these lesions. Thus, the microflora of peri-implantitis lesions resembles that of adult or refractory periodontitis. However, the presence of periodontal pathogens does not always lead to a destructive process. Therefore, the etiologic role of specific microorganisms in implant failure related to infection is still not resolved. Controversy remains as to whether organisms recovered from the original microflora cause the failure (and if so to what extent) or merely result from the infection. Nevertheless, there is accumulating evidence that bacteria cause the disease, while the individual's genetic makeup and environmental influences determine the severity of the disease.


Role of sterics in phosphine-ligated gold clusters.
This study examined the solution-phase exchange reactions of triphenylphosphine (PPh3) ligands on Au8L72+ (L = PPh3) gold clusters with three different tolyl ligands using electrospray ionization mass spectrometry to provide insight into how steric differences in the phosphines influence the extent of ligand exchange and the stability of the resulting mixed-phosphine clusters. The size distributions of tolyl-exchanged gold clusters were found to depend on the position of the methyl group in the tri(tolyl)phosphine ligands (-ortho, -meta, and -para). Due to different sterics, the tri(m-tolyl)phosphine (TMTP) and tri(p-tolyl)phosphine (TPTP) ligands exchanged efficiently onto the Au8L72+ (L = PPh3) clusters while the tri(o-tolyl)phosphine ligands did not exchange. In addition, while TPTP fully exchanged with all seven PPh3 on the Au8L72+ cluster, TMTP exchanged with only six PPh3 ligands. Employing collision-induced dissociation, the tolyl-exchanged mixed-ligand clusters were demonstrated to fragment through loss of neutral ligands and AuL2+. Comparison of the relative fragmentation yields of PPh3vs. TMTP and TPTP from the mixed-ligand clusters indicated that these tolyl ligands are more strongly bonded to the Au82+ gold core than PPh3. To provide molecular-level insight into the experimental results we also performed complementary electronic structure calculations using density functional theory at the B3LYP-D3/SDD level of theory on representative model systems. These computations revealed that steric interactions of the CH3 group on the tri(o-tolyl)phosphine ligand are responsible for the lack of ligand exchange in solution with PPh3. Our joint experimental and theoretical findings demonstrate the subtle interplay of steric and electronic factors that determine the size distribution, stability, and dissociation pathways of phosphine ligated gold clusters.


Biliary brush cytology and the detection of cholangiocarcinoma in primary sclerosing cholangitis: evaluation of specific cytomorphologic features and CA19-9 levels.
Interpreting biliary brush cytology (BBC) findings in primary sclerosing cholangitis (PSC) is problematic. In our study, BBC findings and CA19-9 serum levels were evaluated for their effectiveness in diagnosing cholangiocarcinoma in patients with PSC. We reviewed 107 biliary brushings from 51 patients with PSC and concurrent CA19-9 levels between January 1995 and March 2004 at the University of Washington Medical Center, Seattle. A portion of the brushings were evaluated and scored according to specific cytologic criteria; statistical analysis showed which criteria were most predictive in diagnosing malignancy: nuclear/cytoplasmic ratio, prominent nucleoli, nuclear membrane irregularities, and discohesion were significant predictive features. Sensitivity and specificity of BBC were 62.5% and 100%, respectively. Sensitivity and specificity of CA19-9 at a cutoff of 186 IU/mL were 100% and 94%, respectively. BBC is a specific and relatively sensitive method of detecting cholangiocarcinoma, even in patients with PSC, especially when certain cytomorphologic features are identified. Combining biliary cytology and CA19-9 levels might have an important diagnostic role in PSC.


Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNgamma-induced apoptosis.
Combined injections into experimental tumor nodules of adenovirus encoding IL-12 and certain chemokines are capable to induce immune-mediated complete regressions. In this study, we found that the combination of two adenoviruses, one encoding IL-12 and other MIP3alpha (AdCMVIL-12+AdCMVMIP3alpha) was very successful in treating CT-26-derived colon carcinomas. However, in experimental tumors generated from the pancreatic carcinoma cell line Panc02 such combined treatment induces 50% of macroscopic complete regressions, although local relapses within 1 week are almost constant. We derived cell lines from such relapsing tumors and found that experimental malignancies derived from their inoculum were not amenable to treatment in any case with AdCMVIL-12+AdCMVMIP-3alpha. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNgamma, in clear contrast with the original Panc02 cells. Comparative analyses by cDNA arrays of relapsing cell lines versus wild-type Panc02 were performed revealing an important number of genes (383) whose expression levels were modified more than two-fold. These changes grouped in certain gene ontology categories should harbor the mechanistic explanations of the acquired selective resistance to IFNgamma.


