Structured simulation improves learning of the Fundamental Use of Surgical Energy™ curriculum: a multicenter randomized controlled trial.
Energy devices can result in devastating complications to patients. Yet, they remain poorly understood by trainees and surgeons. A single-institution pilot study suggested that structured simulation improves knowledge of the safe use of electrosurgery (ES) among trainees (Madani et al. in Surg Endosc 28(10):2772-2782, 2014). The purpose of this study was to estimate the extent to which the addition of this structured bench-top simulation improves ES knowledge across multiple surgical training programs. Trainees from 11 residency programs in Canada, the USA and UK participated in a 1-h didactic ES course, based on SAGES' Fundamental Use of Surgical Energy™ (FUSE) curriculum. They were then randomized to one of two groups: an unstructured hands-on session where trainees used ES devices (control group) or a goal-directed hands-on training session (Sim group). Pre- and post-curriculum (immediately and 3 months after) knowledge of the safe use of ES was assessed using separate examinations. Data are expressed as mean (SD) and N (%), *p < 0.05. A total of 289 (145 control; 144 Sim) trainees participated, with 186 (96 control; 90 Sim) completing the 3-month assessment. Baseline characteristics were similar between the two groups. Total score on the examination improved from 46% (10) to 84% (10)* for the entire cohort, with higher post-curriculum scores in the Sim group compared with controls [86% (9) vs. 83% (10)*]. All scores declined after 3 months, but remained higher in the Sim group [72% (18) vs. 64% (15)*]. Independent predictors of 3-month score included pre-curriculum score and participation in a goal-directed simulation. This multi-institutional study confirms that a 2-h curriculum based on the FUSE program improves surgical trainees' knowledge in the safe use of ES devices across training programs with various geographic locations and resident volumes. The addition of a structured interactive bench-top simulation component further improved learning.


[From rhinitis to asthma, one or two diseases?].
Rhinitis and asthma commonly coexist in allergic patients. This observation might be attributable to their coexistence in time, but it is also possible that both diseases are the opposite poles of a single disease affecting the respiratory system, or even an anomalous systemic immune response to the allergen. Nose-lung interactions have been widely studied from epidemiological, physiopathological, aetiological and pharmacological aspects. In the present article we review this topic and its main clinical implications.


Cortical oscillatory activity and the induction of plasticity in the human motor cortex.
Repetitive transcranial magnetic stimulation paradigms such as continuous theta burst stimulation (cTBS) induce long-term potentiation- and long-term depression-like plasticity in the human motor cortex. However, responses to cTBS are highly variable and may depend on the activity of the cortex at the time of stimulation. We investigated whether power in different electroencephalogram (EEG) frequency bands predicted the response to subsequent cTBS, and conversely whether cTBS had after-effects on the EEG. cTBS may utilize similar mechanisms of plasticity to motor learning; thus, we conducted a parallel set of experiments to test whether ongoing electroencephalography could predict performance of a visuomotor training task, and whether training itself had effects on the EEG. Motor evoked potentials (MEPs) provided an index of cortical excitability pre- and post-intervention. The EEG was recorded over the motor cortex pre- and post-intervention, and power spectra were computed. cTBS reduced MEP amplitudes; however, baseline power in the delta, theta, alpha or beta frequencies did not predict responses to cTBS or learning of the visuomotor training task. cTBS had no effect on delta, theta, alpha or beta power. In contrast, there was an increase in alpha power following visuomotor training that was positively correlated with changes in MEP amplitude post-training. The results suggest that the EEG is not a useful state-marker for predicting responses to plasticity-inducing paradigms. The correlation between alpha power and changes in corticospinal excitability following visuomotor training requires further investigation, but may be related to disengagement of the somatosensory system important for motor memory consolidation.


