Orphan strontium-87 in abyssal peridotites: daddy was a granite.
The (87)Sr/(86)Sr ratios in some bulk abyssal and alpine peridotites are too high to be binary mixtures of depleted mantle and seawater components. The apparent excess, or "orphan," (87)Sr appears to be separated from its radioactive parent. Such observations were widely held to be analytical artifacts. Study of several occurrences of orphan (87)Sr shows that the orphan component in abyssal peridotite is located in the alteration products of olivine and enstatite in the peridotite. The orphan (87)Sr is most likely introduced by infiltration of low-temperature (<200 degrees C) seawater bearing suspended detrital particulates. These particulates include grains of detrital clay that are partly derived from continental (that is, granitic) sources and thus are highly radiogenic. Orphan (87)Sr and other radiogenic isotopes may provide a tracer for low-temperature seawater penetrating into the oceanic crust.


Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction.
Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated protein with atherosclerosis-protective and systemic anti-oxidant functions. We recently showed that PON1, myeloperoxidase, and HDL bind to one another in vivo forming a functional ternary complex (Huang, Y., Wu, Z., Riwanto, M., Gao, S., Levison, B. S., Gu, X., Fu, X., Wagner, M. A., Besler, C., Gerstenecker, G., Zhang, R., Li, X. M., Didonato, A. J., Gogonea, V., Tang, W. H., et al. (2013) J. Clin. Invest. 123, 3815-3828). However, specific residues on PON1 involved in the HDL-PON1 interaction remain unclear. Unambiguous identification of protein residues involved in docking interactions to lipid surfaces poses considerable methodological challenges. Here we describe a new strategy that uses a novel synthetic photoactivatable and click chemistry-taggable phospholipid probe, which, when incorporated into HDL, was used to identify amino acid residues on PON1 that directly interact with the lipoprotein phospholipid surface. Several specific PON1 residues (Leu-9, Tyr-185, and Tyr-293) were identified through covalent cross-links with the lipid probes using affinity isolation coupled to liquid chromatography with on-line tandem mass spectrometry. Based upon the crystal structure for PON1, the identified residues are all localized in relatively close proximity on the surface of PON1, defining a domain that binds to the HDL lipid surface. Site-specific mutagenesis of the identified PON1 residues (Leu-9, Tyr-185, and Tyr-293), coupled with functional studies, reveals their importance in PON1 binding to HDL and both PON1 catalytic activity and stability. Specifically, the residues identified on PON1 provide important structural insights into the PON1-HDL interaction. More generally, the new photoactivatable and affinity-tagged lipid probe developed herein should prove to be a valuable tool for identifying contact sites supporting protein interactions with lipid interfaces such as found on cell membranes or lipoproteins.


Determination of local chromatin composition by CasID.
Chromatin structure and function are determined by a plethora of proteins whose genome-wide distribution is typically assessed by immunoprecipitation (ChIP). Here, we developed a novel tool to investigate the local chromatin environment at specific DNA sequences. We combined the programmable DNA binding of dCas9 with the promiscuous biotin ligase BirA* (CasID) to biotinylate proteins in the direct vicinity of specific loci. Subsequent streptavidin-mediated precipitation and mass spectrometry identified both known and previously unknown chromatin factors associated with repetitive telomeric, major satellite and minor satellite DNA. With super-resolution microscopy, we confirmed the localization of the putative transcription factor ZNF512 at chromocenters. The versatility of CasID facilitates the systematic elucidation of functional protein complexes and locus-specific chromatin composition.


Changes in regional brain volumes in social anxiety disorder following 12 weeks of treatment with escitalopram.
It has been suggested that antidepressants, including the selective serotonin reuptake inhibitors have neurotrophic effects. Nevertheless, the impact of treatment with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not been studied. 11 subjects with social anxiety disorder completed magnetic resonance imaging both before and after 12-weeks of treatment with 20 mg/day escitalopram. No increases in structural grey matter were found, but there were decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of treatment with escitalopram. These preliminary findings require replication to determine their reliability, and extension to determine whether or not they are disorder specific.


Characteristics and Surgical Outcomes of Pediatric Intracranial Aneurysms in Romania.
To analyze the demographic characteristics and surgical outcomes of the largest series of patients with pediatric aneurysms reported in Romania, in consideration of the primary factors that lead to good long-term outcomes. Given that all cases involved ruptured aneurysms, we also investigated the ability of microsurgical clipping to prevent massive hemorrhage andaggravation of neurological deficits. This multicenter retrospective study included 47 pediatric patients ( < 16 years old) who underwent operation over the 20-year period between January 1999 and January 2019. We analyzed medical records and imaging findings in each patient. Treatment consisted of open microsurgical dissection (clipping) and endovascular embolization (coiling). Mean patient age was 14.3 years, ranging from 5 months to 16 years, with 28 boys (59.5%) and 19 girls (40.4%). In our series, pediatric aneurysms represented 6.1% of all intracranial aneurysms (771 cases). Clinical features were dominated by headache (45 cases, 95.7%), neck stiffness (43 cases, 91.4%) and vomiting (42 cases, 89.3%). The most frequently involved locations were the anterior communicating artery (17 cases, 36.1%), middle cerebral artery (12 cases, 25.5%), and internal carotid artery bifurcation (9 cases, 19.1%). Glasgow Outcome Scale scores at 6 months indicated good recovery in 36 patients (76.5%), moderate disability in ninepatients (19.1%), severe disability in one patient (2.1%), and (preoperative) death in one patient (2.1%). Intracranial aneurysms in children are very rare. Early diagnosis based on brain imaging and microsurgical treatment is essential for attaining excellent results.Primary factors such as preoperative status, child profile, aneurysm size, treatment choice, and timing of the operation influence both short and long-term outcomes.


Ultrafast radiationless transition pathways through conical intersections in photo-excited 9H-adenine.
We performed CASSCF and MRCI calculations for determination of the effective pathways of ultrafast radiationless transitions from the optically allowed ππ* 1La state to the ground state S0 of 9H-adenine. The nπ*, πσ*, and two ππ* states were taken into account as states involved in the radiationless process. Optimized geometry and conical intersections were searched in the full dimensional space for the vibrational degrees of freedom by using the suite of quantum chemistry codes MOLPRO. The MRCI transition energies to excited states are in good agreement with the experimental values. The mechanisms of three competing pathways, two indirect pathways via the πσ* and nπ* states, 1La→πσ*→S0 and 1La→nπ*→ S0, and a direct pathway 1La→S0, were examined on the basis of the structures and energies of conical intersections involved in ultrafast radiationless transitions from 1La to S0. Any conical intersection between the πσ* and nπ* states was not found. This suggests that the two indirect pathways are independent of each other. The ππ* 1La-πσ* conical intersection lies higher than the ππ* 1La state at the Franck-Condon geometry by 0.19 eV according to the present MRCI calculation, which is consistent with the experimental observation that a new channel is open at the excess energy of 0.2 eV above the band origin of the ππ* 1La state. It is concluded that relaxation from the ππ* 1La-πσ* conical intersection to S0 occurs mainly through the πσ*-S0 conical intersection. The ππ* 1La-nπ* conical intersection lies higher by 0.1 eV (MRCI value) than the ππ* 1La state at the Franck-Condon geometry. The fast decay component in time-resolved spectra of 9H-adenine is attributed to rapid radiationless transitions to the nπ* state via this conical intersection followed by the transition to S0 via the nπ*-S0 (or ππ* 1La-S0) conical intersection. The ππ* 1La-S0 conical intersection of large out-of-plane distortion has the lowest energy among the conical intersections found in this study. We identified the transition state between the ππ* 1La at the Franck-Condon geometry and the ππ* 1La-S0 conical intersection. The MRCI energy of the transition state on the 1La potential surface is higher by 0.21 eV than the vertical excitation energy. The possibility of strong coupling between the two close-lying states 1La and nπ* indicates that, besides this direct pathway, radiationless transitions to S0 via the ππ* 1La-S0 conical intersection can also occur after rapid relaxations between 1La and nπ*. The analysis of the h-vector for each conical intersection has shown that the active coupling for the πσ* pathway is dominated by the out-of-plane normal mode ν10, while the active coupling for the nπ* pathway is distributed among many normal modes. Control of the branching ratio of the two indirect pathways can be achieved by selective excitation of single vibronic levels involving active coupling modes such as the mode ν10.


Sesamol supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of nuclear factor kappaB.
The aim of the present study was to investigate the inhibitory effects of sesamol, a phenolic lignan from sesame, on the systemic inflammation-induced neuroinflammation and amyloidogenesis as well as memory impairment. C57BL/6J mice were treated with 0.05% sesamol (w/v) in the drinking water for 7 weeks, and then the mice were treated by intraperitoneal injection of LPS (0.25 mg/kg) for 9 days. Sesamol supplementation significantly improved (by 36.9%) LPS-induced decreased spontaneous alteration in Y-maze test, as well as significantly restored LPS-elicited mice cognitive deficits through restoring performances such as escape distance in Morris water maze test. Moreover, sesamol prevented LPS-induced increases in Aβ1-42 formation, levels of amyloid precursor protein, and neuronal β-secretase 1 (BACE1) in the brain. Sesamol reduced LPS-induced glial over-activation by inhibiting MAPK and NFκB pathway as well as expressions of inflammatory mediators such as IL-1β and TNFα. Furthermore, LPS-induced transcriptional factor NFκB DNA binding activity was also inhibited by sesamol as examined by the electrophoretic mobility shift assay and molecular modeling. These results indicated that sesamol mitigated LPS-induced amyloidogenesis and memory impairment via inhibiting NFκB signal pathway, suggesting that the compound might be plausible therapeutic intervention for neuroinflammation-related diseases such as AD.