Wilms' tumour--a case of disrupted development.
Wilms' tumour is a paediatric kidney malignancy that arises through aberrant differentiation of nephric stem cells. We are studying the role of one Wilms' tumour predisposition gene, WT1. This is a tumour suppressor gene whose function is required for normal development of the genitourinary system. WT1 encodes a putative transcriptional repressor of the zinc finger family. Here we discuss how one of the normal functions of WT1 may be to suppress myogenesis during kidney development. Furthermore, we describe how we are proposing to use YAC (yeast artificial chromosome) transgenesis to analyse WT1 regulation and function in mice. We also discuss the evolution of the WT1 gene amongst different vertebrate classes and how this may provide insights into genitourinary evolution.


A study on the learning curve of the robotic virtual reality simulator.
A robotic virtual reality simulator (dV-Trainer™, Mimic Technologies) has been accepted as an effective training tool for the da Vinci(®) Surgical System (Intuitive Surgical, Inc.) in previous reports. However, there are no data available so far on how much time is required for an individual using the simulator to become proficient. We investigated how long and how many performances it takes to gain proficiency with the robotic virtual reality simulator through the learning curve. The novice group included 20 medical students who had no previous experience. The "Tube 2" task, a program released for the dV-Trainer that imitates a vesicourethral anastomosis, was repeated more than 80 times to obtain the plateau of the learning curve. The learning curve of "Tube 2" was obtained through the S-curve trend model and cumulative sum control chart graph. In the comparison of the initial and final sessions, every parameter such as mean time, collision, and critical errors was significantly improved. The repeat count for acquiring sufficient proficiency was 74 times, and the total amount of time invested for this was calculated as about 4 hours. The mean time at the plateau of the learning curve was 138 seconds. Our study showed that the robotic virtual reality simulator (dV-Trainer) can yield sufficient improvement in technical performance in the "Tube 2" task within 4 hours. The simulator improves the technical surgical performance, but the development of more applications to reflect actual surgical situations is needed to improve and maximize the usefulness of the simulator.


A global public health strategy for autism spectrum disorders.
In recent years, there has been increasing awareness about autism spectrum disorders (ASD) around the world, including in low and middle income countries. Unlike countries in Western Europe and North America where infrastructure and capacity are available to help meet some of the needs of individuals with ASD, little expertise or capacity exists in most of the developing world. In 2008 Autism Speaks launched the Global Autism Public Health (GAPH) Initiative to facilitate the development of systematic and sustainable solutions for enhancing global autism awareness, research, training and service delivery. In the last 3 years Autism Speaks has established collaboration with stakeholders from over 20 countries who are working alongside dedicated local and international stakeholders to effect change. In this article, the GAPH framework is described, along with a few brief case examples that illustrate how the framework for implementation of the model can occur. GAPH is still in its infancy but has the potential to have significant impact through inclusive collaboration with local and international stakeholders to develop effective and sustainable public health solutions for disseminating best practices and delivering tangible benefits to individuals with ASD and their families.


Type A behaviour and prevalent heart disease in the Caerphilly study: increase in risk or symptom reporting?
Type A behaviour was assessed by modified Framingham scale in a total sample of 1956 employed men in the Caerphilly study. Prevalent heart disease was measured by cardiovascular questionnaire to obtain evidence of myocardial infarction and angina, and by electrocardiogram (ECG) for evidence of ischaemia. Type A was inversely related to age and systolic blood pressure and was positively related to social class and height. It was not related to serum cholesterol or alcohol consumption. After control for age, systolic blood pressure, height, smoking and social class, type A was found to be independent of angina but positively associated with an increased risk of possible myocardial infarction (MI). Type A was also associated with increased risk of confirmed MI. An inverse association was found between type A and asymptomatic ischaemic heart disease (IHD). The association between type A and symptomatic IHD could be due to symptom reporting.


Neural stem cells-trends and advances.
For many years, accepted dogma held that brain is a static organ with no possibility of regeneration of cells in injured or diseased human brain. However, recent preclinical reports have shown regenerative potential of neural stem cells using various injury models. This has resulted in renewed hope for those suffering from spinal cord injury and neural damage. As the potential of stem cell therapy gained impact, these claims, in particular, led to widespread enthusiasm that acute and chronic injury of the nervous system would soon be a problem of the past. The devastation caused by injury or diseases of the brain and spinal cord led to wide premature acceptance that "neural stem cells (NSCs)" derived from embryonic, fetal or adult sources would soon be effective in reversing neural and spinal trauma. However, neural therapy with stem cells has not been realized to its fullest extent. Although, discrete population of regenerative stem cells seems to be present in specific areas of human brain, the function of these cells is unclear. However, similar cells in animals seem to play important role in postnatal growth as well as recovery of neural tissue from injury, anoxia, or disease.


Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response.
Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acid-mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of eitherRNA:DNAhybrid or genome-embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid-sensing pathway. Here, we establishRnaseh2b(A174T/A174T)knock-in mice as a subclinical model of disease, identifying significant interferon-stimulated gene (ISG) transcript upregulation that recapitulates theISGsignature seen inAGSpatients. The inflammatory response is dependent on the nucleic acid sensor cyclicGMP-AMPsynthase (cGAS) and its adaptorSTINGand is associated with reduced cellular ribonucleotide excision repair activity and increasedDNAdamage. This suggests thatcGAS/STINGis a key nucleic acid-sensing pathway relevant toAGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood-onset interferonopathy and adult systemic autoimmune disorders.


The rat hepatocyte plasma membrane organic anion binding protein is immunologically related to the mitochondrial F1 adenosine triphosphatase beta-subunit.
A 55-kD organic anion binding protein (OABP) was identified previously in liver cell plasma membrane sinusoidal subfractions. Although this protein was localized to the surface of hepatocytes by immunofluorescence, immunoblot analysis revealed reactivity toward both plasma membrane and mitochondrial fractions. To clarify these findings, an immunoreactive clone from a rat liver cDNA expression library was isolated, the 1,500-base pair cDNA insert was sequenced, and the corresponding beta-galactosidase fusion protein was expressed and purified. The resulting sequence corresponded to that of the rat mitochondrial F1-adenosine triphosphatase (F1-ATPase) beta-subunit. This protein and OABP are of similar size and are mutually immunologically cross-reactive. That the antigen was present on the cell surface as well as in mitochondria was suggested from studies of immunoprecipitation after cell-surface iodination, and light- and electron-microscopic immunocytochemistry. Photoaffinity labeling of bovine F1-ATPase with high-specific-activity [35S]sulfobromophthalein revealed binding only to the beta-subunit. Hepatocyte uptake of bilirubin and sulfobromophthalein requires cellular ATP and mitochondria also transport these organic anions, which at high doses inhibit respiration. The presence of an organic anion binding site on the F1-ATPase beta-subunit suggests that it may play a role in these processes.


SU-E-T-462: Calculation of Prescribed Dose for Permanent Implant with Cs-131 Using LQ Equation including Resensitization.
To develop a new biological equivalent dose (BED) formulism that includes repair, repopulation and resensitization (redistribution and reoxygenation), and can be used to calculate prescribed dose for permanent implant with Cs-131. Because of lack of sufficient clinical data, the prescribed dose with new isotopes is usually calculated based on BED compared with other isotopes that have already been used in clinical practice. The current widely used formulism of BED calculation for permanent implant which was given by Dale includes cell repair and repopulation but not resensitization. Resensitization can be included in the extended LQ equation (LQR) proposed by Brenner. Applying Dales formulism to Brenners LQR, we obtained a new BED calculation formula that accounts for resensitization. We used this new formulism to calculate the BED that corresponds to the prescribed dose for cervix (with Au-198) and prostate (with I-125) permanent implant. Then, we obtained the prescribed dose with Cs-131 which has the same BED as Au-198 or I-125. The new formulism was used for prostate and cervix cancer permanent implant. The prescribed dose with Cs-131 for cervix was 40 Gy (42 Gy without resensitization) and 66 Gy (69 Gy without resensitization) which were equivalent to 35 Gy and 60 Gy with Au-198, respectively. For prostate implant, the prescribed dose with Cs-131 that corresponded to 144 Gy with I-125 was 135 Gy (124 Gy without resensitization). Resensitization led to significant dose correction for permanent implant. The calculation of BED and dose was dependent on dose itself and thus should be patient-specific. Since this calculation relied on many biological parameters, and may not be accurate if the parameters are not accurate. Also, the dose prescription should be adjusted based on clinical outcomes.