"Run to the hills": Specific contributions of anticipated energy expenditure during active spatial learning.
Grounded views of cognition consider that space perception is shaped by the body and its potential for action. These views are substantiated by observations such as the distance-on-hill effect, described as the overestimation of visually perceived uphill distances. An interpretation of this phenomenon is that slanted distances are overestimated because of the integration of energy expenditure cues. The visual perceptual processes involved are, however, usually tackled through explicit estimation tasks in passive situations. The goal of this study was to consider instead more ecological active spatial processing. Using immersive virtual reality and an omnidirectional treadmill, we investigated the effect of anticipated implicit physical locomotion cost by comparing spatial learning for uphill and downhill routes, while maintaining actual physical cost and walking speed constant. In the first experiment, participants learnt city layouts by exploring uphill or downhill routes. They were then tested using a landmark positioning task on a map. In the second experiment, the same protocol was used with participants who wore loaded ankle weights. The results from the first experiment showed that walking uphill routes led to a global underestimation of distances compared with downhill routes. This inverted distance-of-hill effect was not observed in the second experiment, where an additional effort was applied. These results suggest that the underestimation of distances observed in Experiment 1 emerged from recalibration processes whose function was to solve the transgression of proprioceptive predictions linked with uphill energy expenditure. The results are discussed in relation to constructivist approaches on spatial representations and predictive coding theories.


Pesticide fate and transport throughout unsaturated zones in five agricultural settings, USA.
Pesticide transport through the unsaturated zone is a function of chemical and soil characteristics, application, and water recharge rate. The fate and transport of 82 pesticides and degradates were investigated at five different agricultural sites. Atrazine and metolachlor, as well as several of the degradates of atrazine, metolachlor, acetochlor, and alachlor, were frequently detected in soil water during the 2004 growing season, and degradates were generally more abundant than parent compounds. Metolachlor and atrazine were applied at a Nebraska site the same year as sampling, and focused recharge coupled with the short time since application resulted in their movement in the unsaturated zone 9 m below the surface. At other sites where the herbicides were applied 1 to 2 yr before sampling, only degradates were found in soil water. Transformations of herbicides were evident with depth and during the 4-mo sampling time and reflected the faster degradation of metolachlor oxanilic acid and persistence of metolachor ethanesulfonic acid. The fraction of metolachlor ethanesulfonic acid relative to metolachlor and metolachlor oxanilic acid increased from 0.3 to >0.9 at a site in Maryland where the unsaturated zone was 5 m deep and from 0.3 to 0.5 at the shallowest depth. The flux of pesticide degradates from the deepest sites to the shallow ground water was greatest (3.0-4.9 micromol m(-2) yr(-1)) where upland recharge or focused flow moved the most water through the unsaturated zone. Flux estimates based on estimated recharge rates and measured concentrations were in agreement with fluxes estimated using an unsaturated-zone computer model (LEACHM).


Prenatal exposure to maternal voluntary exercise during pregnancy provides protection against mild chronic postnatal hypoxia in rat offspring.
Postnatal hypoxia is a main cause of neuronal damage in newborn. However, our understanding of the possible preventive or therapeutic methods to reduce the harmful effects of hypoxia is still primary. Pregnant rats were provided with running wheels during their pregnancy. On PND4 (postnatal day 4)to PND8, the rat pups were exposed to postnatal chronic hypoxia (11% O(2), 89% N(2)) in an air-tight plastic chamber for a period of six hours per day. The number of neurons and also angiogenesis in hippocampus were studied. Postnatal exposure to mild hypoxia decreased the number of the neurons in all studied regions of the hippocampus CA1, CA3 (cornu ammonis), DG(dentate gyrus) and SUB(cubiculum) in rat pups. In other words the number of the neurons in rat pups born from voluntary exercise group was not significantly less than control group in CA1, CA3 and DG regions. So maternal Voluntary exercise during pregnancy increases the blood vessel density in the DG region of the hippocampus of the rat pups. In this study for the first time we provide evidences that show the protective effect of maternal voluntary exercise during pregnancy on rat offspring against postnatal hypoxia. We revealed that maternal exercise during pregnancy increases the hippocampal neuron number and angiogenesis in offspring.


Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart.
We previously demonstrated that alpha 6 (Cx45), one of the three connexins of the mammalian myocardium, is preferentially expressed in the peripheral portion of the ventricular conduction system in rats and mice. Here we report that alpha 6 is also prominently immunolocalized in the atrioventricular node and His bundle of these species. The distribution of immunolocalized alpha 6 reveals that the node and bundle form part of an extended central conductive network circumscribing the AV and outflow junctional regions of the fetal, and less continuously, the adult heart. Of the three cardiac connexins, alpha 6 is the isoform most continuously expressed by conduction tissues, and may thus account for the recently reported viability of the alpha 5 (Cx40) knockout mouse. It is concluded that alpha 6 expression is a defining feature of the heterogenous tissues comprising the atrioventricular conduction system of the rodent heart.


Characterization of polypeptides serologically and structurally related to hexosaminidase in cultured fibroblasts.
Human fibroblasts synthesize several polypeptides that assort into the various forms of hexosaminidase (hex). We report here the occurrence of three newly identified, hexosaminidase-related polypeptides resolved by sodium dodecyl sulfate-poly-acrylamide gel electrophoresis of immunoprecipitates from [35S]methionine-labeled cell extracts. These polypeptides, called band 2 (75,000), band 3 (70,000), and band 4 (63,000), were immunoprecipitated by an antiserum specific to placental hex I2. They are distinct from pre-alpha- (60,000) and pre-beta- (58,000) precursor polypeptides and the alpha- (56,000), beta a- (27,000), and beta b- (27,000) polypeptides of the mature hex A (alpha beta a beta b) and hex B (2[beta a beta b]). When fibroblast extracts were chromatographed on DEAE-Sepharose, bands 2, 3, and 4 were eluted together in fractions before hex A, in a position characteristic of serum and placental hex I2 and serum hex P. This suggests that bands 2, 3, and 4 might represent the polypeptides of a fibroblast hex I. The analysis of partial proteolytic digests of the radioactively labeled polypeptides revealed that bands 2 and 3, pre-beta, and beta a had several peptides in common, suggesting that they are structurally related to each other. However, bands 2, 3, and 4 were present in extracts of Tay-Sachs (pre-alpha and alpha deficiency) and Sandhoff cells (pre-beta, beta a, and beta b deficiency) and appeared later than pre-beta in pulse-chase experiments. These results suggest that bands 2 and 3 occur independently of pre-beta and beta a and are probably specified by different mRNA, whether from the same gene or distinct but homologous genes.


Targeting the host response in sepsis: current approaches and future evidence.
Sepsis, a dysregulated host response to infection characterized by organ failure, is one of the leading causes of death worldwide. Disbalances of the immune response play an important role in its pathophysiology. Patients may develop simultaneously or concomitantly states of systemic or local hyperinflammation and immunosuppression. Although a variety of effective immunomodulatory treatments are generally available, attempts to inhibit or stimulate the immune system in sepsis have failed so far to improve patients' outcome. The underlying reason is likely multifaceted including failure to identify responders to a specific immune intervention and the complex pathophysiology of organ dysfunction that is not exclusively caused by immunopathology but also includes dysfunction of the coagulation system, parenchymal organs, and the endothelium. Increasing evidence suggests that stratification of the heterogeneous population of septic patients with consideration of their host response might led to treatments that are more effective. The purpose of this review is to provide an overview of current studies aimed at optimizing the many facets of host response and to discuss future perspectives for precision medicine approaches in sepsis.