Prognostic Value of Residual Urine Volume, GFR by 24-hour Urine Collection, and eGFR in Patients Receiving Dialysis.
Residual kidney function can be assessed by simply measuring urine volume, calculating GFR using 24-hour urine collection, or estimating GFR using the proposed equation (eGFR). We aimed to investigate the relative prognostic value of these residual kidney function parameters in patients on dialysis. Using the database from a nationwide prospective cohort study, we compared differential implications of the residual kidney function indices in 1946 patients on dialysis at 36 dialysis centers in Korea between August 1, 2008 and December 31, 2014. Residual GFR calculated using 24-hour urine collection was determined by an average of renal urea and creatinine clearance on the basis of 24-hour urine collection. eGFR-urea, creatinine and eGFR β2-microglobulin were calculated from the equations using serum urea and creatinine and β2-microglobulin, respectively. The primary outcome was all-cause death. During a mean follow-up of 42 months, 385 (19.8%) patients died. In multivariable Cox analyses, residual urine volume (hazard ratio, 0.96 per 0.1-L/d higher volume; 95% confidence interval, 0.94 to 0.98) and GFR calculated using 24-hour urine collection (hazard ratio, 0.98; 95% confidence interval, 0.95 to 0.99) were independently associated with all-cause mortality. In 1640 patients who had eGFR β2-microglobulin data, eGFR β2-microglobulin (hazard ratio, 0.98; 95% confidence interval, 0.96 to 0.99) was also significantly associated with all-cause mortality as well as residual urine volume (hazard ratio, 0.96 per 0.1-L/d higher volume; 95% confidence interval, 0.94 to 0.98) and GFR calculated using 24-hour urine collection (hazard ratio, 0.97; 95% confidence interval, 0.95 to 0.99). When each residual kidney function index was added to the base model, only urine volume improved the predictability for all-cause mortality (net reclassification index =0.11, P=0.01; integrated discrimination improvement =0.01, P=0.01). Higher residual urine volume was significantly associated with a lower risk of death and exhibited a stronger association with mortality than GFR calculated using 24-hour urine collection and eGFR-urea, creatinine. These results suggest that determining residual urine volume may be beneficial to predict patient survival in patients on dialysis.


Genetic interaction screens with ordered overexpression and deletion clone sets implicate the Escherichia coli GTPase YjeQ in late ribosome biogenesis.
The Escherichia coli protein YjeQ is a circularly permuted GTPase that is broadly conserved in bacteria. An emerging body of evidence, including cofractionation and in vitro binding to the ribosome, altered polysome profiles after YjeQ depletion, and stimulation of GTPase activity by ribosomes, suggests that YjeQ is involved in ribosome function. The growth of strains lacking YjeQ in culture is severely compromised. Here, we probed the cellular function of YjeQ with genetic screens of ordered E. coli genomic libraries for suppressors and enhancers of the slow-growth phenotype of a delta yjeQ strain. Screening for suppressors using an ordered library of 374 clones overexpressing essential genes and genes associated with ribosome function revealed that two GTPases, Era and initiation factor 2, ameliorated the growth and polysome defects of the delta yjeQ strain. In addition, seven bona fide enhancers of slow growth were identified (delta tgt, delta ksgA, delta ssrA, delta rimM, delta rluD, delta trmE/mnmE, and delta trmU/mnmA) among 39 deletions (in genes associated with ribosome function) that we constructed in the delta yjeQ genetic background. Taken in context, our work is most consistent with the hypothesis that YjeQ has a role in late 30S subunit biogenesis.


Immediate results and six-month clinical outcome after percutaneous coronary intervention in patients with prior coronary artery bypass surgery.
Redo coronary artery bypass grafting surgery (CABG) is associated with a higher risk of mortality than the first operation. However, the impact of percutaneous coronary intervention (PCI) on the outcome in such patients is currently unclear. We evaluated the in-hospital and six-month clinical outcomes of post-CABG patients who underwent PCI in our center. Between April 2008 and July 2009, 71 post-CABG patients (16 women and 55 men) underwent 110 stent implantations (74% drug-eluting stents) for 89 lesions. Sixty percent of the PCI procedures were performed on the native coronary arteries, 32% on graft arteries, and 8% on both types of vessels. Major adverse cardiac events (MACE) were recorded in hospital and at six months' follow-up. The procedural success rate was 93%, and the in-hospital MACE rate was 5.6 % (1 death, 3 myocardial infarctions). At 6 months, the incidence of MACE was 5.6% (no death or myocardial infarction, but 4 target lesion revascularizations) and 4 (5.6 %) in-stent restenoses. There was no statistically significant difference in the comparison of MACE between the patients treated in either native arteries or in the grafts (15% vs.12%, p value = 0.8). According to the univariate analysis, hypertension and the use of the bare metal stent vs. the drug-eluting stent were the significant predictors of MACE, whereas the multivariate analysis showed that only hypertension (OR = 3.7, 95% CI 3.4-4, p value < 0.048) was the independent predictor of MACE. The mean of the left ventricular ejection fraction had no effect on the incidence of MACE (p value = 0.9). The multivariate analysis showed hypertension (p value < 0.048) and the use of the bare metal stent (p value < 0.018) were the independent predictors of MACE. The chronic total occlusion (CTO) (p value < 0.01) was the independent predictor of the success rate. The prevalence of diabetes had no impact on the incidence of MACE according to the univariate analysis (p value = 0.9). Our multivariate analysis showed that hypertension and the use of the bare metal stent were the independent predictors of MACE and that chronic total occlusion was the independent predictor of the procedural failure rate. PCI is preferable to redo CABG for post-CABG patients. The independent predictors of MACE were hypertension and bare metal stents.


[Economic Crisis in Portugal: Trajectory of the Incidence of Depression and Correlation With Unemployment].
Previous studies have found an increase in the incidence rate of depression between 2007 - 2013 in Portugal, with a positive correlation with the unemployment rate, namely, in men. So, it was hypothesized that this increase is related with the situation of economic crisis. This study aimed to investigate if the correlation between unemployment rates and the incidence of depression is maintained in the post-crisis period of economic recovery in Portugal (2016 - 2018). An ecological study was carried out, using data from the General Practitioners Sentinel Network concerning depression incidence (first episodes and relapses) and data from the National Statistics Institute on unemployment rates in the Portuguese population. The correlation coefficient was estimated using linear regression and the results were disaggregated by sex. Between 2016 and 2018, there was a consistent decrease in the incidence of depression in both sexes. During the 1995 - 2018 period, a positive correlation was observed between unemployment and depression, with a coefficient of 0.833 (p = 0.005) in males and of 0.742 (p = 0.022) in females. The reduction in the incidence of depression in both sexes observed between 2016 - 2018 corroborates a positive correlation between unemployment and depression in the Portuguese population, previously observed between 2007 - 2013. This study highlights the need to monitor the occurrence of mental illness in the Portuguese population, especially in moments of greatest social vulnerability in order to establish preventive measures, as a way to mitigate the impact of future economic crises.


Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein.
The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.


An MTHFR variant, homocysteine, and cardiovascular comorbidity in renal disease.
It is unclear whether total serum homocysteine (tHcy) and the C677T mutation of methylenetetrahydrofolate reductase (MTHFR) are associated with cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). A cross-sectional sample of 459 patients with ESRD on chronic dialysis was assessed to determine whether tHcy and the C677T mutation are associated with CVD prevalence in multiple logistic regression. As CVD mortality is high, we examined the relationship between homozygosity and duration of dialysis. Mean tHcy was higher in patients without a history of CVD (35.2 micromol/L vs. 30.4 micromol/L, P = 0.02). In multivariate models, CVD was negatively associated with tHcy and positively associated with TT genotype, male gender, and body mass index. Mean tHcy levels were higher among those with the TT genotype compared with those with the CC genotype when adjusted for age, folate, creatinine, and albumin (37.9 micromol/L vs. 31.9 micromol/L, P = 0.005). Among whites, the prevalence of the TT genotype was higher in those having undergone less than one year of dialysis (P = 0.002). The C677T genotype of MTHFR is associated with CVD in ESRD and may be a more meaningful marker than tHcy for abnormal homocysteine metabolism in ESRD. Prospective data from ongoing clinical trials are needed to improve our understanding of these findings. Screening for this polymorphism may help guide prevention measures.


Increased protein kinase C alpha expression in human colonic Caco-2 cells after insertion of human Ha-ras or polyoma virus middle T oncogenes.
The proteins encoded by ras and src protooncogenes are frequently activated in a constitutive state in human colorectal cancers. To investigate the mechanism(s) whereby oncogenic p21ras and pp60c-src contribute to malignant transformation of intestine, human colonic Caco-2 cells transfected with an activated (Val 12) human Ha-ras gene (Caco-2-T cells) or Py-MT oncogene, a constitutive activator of pp60c-src tyrosine kinase activity (Caco-2-MT cells), were analyzed for tumorigenicity, protein kinase C (PKC) isoform expression, and PKC activity. As compared with control vector Caco-2-H cells, Caco-2-T and Caco-2-MT cells displayed: (a) an enhanced tumorigenicity in nude mice; (b) a 4-fold increase in the level of PKC-alpha mRNA which was not due to enhanced mRNA stability and was mediated through a PKC-independent pathway since it persisted after PKC depletion; (c) increased PKC-alpha immunoreactive protein content (3-fold), total PKC catalytic activity (3.5-fold), and total cell number of [3H]phorbol-12,13-dibutyrate binding sites (4-fold); and (d) a 1.7-fold higher membrane-bound/total PKC activity ratio together with 1.8- and 1.5-fold increases in [3H]arachidonate- and [3H]myristate-labeled diacylglycerol levels. In conclusion, the tumorigenic progression induced by oncogenic p21ras or the Py-MT/pp60c-src complex in Caco-2 cells is associated with increased PKC-alpha gene transcription and PKC-alpha expression as well as with constitutive PKC activation. These results provide the first evidence that the PKC-alpha gene is a target for the signaling pathways of oncogenically activated p21ras and pp60c-src in human colonic cells. They raise the possibility that PKC-alpha is an effector of these oncoproteins for activation of Caco-2 cell tumorigenic potential.