Monitoring western corn rootworm (Coleoptera: Chrysomelidae) susceptibility to carbaryl and cucurbitacin baits in the areawide management pilot program.
Areawide pest management involves the uniform application of a pest control strategy over wide geographic areas. Therefore, these programs are likely to impose intense selective pressures, and the risk for resistance development among pest species for which areawide management programs are implemented is likely to be high. Pilot studies for areawide management of western corn rootworm, Diabrotica virgifera virgifera LeConte, were conducted from 1996 to 2002 at four different sites across the Corn Belt. This program used cucurbitacin baits to deliver high doses of a traditional neurotoxic insecticide (carbaryl) to individual insects while reducing the overall rate of insecticide use. Because of the concern and potential for resistance evolution, annual assessments of susceptibility to the active ingredient carbaryl were conducted both within the managed area as well as from untreated control areas. Significantly reduced susceptibility to carbaryl based on survival at a diagnostic concentration was detected in three of the four management sites (Kansas, Iowa, and Illinois/Indiana), whereas susceptibility of beetles collected outside the managed areas remained unchanged. Additionally, significantly reduced responsiveness to cucurbitacin baits was observed in beetles collected from the managed area relative to the control area at the same three sites. These results suggest strongly that areawide management has the potential to select for resistance and that a strategy for managing resistance and reducing selective pressure should be proactively implemented.


Biomonitoring perfluorinated compounds in Catalonia, Spain: concentrations and trends in human liver and milk samples.
Perfluorinated compounds (PFCs) are global environmental pollutants that bioaccumulate in wildlife and humans. Laboratory experiments have revealed toxic effects such as delayed development, humoral suppression, and hepatotoxicity. Although numerous human blood levels have been reported, little is known about distribution in the human body. Knowledge about PFC distribution and accumulation in the human body is crucial to understanding uptake and subsequent effects as well as to conduct risk assessments. The present study reports PFC levels in human liver and breast milk from a general population living in Catalonia, Spain. Liver and milk levels are compared to previously reported levels in blood from the same geographic area as well as to other existing reports on human liver and milk levels in other countries. Human liver (n = 12) and milk (n = 10) samples were collected in 2007 and 2008 in Catalonia, Spain. Liver samples were taken postmortem from six males and six females aged 27-79 years. Milk samples were from healthy primipara women (30-39 years old). Both liver and milk were analyzed by solid-phase extraction and ultra-performance liquid chromatography tandem mass spectrometry. Six PFCs were detected in liver, with perfluorooctanesulfonate (PFOS, 26.6 ng/g wet weight) being the chemical with the highest mean concentration. Other PFCs such as perfluorohexanesulfonate (PFHxS), perfluorooctanoic acid (PFOA), and acids with chain lengths up to C11 were also detected, with mean levels ranging between 0.50 and 1.45 ng/g wet weight. On the other hand, PFOS and PFHxS were the only PFCs detected in human milk, with mean concentrations of 0.12 and 0.04 ng/mL, respectively. While milk concentrations were similar to reported levels from other countries, liver samples contained more PFCs above quantification limits and higher PFOS concentrations compared to the only two other reports found in the literature. Differences between the results of the present study and those concerning previous investigations can be due to declining levels of some PFCs, which have been reported for the USA. The relationship between PFC concentrations in human liver, milk, and blood was assessed using blood concentrations previously determined in Catalonia. Those levels resulted in liver/serum ratios of 1.7:1, 1.4:1, and 2.1:1 for PFOS, perfluorodecanoic acid, and perfluoroundecanoic acid, respectively. Accumulation in liver is suggested for PFOS and the perfluorocarboxylic acids with carbon chain lengths C9, C10, and C11. For PFOA and PFHxS, fivefold and 14-fold higher concentrations, respectively, were seen in serum as compared to liver. The mean concentration of PFOS and PFHxS in milk was only 0.8% and 0.6% of the reported mean serum level, respectively. The results of the present study show that several PFCs could be detected in human liver samples of subjects living in Tarragona. Concerning human milk, the mechanism by which PFCs are transferred from mother's blood to breast milk is still unclear. Considering that PFCs are strongly bound to the protein fraction in blood, the possibility of PFCs entering the milk and accumulating to levels observed in maternal plasma is limited. Interestingly, the potential accumulation difference for PFCs with different chain lengths might be of great importance for risk assessment. Continuing studies on the distribution of different PFCs in human tissue are therefore justified.


Analyzing biological and molecular characteristics and genomic damage induced by exposure to asbestos.
Asbestos is one of the most important occupational carcinogens. Currently, about 125 million people worldwide are exposed to asbestos in the workplace. According to global estimates, at least 107,000 people die each year from lung cancer, mesothelioma, and asbestosis as a result of occupational exposure to asbestos. The high pathogenicity of this material is currently known, being associated with the development of pulmonary diseases, of which lung cancer is the main cause of death due to exposure to this mineral. Pulmonary diseases related to asbestos are a common clinical problem and a major health concern worldwide. Extensive research has identified many important pathogenic mechanisms; however, the precise molecular mechanisms involved, and the generated genomic damage that lead to the development of these diseases, are not completely understood. The modes of action that underlie this type of disease seem to differ depending on the type of fiber, lung clearance, and genetics. This evidences the need to increase our knowledge about these effects on human health. This review focuses on the characteristics of asbestos and the cellular and genomic damage generated in humans via exposure.