Cost-efficient vision screening for astigmatism in native american preschool children.
To design and test a cost-efficient, community-based vision screening program for a population of Native American preschool children in which there is a high prevalence of astigmatism. Based on analysis of vision screening and eye examination data from a preschool population with a 33% prevalence of astigmatism, comparative costs to conduct a 1000-child screening program with a target sensitivity of 90% were estimated for photoscreening, noncycloplegic autorefraction, autokeratometry, and Lea symbols distance visual acuity testing. Results of the cost analysis and examination of sensitivity and specificity data from the preschool population led to development of a hybrid screening program of autokeratometry and visual acuity screening with referral thresholds of 2.25 D of corneal astigmatism or inability to read a 20/63 Lea symbols line on two separate attempts. The screening program was prospectively implemented in a community-based screening of a similar cohort of 167 children, and its efficiency was evaluated by comparison to results of cycloplegic refraction. The community-based screening showed 96.8% sensitivity and 79.2% specificity for detecting the presence of refractive astigmatism of 1.50 D or more. Referring children who have at least 2.25 D of corneal astigmatism or acuity worse than 20/63 on two attempts, provides the high sensitivity and specificity associated with automated keratometry while maintaining an acuity component that can detect other causes of reduced acuity in the absence of astigmatism.


[High performance liquid chromatographic determination of astromicin and piperacillin used in combination in blood samples].
Aminoglycoside and beta-lactam antibiotics are often used in combination, and many synergistic effects have been reported. We describe here a high performance liquid chromatographic determination method for each of astromicin (ASTM) and piperacillin (PIPC) in blood samples of several species. The procedure for ASTM included purification with CM-Sephadex, separation on a reversed phase column (C-18) and derivatization with o-phthalaldehyde (OPA). The procedure for PIPC included deproteinization with acetonitrile, centrifugation and separation on a reversed phase column (C-18). Either of the drugs did not affect the determination of the other. The detection limits were 0.1 microgram/ml for ASTM and 0.5 microgram/ml for PIPC. These sensitivities seem good enough for a clinical application of the method considering usual dosage levels of these drugs.


Boundaries of schizoaffective disorder: revisiting Kraepelin.
Established nosology identifies schizoaffective disorder as a distinct category with boundaries separating it from mood disorders with psychosis and from schizophrenia. Alternative models argue for a single boundary distinguishing mood disorders with psychosis from schizophrenia (kraepelinian dichotomy) or a continuous spectrum from affective to nonaffective psychosis. To identify natural boundaries within psychotic disorders by evaluating associations between symptom course and long-term outcome. The Suffolk County Mental Health Project cohort consists of first-admission patients with psychosis recruited from all inpatient units of Suffolk County, New York (72% response rate). In an inception cohort design, participants were monitored closely for 4 years after admission, and their symptom course was charted for 526 individuals; 10-year outcome was obtained for 413. Global Assessment of Functioning (GAF) and other consensus ratings of study psychiatrists. We used nonlinear modeling (locally weighted scatterplot smoothing and spline regression) to examine links between 4-year symptom variables (ratio of nonaffective psychosis to mood disturbance, duration of mania/hypomania, depression, and psychosis) and 10-year outcomes. Nonaffective psychosis ratio exhibited a sharp discontinuity-10 days or more of psychosis outside mood episodes predicted an 11-point decrement in GAF-consistent with the kraepelinian dichotomy. Duration of mania/hypomania showed 2 discontinuities demarcating 3 groups: mania absent, episodic mania, and chronic mania (manic/hypomanic >1 year). The episodic group had a better outcome compared with the mania absent and chronic mania groups (12-point and 8-point difference on GAF). Duration of depression and psychosis had linear associations with worse outcome. Our data support the kraepelinian dichotomy, although the study requires replication. A boundary between schizoaffective disorder and schizophrenia was not observed, which casts further doubt on schizoaffective diagnosis. Co-occurring schizophrenia and mood disorder may be better coded as separate diagnoses, an approach that could simplify diagnosis, improve its reliability, and align it with the natural taxonomy.