Prosthesis-Patient Mismatch after Mitral Valve Replacement: Comparison of Different Methods of Effective Orifice Area Calculation.
The incidence of prosthesis-patient mismatch (PPM) after mitral valve replacement (MVR) has been reported to vary. The purpose of the current study was to investigate incidence of PPM according to the different methods of calculating effective orifice area (EOA), including the continuity equation (CE), pressure half time (PHT) method and use of reference EOA, and to compare these with various echocardiographic variables. We retrospectively reviewed 166 individuals who received isolated MVR due to rheumatic mitral stenosis and had postoperative echocardiography performed between 12 and 60 months after MVR. EOA was determined by CE (EOA(CE)) and PHT using Doppler echocardiography. Reference EOA was determined from the literature or values offered by the manufacturer. Indexed EOA was used to define PPM as present if ≤1.2 cm²/m². Prevalence of PPM was different depending on the methods used to calculate EOA, ranging from 7% in PHT method to 49% in referred EOA method to 62% in CE methods. The intraclass correlation coefficient was low between the methods. PPM was associated with raised trans-prosthetic pressure, only when calculated by CE (p=0.021). Indexed EOA(CE) was the only predictor of postoperative systolic pulmonary artery (PA) pressure, even after adjusting for age, preoperative systolic PA pressure and postoperative left atrial volume index (p<0.001). Prevalence of mitral PPM varied according to the methods used to calculate EOA in patients with mitral stenosis after MVR. Among the various methods used to define PPM, EOA(CE) was the only predictor of postoperative hemodynamic parameters.


ECM molecules mediate both Schwann cell proliferation and activation to enhance neurite outgrowth.
Tissue engineering using a combination of biomaterials and cells represents a new approach to nerve repair. We have investigated the effect that extracellular matrix (ECM) molecules have on Schwann cell (SC) attachment and proliferation on the nerve conduit material poly-3-hydroxybutyrate (PHB), and SC influence on neurite outgrowth in vitro. Initial SC attachment to PHB mats was unaffected by ECM molecules but proliferation increased (laminin > fibronectin > collagen). SCs seeded onto ECM-coated culture inserts suspended above a monolayer of NG108-15 cells determined the effect of released diffusible factors. The effect of direct contact between the two cell types on ECM molecules was also investigated. In both systems SCs enhanced neurite number per cell and percentage of NG108-15 cells sprouting neurites. NG108-15 cells grown in direct contact with SCs had significantly longer neurites than those exposed to diffusible factors when seeded on laminin or fibronectin. Diffusible factors released from SCs cultured on ECM molecules appear to initiate neurite outgrowth, whereas SC-neuron contact promotes neurite elongation. SC proliferation was maximal on poly-D-lysine-coated surfaces, but these cells did not influence neurite outgrowth to the levels of laminin or fibronectin. This suggests that ECM molecules enhance cell number and activate SCs to release neurite promoting factors. Addition of ECM molecules to PHB nerve conduits containing SCs is likely to provide benefits for the treatment of nerve injuries.


Efficacy of artemether-lumefantrine in area of high malaria endemicity in India and its correlation with blood concentration of lumefantrine.
This study was conducted to correlate blood concentrations of lumefantrine with treatment outcome for patients with Plasmodium falciparum malaria when the drug was given without specific instructions for administration with food. Patients with P. falciparum malaria in the highly endemic state of Orissa, India, were enrolled during 2008 and followed-up for 28 days after admistration of artemether-lumefantrine for three days according to a World Health Organization protocol. Drug concentration in whole blood was determined by using blood spots placed on filter paper on day 7. The technology is suitable for field studies. One hundred percent of the patients had an adequate clinical and parasitological response. These results confirm the efficacy of artemether-lumefantrine in persons from poor tribal communities when given without specific instructions regarding co-administration with food, despite high inter-individual variability in blood concentrations of lumefantrine.


A solid-state dye-sensitized solar cell based on a novel ionic liquid gel and ZnO nanoparticles on a flexible polymer substrate.
This paper describes a new strategy to make a full solid-state, flexible, dye-sensitized solar cell (DSSC) based on novel ionic liquid gel, organic dye, ZnO nanoparticles and carbon nanotube (CNT) thin film stamped onto a polyethylene terephthalate (PET) substrate. The CNTs serve both as the charge collector and as scaffolds for the growth of ZnO nanoparticles, where the black dye molecules are anchored. It opens up the possibility of developing a continuous roll to roll processing for THE mass production of DSSCs.


Neural mechanisms generating respiratory pattern in mammalian brain stem-spinal cord in vitro. I. Spatiotemporal patterns of motor and medullary neuron activity.
1. An analysis of the spatial and temporal patterns of activity of neurons of the respiratory motor-pattern generation system in an in vitro neonatal rat brain stem-spinal cord preparation is presented. Impulse discharge patterns of spinal and cranial moto-neurons as well as respiratory neurons in the medulla were analyzed. Patterns of motoneuronal discharge were characterized at the population level from recordings of motor-nerve discharge and at the single-cell level from intracellular recordings. These patterns were compared to patterns generated in the neonatal rat and adult mammal in vivo to establish the correspondence between in vitro and in vivo states. 2. The in vitro system generated a complex spatiotemporal pattern of spinal and cranial motoneuron activity during inspiratory (I) and expiratory (E) phases of the respiratory cycle. The respiratory cycle consisted of three distinct phases of neuronal activity (I, early E, and late E phase) similar to the temporal organization of the cycle in the intact mammal. The spike discharge pattern of motoneurons during the I phase consisted of a rapidly peaking-slowly decrementing discharge envelope with a high degree of synchronization on a time scale of 25-50 ms (approximately 20-40 Hz). A similar pattern was generated in the neonate in vivo under conditions comparable with the in vitro state (i.e., nervous system isolated from mechanosensory afferent inputs). However, the I-phase-motoneuron discharge pattern and cycle-phase durations differed from those characteristic of the intact neonatal or adult systems in vivo. This difference could be accounted for primarily by removal of vagal mechanosensory afferent inputs. 3. The synaptic drive potentials of spinal motoneurons during the I phase in vitro consisted of a rapidly peaking-slowly decrementing potential envelope similar in shape to the spike-frequency histogram of single motoneurons and the envelope of the motoneuron-population discharge. The drive potentials had prominent high-frequency amplitude fluctuations superimposed on the slower drive-potential envelope that were temporally correlated with the generation of motoneuron action potentials. The dominant frequency components of these fast-membrane-potential oscillations (20-35 Hz) were similar to the frequency components of the amplitude fluctuations in the motoneuron-population discharge. One class of medullary neurons with I-phase discharge also exhibited a rapidly peaking-slowly decrementing pattern of impulse discharge and synaptic drive potential with similar high-frequency components.(ABSTRACT TRUNCATED AT 400 WORDS)


Where Are Adolescents with Soft Tissue Sarcomas Treated? An Italian Nationwide Study on Referrals Based on Hospital Discharge Records.
Purpose: Adolescents (15-19 years) with soft tissue sarcomas (STS) have worse survival than children. One reason is the former's limited access to expert centers. We investigated where adolescents with STS are treated in Italy, analyzing hospital discharge records (HDRs) countrywide. Methods: We applied to the Health Ministry to obtain the HDRs of all adolescents hospitalized in 2002-2015. We excluded prevalent cases hospitalized with STS in 2002-2006 to obtain a cohort of incident cases 2007-2014. We defined main treatments observing 12 months from diagnosis. Thus, the cohorts end in 2014 rather than 2015. We computed "hospital volume" as the number of adolescents treated by a hospital in 8 years. Patient migration across geographical areas was investigated comparing patients' place of residence and of hospitalization. Results: We identified 381 adolescents with STS, 63% of them were treated at AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica [Italian Association of Pediatric Hematology and Oncology]) centers. These patients were treated at 44 different AIEOP centers, with 1 center treating 62 adolescents (26% of all those treated by AIEOP centers). The remaining 142 adolescents with STS were treated at 66 non-AIEOP centers, one of which managed 17 adolescents. Centers in the north of Italy were more likely to attract patients from other regions. Conclusion: Although HDRs have some limitations, they are the only tool for investigating access to care in countries without national cancer registries. Our findings support the use of HDRs for such purposes, confirm the efficacy of the Italian pediatric oncology network, and make the case for closer collaboration between pediatric and adult oncologists.


Passive one-way aberration correction using four-wave mixing.
We have demonstrated a passive method for recovering an optical image that has been degraded by being passed through a thin phase-aberrating medium. This method relies on a point source situated near the object of interest to sample the aberration impressed upon the wave front. Degenerate four-wave mixing in fluorescein-doped boric acid glass was used to reconstruct the wave front.


Base Metal Catalyzed Isocyanide Insertions.
Isocyanides are diverse C1 building blocks considering their potential to react with nucleophiles, electrophiles, and radicals. Therefore, perhaps not surprisingly, isocyanides are highly valuable as inputs for multicomponent reactions (MCRs) and other one-pot cascade processes. In the field of organometallic chemistry, isocyanides typically serve as ligands for transition metals. The coordination of isocyanides to metal centers alters the electronic distribution of the isocyano moiety, and reaction pathways can therefore be accessed that are not possible in the absence of the metal. The tunable reactivity of the isocyanide functional group by transition metals has evolved into numerous useful applications. Especially palladium-catalyzed isocyanide insertion processes have emerged as powerful reactions in the past decade. However, reports on the use of earth-abundant and cheap base metals in these types of transformations are scarce and have received far less attention. In this Minireview, we focus on these emerging base metal catalyzed reactions and highlight their potential in synthetic organic chemistry. Although mechanistic studies are still scarce, we discuss distinct proposed catalytic cycles and categorize the literature according to 1) the (hetero)atom bound to and 2) the type of bonding with the transition metal in which the (formal) insertion occurs.