Emerging investigator series: interdependency of green rust transformation and the partitioning and binding mode of arsenic.
We investigated the impact of aging-induced structural modifications of carbonate green rust (GR), a mixed valent Fe(ii,iii) (hydr)oxide with a high oxyanion sorption affinity, on the partitioning and binding mode of arsenic (As). Suspensions of carbonate GR were produced in the presence of As(v) or As(iii) (i.e. co-precipitated with As(iii) or As(v)) and aged in anoxic and oxic conditions for up to a year. We tracked aqueous As over time and characterized the solid phase by X-ray absorption spectroscopy (XAS). In experiments with initial As(v) (4500 μg L-1, As/Fe = 2 mol%), the fresh GR suspension sorbed >99% of the initial As, resulting in approximately 14 ± 8 μg L-1 residual dissolved As. Anoxic aging of the As(v)-laden GR for a month increased aqueous As to >60 μg L-1, which was coupled to an increase in GR structural order revealed by Fe K-edge XAS. Further anoxic aging up to a year transformed As(v)-laden GR into magnetite and decreased significantly the aqueous As to <2 μg L-1. The As binding mode was also modified during GR transformation to magnetite from sorption to GR particle edges to As substitution for tetrahedral Fe in the magnetite structure. These GR structural modifications altered the ratio of As partitioning to the solid (μg As/mg Fe) and liquid (μg As per L) phase from 2.0 to 0.4 to 14 L mg-1 for the fresh, month, and year aged suspensions, respectively. Similar trends in GR transformation and As partitioning during anoxic aging were observed for As(iii)-laden suspensions, but occurred on more rapid timescales: As(iii)-laden GR transformed to magnetite after a day of anoxic aging. In oxic aging experiments, rapid GR oxidation by dissolved oxygen to Fe(iii) precipitates required only an hour for both As(v) and As(iii) experiments, with lepidocrocite favored in As(v) experiments and hydrous ferric oxide favored in As(iii) experiments. Aqueous As during GR oxidation decreased to <10 μg L-1 for both As(v) and As(iii) series. Knowledge of this interdependence between GR aging products and oxyanion fate improves biogeochemical models of contaminant and nutrient dynamics during Fe cycling and can be used to design more effective arsenic remediation strategies that rely on arsenic sorption to GR.


Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention.
Snail1 is the founding member of the Snail superfamily of zinc-finger transcription factors, which also includes Snail2 (Slug) and Snail3 (Smuc). The superfamily is involved in cell differentiation and survival, two processes central in cancer research. Encoded by the SNAI1 gene located on human chromosome 20q13.2, Snail1 is composed of 264 amino acids and usually acts as a transcriptional repressor. Phosphorylation and nuclear localization of Snail1, governed by PI3K and Wnt signaling pathways crosstalk, are critical in Snail1's regulation. Snail1 has a pivotal role in the regulation of epithelial-mesenchymal transition (EMT), the process by which epithelial cells acquire a migratory, mesenchymal phenotype, as a result of its repression of E-cadherin. Snail1-induced EMT involves the loss of E-cadherin and claudins with concomitant upregulation of vimentin and fibronectin, among other biomarkers. While essential to normal developmental processes such as gastrulation, EMT is associated with metastasis, the cancer stem cell phenotype, and the regulation of chemo and immune resistance in cancer. Snail1 expression is a common sign of poor prognosis in metastatic cancer, and tumors with elevated Snail1 expression are disproportionately difficult to eradicate by current therapeutic treatments. The significance of Snail1 as a prognostic indicator, its involvement in the regulation of EMT and metastasis, and its roles in both drug and immune resistance point out that Snail1 is an attractive target for tumor growth inhibition and a target for sensitization to cytotoxic drugs.


The Effect of Socioeconomic Status Across Adulthood on Trajectories of Frailty in Older Women.
To investigate whether distinct trajectories of frailty exist in older women and whether they are associated with measures of socioeconomic status (SES) across adulthood. Participants were 7484 women born in 1921-1926 from the Australian Longitudinal Study on Women's Health who were surveyed every 3 years from 1999 to 2011. Frailty was measured at each survey using the FRAIL scale. Group-based trajectory modeling was used to assess patterns of frailty. Multinomial logistic regression was used to examine associations of trajectories with SES (level of education, occupation, and ability to manage on income) across adulthood. Three trajectory groups were identified: low (19.5%), increasing (40.7%), and high (39.9%). Compared with women in the increasing frailty group, those who reported difficulty managing on their income in 1999 were less likely to be in the low frailty group (relative risk ratio 0.57, 95% confidence interval 0.39-0.84) and more likely to be in the high frailty group (relative risk ratio 2.65, 95% confidence interval 2.07-3.39), after adjusting for other SES variables, age, and social support. Occupation and education were not associated with trajectories of frailty. Some women remain frailty free until age 85-90 years. The strongest impact on frailty is late-life SES.


Toward Precision Medicine in Atopic Dermatitis Using Molecular-Based Approaches.
Atopic dermatitis is the most common chronic inflammatory skin disorder, affecting up to 20% of children and 10% of adults in developed countries. The pathophysiology of atopic dermatitis is complex and involves a strong genetic predisposition and T-cell driven inflammation. Although our understanding of the pathology and drivers of this disease has improved in recent years, there are still knowledge gaps in the immune pathways involved. Therefore, advances in new omics technologies in atopic dermatitis will play a key role in understanding the pathogenesis of this burden disease and could develop preventive strategies and personalized treatment strategies. In this review, we discuss the latest developments in genetics, transcriptomics, epigenomics, proteomics, and metagenomics and understand how integrating multiple omics datasets will identify potential biomarkers and uncover nets of associations between several molecular levels.


Fenfluramine in Prader-Willi syndrome: a double blind, placebo controlled trial.
A double blind trial was conducted to determine the effect of fenfluramine on the weight and behaviour of patients with the Prader-Willi syndrome. Fifteen subjects, aged 5.5 to 27 years, received the placebo and the active drug, each for a period of six weeks. The dose of fenfluramine varied according to the age of the patient. Treatment with fenfluramine was associated with significant weight loss, improvement in food related behaviour, and a decrease in aggressive behaviour directed towards others. Skin picking and other self mutilation were unaffected by the drug. None of the subjects suffered from any side effects while taking the drug. These findings suggest that short term treatment with fenfluramine may have a role in the management of some patients with Prader-Willi syndrome. It could be used during periods when exposure to large amounts of food cannot be avoided and aggressive behaviour is particularly difficult to contain. It may also be useful in those whose lives are threatened by the complications of obesity.


Mutations in the Drosophila gene bullwinkle cause the formation of abnormal eggshell structures and bicaudal embryos.
Subcellular localization of gene products and cell migration are both critical for pattern formation during development. The bullwinkle gene is required in Drosophila for disparate aspects of these processes. In females mutant at the bullwinkle locus, the follicle cells that synthesize the dorsal eggshell filaments do not migrate properly, creating short, broad structures. Mosaic analyses demonstrate that wild-type BULLWINKLE function is required in the germ line for these migrations. Since the mRNA for gurken, the putative ligand that signals dorsal follicle cell fate, is correctly localized in bullwinkle mutants, we conclude that our bullwinkle alleles do not affect the dorsoventral polarity of the oocyte and thus must be affecting the follicle cell migrations in some other way. In addition, the embryos that develop from bullwinkle mothers are bicaudal. A KINESIN:beta-GALACTOSIDASE fusion protein is correctly localized to the posterior pole of bullwinkle oocytes during stage 9. Thus, the microtubule structure of the oocyte and general transport along it do not appear to be disrupted prior to cytoplasmic streaming. Unlike other bicaudal mutants, oskar mRNA is localized correctly to the posterior pole of the oocyte at stage 10. By early embryogenesis, however, some oskar mRNA is mislocalized to the anterior pole. Consistent with the mislocalization of oskar mRNA, a fraction of the VASA protein and nanos mRNA are also mislocalized to the anterior pole of bullwinkle embryos. Mislocalization of nanos mRNA to the anterior is dependent on functional VASA protein. Although the mirror-image segmentation defects appear to result from the action of the posterior group genes, germ cells are not formed at the anterior pole. The bicaudal phenotype is also germ-line dependent for bullwinkle. We suspect that BULLWINKLE interacts with the cytoskeleton and extracellular matrix and is necessary for gene product localization and cell migration during oogenesis after stage 10a.