Vital prognosis in intrathoracic sarcoidosis with special reference to pulmonary function and radiological stage.
A follow-up of 254 patients with intrathoracic sarcoidosis has been carried out after a median of 27 yrs from the diagnostic admission. All patients could be traced. At the end of follow-up there was no excess mortality (80 deaths observed versus 65.5 expected). However, during the first 20 yrs of follow-up a slight excess mortality was seen. Thirty three out of the 80 deaths were related to sarcoidosis. No excess number of deaths from lung cancer or lymphoma was observed. Erythema nodosum was of no prognostic significance concerning survival. X-ray stage was related to survival with a significant excess mortality for stage 3. Early clearing of X-ray changes gave a favourable vital prognosis. Survival was related to lung function, and for forced expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC) index and total lung capacity (TLC) this relationship reached levels of statistical significance. In multivariate Cox regression models, with age and sex entered as covariates, the same parameters were found to be significant predictors of mortality. Patients with FEV1 < or = 50% predicted had an increased mortality risk of 4.2 (95% confidence interval 1.8-9.6) when compared to patients with FEV1 > 80% predicted. Likewise, patients with TLC < or = 80% predicted had a mortality risk of 2.6 (1.5-4.5) when compared to patients with TLC > 80% predicted. In conclusion, a modest excess mortality was observed during the first 20 yrs of follow-up. Furthermore, both X-ray staging and lung function at the time of diagnosis influenced long-term mortality in patients with intrathoracic sarcoidosis.


Scanning near-field optical microscopy.
An average human eye can see details down to 0,07 mm in size. The ability to see smaller details of the matter is correlated with the development of the science and the comprehension of the nature. Today's science needs eyes for the nano-world. Examples are easily found in biology and medical sciences. There is a great need to determine shape, size, chemical composition, molecular structure and dynamic properties of nano-structures. To do this, microscopes with high spatial, spectral and temporal resolution are required. Scanning Near-field Optical Microscopy (SNOM) is a new step in the evolution of microscopy. The conventional, lens-based microscopes have their resolution limited by diffraction. SNOM is not subject to this limitation and can offer up to 70 times better resolution.


Photolysis of caged sphingosine-1-phosphate induces barrier enhancement and intracellular activation of lung endothelial cell signaling pathways.
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates cellular functions by ligation via G protein-coupled S1P receptors. In addition to its extracellular action, S1P also has intracellular effects; however, the signaling pathways modulated by intracellular S1P remain poorly defined. We have previously demonstrated a novel pathway of intracellular S1P generation in human lung endothelial cells (ECs). In the present study, we examined the role of intracellular S1P generated by photolysis of caged S1P on EC barrier regulation and signal transduction. Intracellular S1P released from caged S1P caused mobilization of intracellular calcium, induced activation of MAPKs, redistributed cortactin, vascular endothelial cadherin, and β-catenin to cell periphery, and tightened endothelial barrier in human pulmonary artery ECs. Treatment of cells with pertussis toxin (PTx) had no effect on caged S1P-mediated effects on Ca(2+) mobilization, reorganization of cytoskeleton, cell adherens junction proteins, and barrier enhancement; however, extracellular S1P effects were significantly attenuated by PTx. Additionally, intracellular S1P also activated small GTPase Rac1 and its effector Ras GTPase-activating-like protein IQGAP1, suggesting involvement of these proteins in the S1P-mediated changes in cell-to-cell adhesion contacts. Downregulation of sphingosine kinase 1 (SphK1), but not SphK2, with siRNA or inhibition of SphK activity with an inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (CII) attenuated exogenously administrated S1P-induced EC permeability. Furthermore, S1P1 receptor inhibitor SB649164 abolished exogenous S1P-induced transendothelial resistance changes but had no effect on intracellular S1P generated by photolysis of caged S1P. These results provide evidence that intracellular S1P modulates signal transduction in lung ECs via signaling pathway(s) independent of S1P receptors.


Giant transmural lipoma of the sigmoid colon.
Lipomas of the colon are relatively rare benign tumors of mesenchymatic origin. They are usually asymptomatic but as they become larger they can cause symptoms including abdominal pain, diarrhea, nausea, constipation, haematochezia, loss of body weight, anemia or even intussusception and colonic obstruction. We present a 52 year old male patient who visited the emergency room complaining of constipation, rectal bleeding, mucus in stools and a palpable rectal mass. Colonoscopy revealed a polypoid mass of the sigmoid colon lying about 30 cm from the anal verge. Sigmoidectomy was performed. The postoperative recovery was uneventful and he was discharged five days later. At follow up a month after surgery the patient was asymptomatic. The pathological examination revealed a transmural tumor of the sigmoid colon measuring a 9x5x2.5cm and histologically compatible with a lipoma.


Low operative mortality with implantation of a continuous-flow left ventricular assist device and impact of concurrent cardiac procedures.
The objective of this study was to determine the impact of concurrent cardiac procedures (CCP) on patient outcomes after HeartMate II (HMII) left ventricular assist device implantation. Two hundred eighty-one patients underwent implantation of a HMII as a bridge to transplantation from March 2005 to March 2007. One hundred seventy patients had an HMII implanted only, and 81 patients underwent concurrent cardiac procedures in conjunction with HMII implantation (HMII+CCP). Of these, 47 patients had concurrent valvular procedures, 15 patients had simultaneous closure of patent foramen ovale, and 19 patients had other various cardiac procedures. Patients requiring right ventricular assist device support or noncardiac procedures were excluded. Preoperative characteristics were similar for patients with and without concurrent cardiac procedures. Overall 30-day mortality was 5.8% for the HMII group and 11.3% for the HMII+CCP group. Subgroup analysis demonstrated that simultaneous patent foramen ovale closure was not associated with an increased 30-day mortality rate, but concurrent valvular procedures increased the risk to 8.5%. Patients who underwent an aortic valve procedure had a 30-day mortality rate of 25%, higher than for isolated concurrent mitral (0%) or tricuspid repair (3.3%). Survival at 180 days was 87% for HMII alone and 80% for HMII+CCP. The hazard ratio for concurrent cardiac procedures adjusted for baseline parameters was 1.82 (95% CI, 1.07 to 3.10, P=0.026). There is a low 5.8% operative mortality rate for patients requiring uncomplicated HMII implantation, with no apparent increased risk for concurrent patent foramen ovale closure or mitral or tricuspid repair. However, concurrent aortic valve and other cardiac procedures are associated with significantly decreased perioperative and long-term survival.


CT of the paranasal sinuses and functional endoscopic surgery: a critical analysis of 100 symptomatic patients.
CT scans of 100 patients from the Rhinology Clinic at the Royal National Throat, Nose and Ear Hospital were reviewed in order to test the precepts forming the basis of functional endoscopic sinus surgery, especially as they relate to the radiological investigation. These were: (a) the site of origin of sinus infection, (b) The relevance of certain anatomical variants in the middle meatus to sinus infection and (c) The use of CT as the radiological method of diagnosis in all cases. Obstruction in the middle meatus and ostiomeatal complex was associated with an increased incidence of opacity in the sinuses but the primary site of disease was not established: the concept that sinus disease takes origin in the middle meatus was not proven. Anatomical variants in the middle meatus were not associated with an increase in sinus opacity and there was no evidence that these anomalies have any effect on sinus disease by causing middle meatal stenosis. The radiological assessment of patients with inflammatory naso-sinus disease should start with plain X-ray. CT is unnecessary as a routine examination. It should be reserved for the pre-operative assessment of patients for endoscopic surgery, its main function being to show important anatomical landmarks.


How effect is educational counseling prior to middle ear surgery for patients with both middle ear diseases and consistent tinnitus?
Background: The management of patients with tinnitus who receive middle ear surgery has not been established.Aims: The aim of this study is (1) how many patients who receive middle ear surgery have tinnitus and (2) how educational counselling and middle ear surgery is effective with consistent tinnitus.Subjects and methods: Twenty four cases out of 90 cases accounted for 26.7% of the middle ear diseases scheduled for surgery in the past two years. Of the 42 patients with hearing loss in the second year, 14 had consistent and intermittent tinnitus. Among them we have 6 patients complaining consistent tinnitus and we examined the change in the Tinnitus Handicap Inventory (THI) for patients with tinnitus before and after surgery.Results: Ten out of 13 cases (about 76.9%) reported that postoperative tinnitus improved. THI score in two cases showed worse.Conclusions and significance: Two cases showed worse THI in both mixed hearing loss cases with a small hearing improvement. The mechanism of improvement is similar to tinnitus retraining therapy including hearing aid because the increase in external sound input through hearing restoration after surgery to avoid silence.