On-surface synthesis: a promising strategy toward the encapsulation of air unstable ultra-thin 2D materials.
2D black phosphorus (BP) and transition metal chalcogenides (TMCs) have beneficial electronic, optical, and physical properties at the few-layer limit. However, irreversible degradation of exfoliated or chemical vapor deposition-grown ultrathin BP and TMCs like GaSe via oxidation under ambient conditions limits their applications. Herein, the on-surface growth of an oxidation-resistant 2D thin film of a metal coordination polymer is demonstrated by multiscale simulations. We show that the preparation of such heterostructures can be conducted in solution, in which pristine BP and GaSe present better stability than in an air environment. Our calculations reveal that the interaction between the polymer layer and 2D materials is dominated by van der Waals forces; thus, the electronic properties of pristine BP and GaSe are well preserved. Meanwhile, the isolation from oxygen and water can be achieved by monolayer polymers, due to the nature of their close-packed layers. Our facile strategy for enhancing the environmental stability of ultrathin materials is expected to accelerate efforts to implement 2D materials in electronic and optoelectronic applications.


Laparoscopic surgery in patients with a ventriculoperitoneal shunt. A case report.
Ventriculoperitoneal shunts have afforded many patients the opportunity to expect a normal lifespan. Since laparotomy is more likely to be associated with adhesion formation, potentially reducing the functional capacity of ventriculoperitoneal shunts, laparoscopy may be a preferable surgical alternative. A 64-year-old woman presented with a pelvic mass requiring surgical evaluation to rule out ovarian cancer. She had a ventriculoperitoneal shunt. Diagnostic laparoscopy was performed without complication. However, due to the significant adhesions from previous surgery, the mass could not be safely evaluated, and the procedure was completed by laparotomy. This is the first report of laparoscopy for a pelvic mass in an adult with a ventriculoperitoneal shunt. Laparoscopy is preferable to laparotomy for the replacement or repair of ventriculoperitoneal shunts. Also, laparoscopy should be considered for other problems requiring surgical intervention.


Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies.
A traumatic cerebral contusion causes a zone of perifocal neuronal necrosis, the cause of which is not known; the surgical management of these lesions remains controversial. To determine the pathophysiological mechanisms responsible for brain damage after contusions, the authors performed cerebral blood flow (CBF) mapping studies and related these to change in local cerebral blood volume (CBV) and ultrastructure. In 11 severely head injured patients with contusion, CBF and CBV were measured in pericontusional areas using stable xenon-computerized tomography (CT). These studies demonstrated a profound reduction in perilesional CBF (mean 17.5 +/- 4 ml/100 g/min), which was always accompanied by a zone of edema defined by CT density measurements. Mean CBV in these regions was 2.3 +/- 0.4 ml/100 g, a reduction to approximately one-half the value of 4.8 ml/100 g found in the nonedematous regions, and to approximately 35% of the value of 6.0 ml/100 g found in normal volunteers. Ultrastructural analysis of the pericontusional tissue, taken at surgery in four patients with high intracranial pressure showed glial swelling with narrowing of the microvascular lumina due to massive podocytic process swelling. Additionally, some suggestion of vascular occlusion due to erythrocyte and leukocyte stasis was seen. These data support the conclusion that microvascular compromise by compression and/or occlusion is a major event associated with profound perilesional hypoperfusion, which is a uniform finding within edematous pericontusional tissue.


Perception, Awareness, and Acceptance of Human Papillomavirus Disease and Vaccine Among Parents of Boys Aged 9 to 18 Years.
Male human papillomavirus (HPV) vaccination rates remain very low. The study objective was to gain an understanding of the perceptions of HPV disease and acceptance/barriers to HPV vaccine by parents of boys aged 9 to 18 years. An anonymous, written survey was administered from January 1, 2011 to September 30, 2013 in private pediatric offices (PPOs) and public health clinics (PHCs) in Chicago, Illinois. A total of 230 PPO parents (PPOPs) and 286 PHC parents (PHCPs) completed the survey. Despite significant differences ( P < .0001) in education level, socioeconomic status, and HPV disease and vaccine knowledge/awareness between the PPOP and PHCP, there was no difference between PPOP and PHCP who would vaccinate their sons with HPV vaccine. For both groups, health care provider recommendation was the primary influence for vaccination. The major barrier to vaccination was lack of information on HPV disease/vaccine. Health care providers need to proactively discuss and use HPV vaccine in male patients.


Neuropsychological impairment as a consequence of football (soccer) play and football heading: a preliminary analysis and report on school students (13-16 years).
Footballers run the risk of incurring mild head injury from a variety of sources, including the intentional use of the head to play the ball, known as heading. This paper presents a preliminary exploratory analysis of data collected to examine whether cumulative incidence of mild head injury, or cumulative heading frequency, are related to neuropsychological functioning in male adolescent footballers. In a quasi-experimental cross-sectional design, neuropsychological test scores of school team footballers were compared with those of similarly aged rugby players and noncontact sport players. Cumulative mild head injury incidence was estimated using self-reports, and cumulative heading was estimated using a combination of observation and self-reports. No participants had sustained a head injury within 3 months of testing. There was no relationship between head injury and neuropsychological performance, and there were no decrements in either the footballers or the rugby players in comparison with the noncontact sport players. Within the footballers, cumulative heading did not predict any of the neuropsychological test scores. These findings indicate the absence of neuropsychological impairment arising due to cumulative mild head injury incidence, or cumulative heading. Although these null findings may be reassuring to players, parents, and football organizers, we stress that they are preliminary. Further data is being collected from the same populations to provide more reliable effect estimates.