Associations Between the Built Environment and Objective Measures of Sleep: The Multi-Ethnic Study of Atherosclerosis.
Although dense neighborhood built environments support increased physical activity and lower obesity, these features may also disturb sleep. Therefore, we sought to understand the association between the built environment and objectively measured sleep. From 2010 to 2013, we analyzed data from examination 5 of the Multi-Ethnic Study of Atherosclerosis, a diverse population from 6 US cities. We fit multilevel models that assessed the association between the built environment (Street Smart Walk Score, social engagement destinations, street intersections, and population density) and sleep duration or efficiency from 1-week wrist actigraphy in 1,889 individuals. After adjustment for covariates, a 1-standard-deviation increase in Street Smart Walk Score was associated with 23% higher odds of short sleep duration (≤6 hours; odds ratio = 1.2, 95% confidence interval: 1.0, 1.4), as well as shorter average sleep duration (mean difference = -8.1 minutes, 95% confidence interval: -12.1, -4.2). Results were consistent across other built environment measures. Associations were attenuated after adjustment for survey-based measure of neighborhood noise. Dense neighborhood development may have multiple health consequence. In promoting denser neighborhoods to increase walkability, it is important to also implement strategies that reduce the adverse impacts of this development on sleep, such as noise reductions efforts.


Minimal detectable change in quadriceps strength and voluntary muscle activation in patients with knee osteoarthritis.
To examine the test-retest reliability and quantify the minimal detectable change (MDC) in quadriceps strength and voluntary activation in patients with knee osteoarthritis (OA). Repeated measures over a 1-week interval. Tertiary care center. A convenience sample of patients (N=20) diagnosed with knee OA. Isokinetic and isometric quadriceps strength testing and voluntary quadriceps activation testing using interpolated twitch technique. Peak isokinetic and isometric knee extension torque (Nm) and percentage of voluntary quadriceps activation (%). The mean differences with 95% confidence intervals between the 2 test sessions for quadriceps isokinetic strength, isometric strength, and percent of voluntary activation were -4.34Nm (-14.01 to 5.34Nm), 1.56Nm (-5.56 to 8.68Nm), and 1.34% (-.53 to 3.22%), respectively. The intraclass correlation coefficients for all measures ranged from .93 to .98. The standard errors of measurement (SEMs) for quadriceps isokinetic and isometric strength were 14.57Nm and 10.76Nm, respectively. The SEM for percentage of voluntary activation was 2.84%. Based on these values, the MDCs were 33.90Nm, 25.02Nm, and 6.60% for quadriceps isokinetic strength, isometric strength, and percentage of voluntary activation, respectively. Maximal quadriceps isokinetic strength, isometric strength, and percentage of voluntary activation measures demonstrate excellent test-retest reliability in patients with knee OA. In addition to research applications, the present findings suggest these measures are appropriate for use when evaluating change in neuromuscular function of the quadriceps in individual patients.


Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept.
Geriatricians have embraced the term "geriatric syndrome," using it extensively to highlight the unique features of common health conditions in older people. Geriatric syndromes, such as delirium, falls, incontinence, and frailty, are highly prevalent, multifactorial, and associated with substantial morbidity and poor outcomes. Nevertheless, this central geriatric concept has remained poorly defined. This article reviews criteria for defining geriatric syndromes and proposes a balanced approach of developing preliminary criteria based on peer-reviewed evidence. Based on a review of the literature, four shared risk factors-older age, baseline cognitive impairment, baseline functional impairment, and impaired mobility-were identified across five common geriatric syndromes (pressure ulcers, incontinence, falls, functional decline, and delirium). Understanding basic mechanisms involved in geriatric syndromes will be critical to advancing research and developing targeted therapeutic options, although given the complexity of these multifactorial conditions, attempts to define relevant mechanisms will need to incorporate more-complex models, including a focus on synergistic interactions between different risk factors. Finally, major barriers have been identified in translating research advances, such as preventive strategies of proven effectiveness for delirium and falls, into clinical practice and policy initiatives. National strategic initiatives are required to overcome barriers and to achieve clinical, research, and policy advances that will improve quality of life for older persons.


TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice.
Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell-independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-β (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.


Recalled sex-typed behavior in childhood and sports' preferences in adulthood of heterosexual, bisexual, and homosexual men from Brazil, Turkey, and Thailand.
This research used interview and questionnaire data from homosexual (n = 177), bisexual (n = 157), and heterosexual (n = 544) men between 20 and 30 years of age among lower class men and university students in three countries: Brazil, Thailand, and Turkey. The main goal of the study was to examine the recalled childhood sex-typed behavior and adult sports preferences that distinguish homosexuals from bisexuals and heterosexuals. In all three cultures and both social groups, homosexual men were almost always more likely as children to have wanted to be a girl, to cross-dress, to play with girls, to do girls' tasks, and to practice fewer sports. They were also less likely to bully others or to engage in physical fights. As children, homosexual men were more likely to prefer swimming and playing volleyball rather than soccer and, as adults, they preferred watching gymnastics and swimming over soccer. The bisexuals scored intermediate mostly in "desire to be a girl" and "cross-dressing," although they were much closer to the heterosexuals. These results, coupled with previous cross-cultural research, suggest that cross-gender behavior in childhood may characterize most male homosexuals regardless of their cultural milieu.


Disruption of the Aspergillus fumigatus RNA interference machinery alters the conidial transcriptome.
The RNA interference (RNAi) pathway has evolved numerous functionalities in eukaryotes, with many on display in Kingdom Fungi. RNAi can regulate gene expression, facilitate drug resistance, or even be altogether lost to improve growth potential in some fungal pathogens. In the WHO fungal priority pathogen, Aspergillus fumigatus, the RNAi system is known to be intact and functional. To extend our limited understanding of A. fumigatus RNAi, we first investigated the genetic variation in RNAi-associated genes in a collection of 217 environmental and 83 clinical genomes, where we found that RNAi components are conserved even in clinical strains. Using endogenously expressed inverted-repeat transgenes complementary to a conditionally essential gene (pabA) or a nonessential gene (pksP), we determined that a subset of the RNAi componentry is active in inverted-repeat transgene silencing in conidia and mycelium. Analysis of mRNA-seq data from RNAi double-knockout strains linked the A. fumigatus dicer-like enzymes (DclA/B) and RNA-dependent RNA polymerases (RrpA/B) to regulation of conidial ribosome biogenesis genes; however, surprisingly few endogenous small RNAs were identified in conidia that could explain this broad change. Although RNAi was not clearly linked to growth or stress response defects in the RNAi knockouts, serial passaging of RNAi knockout strains for six generations resulted in lineages with diminished spore production over time, indicating that loss of RNAi can exert a fitness cost on the fungus. Cumulatively, A. fumigatus RNAi appears to play an active role in defense against double-stranded RNA species alongside a previously unappreciated housekeeping function in regulation of conidial ribosomal biogenesis genes.


A ketogenic diet suppresses seizures in mice through adenosine A₁ receptors.
A ketogenic diet (KD) is a high-fat, low-carbohydrate metabolic regimen; its effectiveness in the treatment of refractory epilepsy suggests that the mechanisms underlying its anticonvulsive effects differ from those targeted by conventional antiepileptic drugs. Recently, KD and analogous metabolic strategies have shown therapeutic promise in other neurologic disorders, such as reducing brain injury, pain, and inflammation. Here, we have shown that KD can reduce seizures in mice by increasing activation of adenosine A1 receptors (A1Rs). When transgenic mice with spontaneous seizures caused by deficiency in adenosine metabolism or signaling were fed KD, seizures were nearly abolished if mice had intact A1Rs, were reduced if mice expressed reduced A1Rs, and were unaltered if mice lacked A1Rs. Seizures were restored by injecting either glucose (metabolic reversal) or an A1R antagonist (pharmacologic reversal). Western blot analysis demonstrated that the KD reduced adenosine kinase, the major adenosine-metabolizing enzyme. Importantly, hippocampal tissue resected from patients with medically intractable epilepsy demonstrated increased adenosine kinase. We therefore conclude that adenosine deficiency may be relevant to human epilepsy and that KD can reduce seizures by increasing A1R-mediated inhibition.


Binding of thrombin to cultured human fibroblasts: evidence for receptor modulation.
Previous work from this laboratory has indicated that thrombin's influence on cell growth can be negative as well as positive. Addition of enzyme to actively growing or confluent cultures of human skin fibroblasts produced growth stimulation, whereas cultures receiving thrombin at the time of subculture displayed inhibited DNA synthesis and mitosis. The specific binding of [125I]thrombin to cells under stimulatory and inhibitory conditions has been studied. Fibroblasts receiving enzyme at subculture bound about two times more [125I]thrombin than those processed in the same way several hours later. The apparent dissociation constant for both groups was approximately 1.5 x 10(-8) M. In each case binding was saturable, although cells receiving enzyme at subculture showed a much higher rate of binding. Experiments were conducted in which enzyme was added to cells at various times after subculture. It was found that the ability of these fibroblasts to specifically bind [125I]thrombin decreased progressively over a 2-h period after subculture and then remained constant for at least 24 h. Evidence is also presented indicating that the binding of [125I]thrombin in both experimental groups was inversely dependent upon the culture density. The biological effects of elevated thrombin binding in cells receiving enzyme at subculture were examined. It was found that inhibited DNA synthesis and altered cellular morphology were directly to this parameter. This study suggests that fibroblasts may possess cryptic thrombin receptors that become exposed during subculture or after injury in vivo. These possibilities and the relationship of cell shape to the availability of thrombin receptors are discussed.


Physician interest in breast cancer screening education. A survey of Vermont family physicians.
A mailed survey of 141 Vermont family physicians (74% participating) was conducted to determine their breast cancer screening practices and beliefs and their interest in receiving training in breast cancer screening. Of these, only 12% reported that at least three fourths of their female patients older than 50 years received mammograms at least once a year, compared with 33% who reported providing breast self-examination instruction and 35% who administered clinical breast examination with at least three fourths of these patients at least once a year. Nevertheless, 55% of the physicians rated mammography as a very effective breast-screening procedure; 28% rated breast self-examination and 16% rated clinical breast examination as very effective. Three fourths of the physicians showed great interest in learning more about breast palpation, breast self-examination instruction, and mammography. Individual instruction in the office was preferred over a group workshop format, and a trained nonphysician health professional was considered as acceptable as a physician to provide the instruction. Results suggest that breast cancer screening education for family physicians is a high priority, and that physicians will welcome such training, particularly if it is office-based.


Scalable combinatorial tools for health disparities research.
Despite staggering investments made in unraveling the human genome, current estimates suggest that as much as 90% of the variance in cancer and chronic diseases can be attributed to factors outside an individual's genetic endowment, particularly to environmental exposures experienced across his or her life course. New analytical approaches are clearly required as investigators turn to complicated systems theory and ecological, place-based and life-history perspectives in order to understand more clearly the relationships between social determinants, environmental exposures and health disparities. While traditional data analysis techniques remain foundational to health disparities research, they are easily overwhelmed by the ever-increasing size and heterogeneity of available data needed to illuminate latent gene x environment interactions. This has prompted the adaptation and application of scalable combinatorial methods, many from genome science research, to the study of population health. Most of these powerful tools are algorithmically sophisticated, highly automated and mathematically abstract. Their utility motivates the main theme of this paper, which is to describe real applications of innovative transdisciplinary models and analyses in an effort to help move the research community closer toward identifying the causal mechanisms and associated environmental contexts underlying health disparities. The public health exposome is used as a contemporary focus for addressing the complex nature of this subject.


Transforaminal Epidural Steroid Injections: A Systematic Review and Meta-Analysis of Efficacy and Safety.
Transforaminal epidural injections have been used since the late 1990s to treat lumbar radicular pain. They have been the subject of considerable attention, with varying conclusions from systematic reviews as to their efficacy. Transforaminal injections have been associated with rare but major complications. Further, the use of transforaminal injections has increased since the passage of the Affordable Care Act. Finally, with the SARS-CoV-2 pandemic, there has been heightened concern regarding the risk associated with steroid injections. To evaluate and update the effectiveness of transforaminal injections for 4 indications: radicular pain; from spinal stenosis; from failed back surgery syndrome; and for axial low back pain; and to evaluate the safety of the procedure. A systematic review and meta-analysis of the efficacy of transforaminal injections. The available literature on transforaminal injections was reviewed and the quality assessed. The level of evidence was classified on a 5-point scale based on the quality of evidence developed by the US Preventive Services Task Force (USPSTF) and modified by the American Society of Interventional Pain Physicians (ASIPP). Data sources included relevant literature from 1966 to April 2020, and manual searches of the bibliographies of known primary and review articles. Pain relief and functional improvement were the primary outcome measures. A minimum of 6 months pain relief follow-up was required. For this systematic review, 66 studies were identified. Eighteen randomized controlled trials met the inclusion criteria. No observational studies were included. Eleven randomized controlled trials dealt with various aspects of transforaminal injections for radicular pain owing to disc herniation. Based on these studies, there is Level 1 evidence supporting the use of transforaminal injections for radicular pain owing to disc herniation. A meta-analysis showed that at both 3 and 6 months, there was highly statistically significant improvement in both pain and function with both particulate and nonparticulate steroids. For radicular pain from central stenosis there is one moderate quality study, with Level IV evidence. For radicular pain caused by failed back surgery syndrome there is one moderate quality study, with Level IV evidence. For radicular pain from foraminal stenosis and for axial pain there is Level V evidence, opinion-based/consensus, supporting the use of transforaminal injections. Transforaminal injections are generally safe. However, they have been associated with major neurologic complications related to cord infarct. Causes other than intraluminal injection of particulates appear to be at play. The use of an infraneural approach and of blunt needles appear to offer the greatest patient safety. Because of concern over the role of particulate steroids, multiple other injectates have been evaluated, including nonparticulate steroids, tumor necrosis factor alpha (TNF-a) inhibitors, and local anesthetics without steroids. No injectate has been proven superior. If there is concern about immunosuppression because of risk of COVID-19 infection, either the lowest possible dose of steroid or no steroid should be used. The study was limited by the paucity of literature for some indications. There is Level I evidence for the use of transforaminal injections for radicular pain from disc herniations.


Designed divergent evolution of enzyme function.
It is generally believed that proteins with promiscuous functions divergently evolved to acquire higher specificity and activity, and that this process was highly dependent on the ability of proteins to alter their functions with a small number of amino acid substitutions (plasticity). The application of this theory of divergent molecular evolution to promiscuous enzymes may allow us to design enzymes with more specificity and higher activity. Many structural and biochemical analyses have identified the active or binding site residues important for functional plasticity (plasticity residues). To understand how these residues contribute to molecular evolution, and thereby formulate a design methodology, plasticity residues were probed in the active site of the promiscuous sesquiterpene synthase gamma-humulene synthase. Identified plasticity residues were systematically recombined based on a mathematical model in order to construct novel terpene synthases, each catalysing the synthesis of one or a few very different sesquiterpenes. Here we present the construction of seven specific and active synthases that use different reaction pathways to produce the specific and very different products. Creation of these enzymes demonstrates the feasibility of exploiting the underlying evolvability of this scaffold, and provides evidence that rational approaches based on these ideas are useful for enzyme design.


CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies. Desmoplasia and tumor-supporting inflammation are hallmarks of PDAC. The tumor microenvironment contributes significantly to tumor progression and spread. Cancer-associated fibroblasts (CAFs) facilitate therapy resistance and metastasis. Recent reports emphasized the concurrence of multiple subtypes of CAFs with diverse roles, fibrogenic, and secretory. C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor known for its role during inflammation and its adverse role in PDAC. Oncogenic Kras upregulates CXCR2 and its ligands and, thus, contribute to tumor proliferation and immunosuppression. CXCR2 deletion in a PDAC syngeneic mouse model produced increased fibrosis revealing a potential undescribed role of CXCR2 in CAFs. In this study, we demonstrate that the oncogenic Kras-CXCR2 axis regulates the CAFs function in PDAC and contributes to CAFs heterogeneity. We observed that oncogenic Kras and CXCR2 signaling alter CAFs, producing a secretory CAF phenotype with low fibrogenic features; and increased secretion of pro-tumor cytokines and CXCR2 ligands, utilizing the NF-κB activity. Finally, using syngeneic mouse models, we demonstrate that oncogenic Kras is associated with secretory CAFs and that CXCR2 inhibition promotes activation of fibrotic cells (myofibroblasts) and impact tumors in a mutation-dependent manner.


[Clinical evaluation of cefixime (CFIX) in the treatment of urinary tract infection].
Cefixime (CFIX, Cefspan), a new oral cephem, was used in the treatment of urinary tract infections, and was evaluated for its therapeutic effectiveness and safety at the Department of Urology, Osaka University Hospital and 16 affiliated hospitals. A total of 238 patients were administered daily doses of 200 or 400 mg. Clinical efficacy was assessed on 92 female patients with acute uncomplicated cystitis and 42 patients with complicated UTI according to the Criteria for Clinical Evaluation of Antimicrobial Agents in UTI (3rd ed.) recommended by the Japan UTI Committee, to which we added our own minimum modification. Clinical efficacy was evaluated as excellent in 57 of the acute uncomplicated cystitis cases, moderate in 33 and poor in 2, with an overall clinical effectiveness rate of 98%. Clinical efficacy was evaluated as excellent in 12 of the complicated UTI cases moderate in 12 and poor in 18, with an overall clinical effectiveness rate of 57%. In one case of uncomplicated pyelonephritis, CFIX showed an excellent efficacy. Of the total of 102 bacterial strains isolated from uncomplicated UTIs, 95 (93%) were eradicated by CFIX, while 36 (72%) eradicated in 50 strains isolated from complicated UTIs. Subjective adverse reactions were seen in 4 cases (1.7%) of the 236 patients, as generalized pruritus and upper gastrointestinal discomforts. Abnormal laboratory findings were recorded in 6 out of 141 cases. They were increases in serum GPT, GOT, alkaline phosphatases, total bilirubin, as well as increases in peripheral leukocytes. These adverse symptoms and abnormal laboratory findings disappeared after the termination of CFIX administration. CFIX might therefore be considered as a clinically useful oral antibiotic in the treatment of UTI.


Simultaneous existence of phononic and photonic band gaps in periodic crystal slabs.
We discuss the simultaneous existence of phononic and photonic band gaps in a periodic array of holes drilled in a Si membrane. We investigate in detail both the centered square lattice and the boron nitride (BN) lattice with two atoms per unit cell which include the simple square, triangular and honeycomb lattices as particular cases. We show that complete phononic and photonic band gaps can be obtained from the honeycomb lattice as well as BN lattices close to honeycomb. Otherwise, all investigated structures present the possibility of a complete phononic gap together with a photonic band gap of a given symmetry, odd or even, depending on the geometrical parameters.


A smartphone-based quantitative detection platform of mycotoxins based on multiple-color upconversion nanoparticles.
The detection of mycotoxins in food is urgently needed because they pose a significant threat to public health. In this study, we developed a quantitative detection platform for mycotoxins by integrating multicolor upconversion nanoparticle barcode technology with fluorescence image processing using a smartphone-based portable device. The multi-colored upconversion nanoparticle encoded microspheres (UCNMs) were used as encoded signals for detecting different mycotoxins simultaneously. After indirect competitive immunoassays using UCNMs, images could be captured by the portable device and the camera of a smartphone. Then, a self-written Android application, which is an HSV-based image recognition program installed on a smartphone, analyzed images and offered a reliable and accurate result in less than 1 min. The quantitative detection platform of mycotoxins proved to be feasible and reliable, and the limit of detection (LOD) was 1 ng, which was lower than that obtained from standard assays. This study demonstrates a method for detecting mycotoxins in food and other point of care analysis.