The effects of the transcendental meditation program on mindfulness.
Mindfulness is associated with low levels of neuroticism, anxiety, and depressive symptoms, as well as high levels of self-esteem and satisfaction with life (Brown & Ryan, 2003). As part of a 3-month randomized waitlist-controlled trial of the effects of the Transcendental Meditation (TM) program on university students (N=295), we examined the impact of TM practice on mindfulness as measured by the Kentucky Inventory of Mindfulness Skills (KIMS; Baer, Smith, & Allen, 2004). A repeated measures ANOVA on total KIMS scores showed a significant timextreatment interaction, with the TM participants reporting greater increases in mindfulness than the waitlist participants. All KIMS subscales were positively intercorrelated at pretreatment, and there were no differences over time or as a function of treatment condition in subscale intercorrelations. Therefore, previously published findings of a positive correlation between subscales measuring the skills of observing and accepting-without-judgment one's inner experiences only among those with meditation experience may have reflected a self-selection effect rather than a change in the relation of these mindfulness components resulting directly from meditation practice.


Metabolism and its sequelae in cancer evolution and therapy.
Cancers progress through a series of events that can be characterized as "somatic evolution." A central premise of Darwinian evolutionary theory is that the environment imparts pressure to select for species that are most fit within that particular microenvironmental context. Furthermore, the rate of evolution is proportional to both (1) the strength of the environmental selection and (2) the phenotypic variance of the selected population. It is notable that, during the progression of cancers from carcinogenesis to local invasion to metastasis, the selective landscape continuously changes, and throughout this process, there is increased selection for cells that have altered metabolic phenotypes: implying that these phenotypes impart a selective advantage during the process of environmental selection. One of the most prevalent selected phenotypes is that of aerobic glycolysis, that is, the continued fermentation of glucose even in the presence of adequate oxygen. The mechanisms of this so-called "Warburg effect" have been well studied, and there are multiple models to explain how this occurs at the molecular level. Herein, we propose that unifying insights can be gained by evaluating the environmental context within which this phenotype arises. In other words, we focus not on the "how" but the "why" do cancer cells exhibit high aerobic glycolysis. This is best approached by examining the sequelae of aerobic glycolysis that may impart a selective advantage. Many of these have been considered, including generation of anabolic substrates, response rates of glycolysis vis-à-vis respiration, and generation of antioxidants. A further sequeala considered here is that aerobic glycolysis results in a high rate of lactic acid production; resulting in acidification of the extracellular space. Indeed, it has been shown that a low extracellular pH promotes local invasion, promotes metastasis, and inhibits antitumor immunity. In naturally occurring cancers, low extracellular pH is a strong negative prognostic indicator of metastasis-free survival. Furthermore, it has been shown that inhibition of extracellular acidosis can inhibit metastasis and promote antitumor immunity. Hence, we propose that excess acid production confers a selective advantage for cells during the somatic evolution of cancers.


A Prüfer-Sequence Based Algorithm for Calculating the Size of Ideal Randomly Branched Polymers.
Branched polymers can be represented as tree graphs. A one-to-one correspondence exists between a tree graph comprised of N labeled vertices and a sequence of N - 2 integers, known as the Prüfer sequence. Permutations of this sequence yield sequences corresponding to tree graphs with the same vertex-degree distribution but (generally) different branching patterns. Repeatedly shuffling the Prüfer sequence we have generated large ensembles of random tree graphs, all with the same degree distributions. We also present and apply an efficient algorithm to determine graph distances directly from their Prüfer sequences. From the (Prüfer sequence derived) graph distances, 3D size metrics, e.g., the polymer's radius of gyration, Rg, and average end-to-end distance, were then calculated using several different theoretical approaches. Applying our method to ideal randomly branched polymers of different vertex-degree distributions, all their 3D size measures are found to obey the usual N(1/4) scaling law. Among the branched polymers analyzed are RNA molecules comprised of equal proportions of the four-randomly distributed-nucleotides. Prior to Prüfer shuffling, the vertices of their representative tree graphs, these "random-sequence" RNAs exhibit an Rg ∼ N(1/3) scaling.