Rho/Rho kinase as a potential target for the treatment of renal disease.
The small G-protein Rho and its downstream effector Rho kinase constitute important mediators not only of vascular contraction but also of actin cytoskeleton reorganization, cellular morphology, motility, adhesion and proliferation. The Rho/Rho kinase pathway plays an important role in the structure and function of various kidney cells including tubular epithelial cells, mesangial cells and podocytes. The Rho/Rho kinase pathway also regulates glomerular blood flow and glomerular filtration rate by modulating renal arteriolar contractility. Potent and specific inhibitors of Rho kinase have recently been developed and their therapeutic effects on a variety of renal injury models have been examined. In the rat models of hypertensive glomerulosclerosis, unilateral ureteral obstruction (for interstitial renal fibrosis) and ischemia/reperfusion acute renal failure, treatment with novel Rho kinase inhibitors attenuates the development of renal damage. Although human data connecting the activation of Rho/Rho kinase pathway and kidney disease are still lacking, these studies have provided compelling evidence for the renoprotective effects of Rho kinase inhibitors.


A cross-lagged panel analysis of children's sleep, attention, and mood in a prenatally stressed cohort: The QF2011 Queensland flood study.
It is well recognized that childhood sleep, attention and mood problems increase risk for multiple adverse outcomes across the life-span; therefore, understanding factors, such as prenatal maternal stress, that underlie these types of childhood problems is critical for developing interventions that may optimize longer-term functioning. Our goal was to determine the association between disaster-related stress in pregnancy and young children's sleep, attention, and anxious/depressed symptoms. Soon after a major flood in Australia in 2011, we assessed various aspects of disaster-related prenatal maternal stress (PNMS) in women who had been pregnant at the time. Mothers rated several domains of their children's development with the Child Behavior Checklist (CBCL) at ages 2½ (n = 134) and 4 years (n = 118). The primary finding was that more severe objective flood-related hardship in pregnancy predicted higher sleep problem scores at 2½ years, and that a negative maternal cognitive appraisal of the flood predicted lower attention problem scores at 2½ years. A cross-lagged panel analysis examined the association between children's sleep, attention, and anxious/depressed symptoms within and across ages. Results showed that these problems were likely to co-occur at each age, and that they were stable from 2½ to 4 years. Additionally, anxious/depressed scores at age 2½ predicted sleep problem scores at 4 years, all else being equal. Limitations of the study include a relatively small sample size and the children's outcome data relied on maternal report using the CBCL, rather than independent observation of the children's functioning, which may have introduced reporter bias. These findings highlight the importance of early intervention for these childhood problems to optimize long-term mental health, particularly under conditions of prenatal stress.


Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation.
PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel⁻/⁻). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel⁻/⁻ melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.


Legalization of marijuana: potential impact on youth.
As experts in the health care of children and adolescents, pediatricians may be called on to advise legislators concerning the potential impact of changes in the legal status of marijuana on adolescents. Parents, too, may look to pediatricians for advice as they consider whether to support state-level initiatives that propose to legalize the use of marijuana for medical purposes or to decriminalize possession of small amounts of marijuana. This policy statement provides the position of the American Academy of Pediatrics on the issue of marijuana legalization, and the accompanying technical report (available online) reviews what is currently known about the relationship between adolescents' use of marijuana and its legal status to better understand how change might influence the degree of marijuana use by adolescents in the future.


A significant component of ageing (DNA damage) is reflected in fading breeding colors: an experimental test using innate antioxidant mimetics in painted dragon lizards.
A decade ahead of their time, von Schantz et al. united sexual selection and free radical biology by identifying causal links between deep-rooted physiological processes that dictate resistance to toxic waste from oxidative metabolism (reactive oxygen species, ROS), and phenotypic traits, such as ornaments. Ten years later, these ideas have still only been tested with indirect estimates of free radical levels (oxidative stress) subsequent to the action of innate and dietary antioxidants. Here, we measure net superoxide (a selection pressure for antioxidant production) and experimentally manipulate superoxide antioxidation using a synthetic mimetic of superoxide dismutase (SOD), Eukarion 134 (EUK). We then measure the toxic effect of superoxide in terms of DNA erosion and concomitant loss of male breeding coloration in the lizard, Ctenophorus pictus. Control males suffered more DNA damage than EUK males. Spectroradiometry showed that male coloration is lost in relation to superoxide and covaries with DNA erosion; in control males, these variables explained loss of color, whereas in EUK males, the fading of coloration was unaffected by superoxide and unrelated to DNA damage. Thus, EUK's powerful antioxidation removes the erosion effect of superoxide on coloration and experimentally verifies the prediction that colors reflect innate capacity for antioxidation.


Response of an Escherichia coli-bound fluorescent probe to colicin E1.
The fluorescent probe, 8-anilino-1-napthalenesulfonate (ANS) binds to Escherichia coli, showing an enhanced fluorescence. The interaction of colicin E1 with sensitive cells causes an increase of about 100% in the fluorescence of the bound ANS, and this change at equilibrium has an apparent "all-or-none" nature as a function of E1 multiplicity. Approximately 6 to 8% of the ANS is bound to the cells at equilibrium. The colicin E1-induced fluorescence increase can be attributed partly to an increase in ANS binding and partly to an increase in the fluorescence yield of the bound ANS. The kinetics of the E1-induced fluorescence increase in sensitive cells are very similar to those of the adenosine triphosphate decrease. The phosphorylation uncoupler p-trifluoromethoxy-carbonylcyanidephenylhydrazone also causes a large change in the fluorescence of bound ANS. Colicin E2 or E3 does not cause any fluorescence change, nor does colicin E1 cause fluorescence change with a colicinogenic strain. ANS appears to be a probe of structural or conformational change in the cell envelope that is closely associated with the colicin E1-induced adenosine triphosphate decrease.


A huge lymphangioma mimicking pleural effusion with extension to both chest cavities: a case report and review of literature.
Mediastinal lymphangioma is primarily a benign lesion and the majority of the cases are found incidentally. These lesions account for approximately 1% of all mediastinal tumors. Here we present a giant mediastinal cystic mass in a 35-year-old female who was presented with severe respiratory distress. On the plain chest radiography and CT scan, a massive left pleural effusion with large parasternal and mediastinal lymphadenopathy was seen. Thoracentesis was performed and 400 cm³ of clear fluid was drained from the left hemithorax. However, a subsequent CT scan with contrast and the same technique 40 days later showed a large cystic mass in the mediastinum protruding to the right and left hemi thoraces. The giant cystic mass was resected via right and left anterior thoracotomies. Histopathological examination revealed a diagnosis of lymphangioma. The patient has been alive and without tumor recurrence and has been followed for 2 years.


Pathway to clozapine use: a comparison between a patient cohort from New Zealand and a cohort from the United Kingdom.
Clozapine has been available since the early 1990s. Studies continue to demonstrate its superior efficacy in treatment-resistant schizophrenia. Despite this, numerous studies show under-utilisation, delayed access and reluctance by psychiatrists to prescribe clozapine. This retrospective cross-sectional study compared the prescribing of clozapine in two adult cohorts under the care of large public mental health services in Auckland (New Zealand) and Birmingham (United Kingdom) on 31 March 2007. Time from first presentation to clozapine initiation, prior antipsychotics trialled and antipsychotic co-prescribing were compared. Data included demographics, psychiatric diagnosis, co-morbid conditions, year of first presentation, admissions and pharmacological treatment (clozapine dose, start date, prior antipsychotics, co-prescribed antipsychotic). Overall, 664 people were prescribed clozapine (402 Auckland; 262 Birmingham); mean daily dose of 384 mg (Auckland) and 429 mg (Birmingham). 53 % presented after 1990 and the average duration of time before starting clozapine was significantly longer in the Birmingham cohort (6.5 vs. 5.3 years) but this reduced in both cohorts to a 1-year mean in those presenting within the last 3 years. The average number of antipsychotics trialled pre-clozapine for those presenting since 1990 was significantly higher in the Birmingham cohort (4.3 vs. 3.1) but in both cohorts this similarly reduced in those presenting within the last 3 years. Antipsychotic co-prescribing was significantly higher in the Birmingham cohort (22.9 vs. 10.7 %). There is evidence that access to clozapine has improved over time in both cohorts, with a reduction in the duration between presentation and initiation of clozapine and number of different antipsychotics trialled pre-clozapine. These are very positive findings in terms of optimising outcomes with clozapine and are possibly due to the impact of guideline recommendations, increasing clinician, consumer and carer knowledge, and experience with clozapine and funding changes.


Orally administered Lactobacillus rhamnosus modulates the respiratory immune response triggered by the viral pathogen-associated molecular pattern poly(I:C).
Some studies have shown that probiotics, including Lactobacillus rhamnosus CRL1505, had the potential to beneficially modulate the outcome of certain bacterial and viral respiratory infections. However, these studies did not determine the mechanism(s) by which probiotics contribute to host defense against respiratory viruses. In this work we demonstrated that orally administered Lactobacillus rhamnosus CRL1505 (Lr1505) was able to increase the levels of IFN-γ, IL-10 and IL-6 in the respiratory tract and the number of lung CD3(+)CD4(+)IFN-γ(+) T cells. To mimic the pro-inflammatory and physiopathological consecuences of RNA viral infections in the lung, we used an experimental model of lung inflammation based on the administration of the artificial viral pathogen-associated molecular pattern poly(I:C). Nasal administration of poly(I:C) to mice induced a marked impairment of lung function that was accompanied by the production of pro-inflammatory mediators and inflammatory cell recruitment into the airways. The preventive administration of Lr1505 reduced lung injuries and the production of TNF-α, IL-6, IL-8 and MCP-1 in the respiratory tract after the challenge with poly(I:C). Moreover, Lr1505 induced a significant increase in lung and serum IL-10. We also observed that Lr1505 was able to increase respiratory IFN-γ levels and the number of lung CD3(+)CD4(+)IFN-γ(+) T cells after poly(I:C) challenge. Moreover, higher numbers of both CD103(+) and CD11b(high) dendritic cells and increased expression of MHC-II, IL-12 and IFN-γ in these cell populations were found in lungs of Lr1505-treated mice. Therefore, Lr1505 treatment would beneficially regulate the balance between pro-inflammatory mediators and IL-10, allowing an effective inflammatory response against infection and avoiding tissue damage. Results showed that Lr1505 would induce a mobilization of cells from intestine and changes in cytokine profile that would be able to beneficially modulate the respiratory mucosal immunity. Although deeper studies are needed using challenges with respiratory viruses, the results in this study suggest that Lr1505, a potent inducer of antiviral cytokines, may be useful as a prophylactic agent to control respiratory virus infection.


Non-invasive imaging of cardiac transgene expression with PET: comparison of the human sodium/iodide symporter gene and HSV1-tk as the reporter gene.
Genes encoding for intracellular enzymes or transmembrane proteins are suitable as reporters, but may differ in terms of applicability for cardiac imaging. The aim of this study was to compare the human sodium iodide symporter gene (hNIS) with the herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) as the reporter gene in non-invasive imaging of cardiac transgene expression with positron emission tomography (PET). Equal doses of adenoviral vectors encoding for hNIS, wild-type HSV1-tk, mutant HSV1-sr39tk or LacZ as the control gene were directly injected into the myocardium of 34 animals. Two days later, dynamic PET was performed with a clinical scanner, using reporter probes specific for the respective reporter gene. Imaging with (13)N-ammonia was also performed to identify cardiac regions of interest. Kinetics differed significantly: (124)I as the probe for hNIS showed rapid early uptake, remaining stable over time. Maximal myocardial concentration was 3.61+/-1.15%. The nucleoside (18)F-FHBG, as the specific probe for HSV1-sr39tk, showed increasing uptake over time, but maximal accumulation was significantly lower (1.45+/-0.54%, P=0.0009). (124)I-FIAU, as the specific probe for wild-type HSV1-tk, showed early uptake with subsequent washout. Maximal accumulation was lowest (0.63+/-0.23%, P<0.0001). Post-mortem analysis by autoradiography and gamma counting confirmed the in vivo data. Reporter genes encoding for transporter proteins such as hNIS are an attractive alternative to overexpression of intracellular enzymes for cardiac gene product imaging. hNIS yielded higher signal intensity and imaging contrast for PET than did HSV1-tk and HSV1-sr39tk. Therefore, this approach may be preferable for the future monitoring of cardiac gene- or cell-based therapy.


100 years of training and development research: What we know and where we should go.
Training and development research has a long tradition within applied psychology dating back to the early 1900s. Over the years, not only has interest in the topic grown but there have been dramatic changes in both the science and practice of training and development. In the current article, we examine the evolution of training and development research using articles published in the Journal of Applied Psychology (JAP) as a primary lens to analyze what we have learned and to identify where future research is needed. We begin by reviewing the timeline of training and development research in JAP from 1918 to the present in order to elucidate the critical trends and advances that define each decade. These trends include the emergence of more theory-driven training research, greater consideration of the role of the trainee and training context, examination of learning that occurs outside the classroom, and understanding training's impact across different levels of analysis. We then examine in greater detail the evolution of 4 key research themes: training criteria, trainee characteristics, training design and delivery, and the training context. In each area, we describe how the focus of research has shifted over time and highlight important developments. We conclude by offering several ideas for future training and development research. (PsycINFO Database Record


Essential role for a long-term depression mechanism in ocular dominance plasticity.
The classic example of experience-dependent cortical plasticity is the ocular dominance (OD) shift in visual cortex after monocular deprivation (MD). The experimental model of homosynaptic long-term depression (LTD) was originally introduced to study the mechanisms that could account for deprivation-induced loss of visual responsiveness. One established LTD mechanism is a loss of sensitivity to the neurotransmitter glutamate caused by internalization of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Although it has been shown that MD similarly causes a loss of AMPARs from visual cortical synapses, the contribution of this change to the OD shift has not been established. Using an herpes simplex virus (HSV) vector, we expressed in visual cortical neurons a peptide (G2CT) designed to block AMPAR internalization by hindering the association of the C-terminal tail of the AMPAR GluR2 subunit with the AP2 clathrin adaptor complex. We found that G2CT expression interferes with NMDA receptor (NMDAR)-dependent AMPAR endocytosis and LTD, without affecting baseline synaptic transmission. When expressed in vivo, G2CT completely blocked the OD shift and depression of deprived-eye responses after MD without affecting baseline visual responsiveness or experience-dependent response potentiation in layer 4 of visual cortex. These data suggest that AMPAR internalization is essential for the loss of synaptic strength caused by sensory deprivation in visual cortex.


Mutations in VANGL1 associated with neural-tube defects.
Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting. In a protein-protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3. These findings implicate VANGL1 as a risk factor in human neural-tube defects.


Phrenic neuropathy and diaphragm dysfunction in neuralgic amyotrophy.
To describe the clinical phenotype and recovery of diaphragm dysfunction caused by neuralgic amyotrophy in a large cohort of patients, to improve accurate awareness of this entity, and to encourage adoption of a standardized approach for diagnosis and treatment. This observational cohort study recruited adult patients with neuralgic amyotrophy and symptoms of idiopathic phrenic neuropathy from the database of the Dutch expert center for neuralgic amyotrophy and the Dutch centers for home mechanical ventilation. Demographic and clinical information on diagnosis, symptoms, and recovery was obtained from chart review. We attempted to contact all patients for a follow-up interview. Phrenic neuropathy occurs in 7.6% of patients with neuralgic amyotrophy. Unilateral diaphragmatic dysfunction and bilateral diaphragmatic dysfunction are frequently symptomatic, causing exertional dyspnea, orthopnea, disturbed sleep, and excessive fatigue. Diagnostic practices varied widely and were often not optimally targeted. The majority of patients experienced at least moderate recovery within 2 years. We recommend screening every patient with neuralgic amyotrophy for diaphragm dysfunction by asking about orthopnea and by performing upright and supine vital capacity screening and diaphragm ultrasound in cases of suspected phrenic neuropathy to optimize diagnosis and care.


Fungicide Sensitivity of Pythium spp. Associated with Cavity Spot of Carrot in California and Michigan.
The identity of 172 isolates of Pythium spp. from cavity spot lesions on carrot produced in California and Michigan was determined, and their sensitivity to three fungicides was examined. Pythium violae accounted for 85% of California isolates, with P. irregulare, P. dissotocum (the first report as a carrot pathogen in the United States), P. ultimum, and P. sulcatum making the balance. P. sulcatum, P. sylvaticum, and P. intermedium were the most commonly recovered (85%) species in Michigan; others from Michigan included P. intermedium, P. irregulare, and an unclassified strain, M2-05. On fungicide-amended media, 93% of isolates were sensitive to mefenoxam (inhibition of mycelial growth was >60% at 10 μg active ingredient [a.i.]/ml); however, two of five isolates of P. irregulare from California were highly resistant (≤60% inhibition at 100 μg a.i./ml); about half of the isolates of P. intermedium and P. sylvaticum and a single isolate of P. violae were highly or intermediately resistant to mefenoxam (>60% inhibition at 100 μg a.i./ml, or ≤60% inhibition at 10 μg a.i./ml). P. dissotocum, P. irregulare, P. sulcatum, M2-05, and three of seven isolates of P. intermedium were insensitive to fluopicolide (effective concentrations for 50% growth inhibition [EC50] were >50 μg a.i./ml), while P. sylvaticum, P. ultimum, P. violae, and some isolates in P. intermedium were sensitive (EC50 < 1 μg a.i./ml). All isolates were sensitive to zoxamide (EC50 < 1 μg a.i./ml). Sensitivity baselines of P. violae to zoxamide and fluopicolide were established.


Disease progression in HIV-infected patients treated with stavudine vs. zidovudine.
This prospective, observational study compared disease progression and death in HIV-1 patients treated with stavudine vs. zidovudine in the Collaborations in HIV Outcomes Research/U.S. (CHORUS) cohort. Patients with a first occurrence of CD4 count <500 cells/microL (n=3301) were grouped as: no nucleoside reverse transcriptase inhibitor (NRTI) use; other NRTI without stavudine or zidovudine; stavudine with no zidovudine, with or without other NRTIs; and zidovudine with no stavudine, with or without other NRTIs. The risk for death or disease progression was evaluated in unadjusted analyses and using a Cox proportional hazards model, adjusting for: study site, age, gender, race, route of HIV infection, previous AIDS-defining conditions, number of previous antiretroviral regiments, CD4 count, HIV-1 RNA, and treatment variables. Sensitivity analyses were conducted to determine the sensitivity of the results to major modeling assumptions. A landmark analysis was conducted to determine the absolute difference in time to event. During a median follow-up of 2.4 years, there were 57 deaths and 348 AIDS-defining conditions in 405 patients. Stavudine treatment compared with zidovudine resulted in a greater percentage of patients with AIDS-defining events (14.5 vs. 10.9%; P=.013), and an increased risk of disease progression (HR=1.30; 95% CI: 1.01,1.7; P=.04). This result was not sensitive to modeling assumptions. Landmark analysis demonstrated an absolute difference in time to 95% event-free survival of 2.7 months for those with a CD4< or =200 cells/microL and 11 months for those 6 months after model entry. In unadjusted and adjusted analyses of 3301 HIV-1 infected patients, stavudine containing combination therapy was associated with an increased risk of disease progression or death compared to therapy containing zidovudine. Most of the difference was attributable to new cases of wasting.