Curcumin exhibits antimetastatic properties by modulating integrin receptors, collagenase activity, and expression of Nm23 and E-cadherin.
Curcumin (diferuloyl methane), the major pigment from the rhizome of Curcuma longa L., has been widely studied for its tumor-inhibiting properties. Recent studies indicate that curcumin can modify cell receptor binding, it also affects intracellular signalling reactions. Curcumin-treated B16F10 melanoma cells formed eight-fold fewer lung metastases in C57BL6 mice. In the cell adhesion assays, curcumin-treated cells showed a dose-dependent reduction in their binding to four extracellular matrix (ECM) proteins. The binding to fibronectin, vitronectin, and collagen IV decreased by over 50% in 24 hours, and by 100% after 48 hours of curcumin treatment, it persisted at this level even after 15 days of cultivating cells in curcumin-free medium. Curcumin-treated cells showed a marked reduction in the expression of alpha5beta1 and alpha(v)beta3 integrin receptors. In addition, curcumin treatment inhibited pp125 focal adhesion kinase (FAK), tyrosine phosphorylation of a 120 kD protein, and collagenase activity. Curcumin enhances the expression of antimetastatic proteins, tissue inhibitor metalloproteinase (TIMP)-2, nonmetastatic gene 23 (Nm23), and E-cadherin. In this article we report on the effect of curcumin on the expression of integrin, TIMP-2, Nm23, E-cadherin, adhesion, and metalloproteinase activity.


Expression of monocarboxylate transporters I and IV and the ancillary protein CD147 in the intestinal tract of healthy horses and ponies.
To characterize the expression of monocarboxylate transporters (MCTs) 1 and 4 and the ancillary protein CD147 in the intestinal tract of healthy equids and determine the cellular location of CD147 in the intestinal epithelium. 12 healthy horses and ponies slaughtered for meat production or euthanized for reasons unrelated to gastrointestinal tract disease. The entire gastrointestinal tract was removed from each equid within 45 minutes after slaughter or euthanasia. Tissue samples were obtained from the antimesenteric side of the duodenum, jejunum, ileum, middle part of the cecum, sternal flexure of the ventral colon, pelvic flexure, sternal flexure of the dorsal colon, and descending colon (small colon). Expressions of MCT1, MCT4, and the ancillary protein CD147 were examined in tissue samples from each of the 8 intestinal locations by means of quantitative PCR assay, immunoblotting, and immunohistochemical analyses. Expression of MCT1 was most abundant in the cecum and colonic sites, whereas expression of MCT4 was predominantly in the proximal section of the intestine (small intestinal sites and cecum). Immunohistochemical analysis revealed that MCT1 and CD147 were present in the membranes of enterocytes (in crypts and villi). The anatomic distribution of MCT1 and MCT4 in the equine intestinal tract determined in this study together with the previous knowledge of the sites of substrate absorption indicated that MCT1 might predominantly contribute to the uptake of short-chain fatty acids in the large intestine and MCT4 might predominantly contribute to the uptake of lactate in the small intestine.


Design and study of the efflux function of the EGFP fused MexAB-OprM membrane transporter in Pseudomonas aeruginosa using fluorescence spectroscopy.
Multidrug membrane transporters (efflux pumps) can selectively extrude a variety of structurally and functionally diverse substrates (e.g., chemotoxics, antibiotics), leading to multidrug resistance (MDR) and ineffective treatment of a wide variety of diseases. In this study, we have designed and constructed a fusion gene (egfp-mexB) of N-terminal mexB with C-terminal egfp, inserted it into a plasmid vector (pMMB67EH), and successfully expressed it in the ΔMexB (MexB deletion) strain of Pseudomonas aeruginosa to create a new strain that expresses MexA-(EGFP-MexB)-OprM. We characterized the fusion gene using gel electrophoresis and DNA sequencing, and determined its expression in live cells by measuring the fluorescence of EGFP in single live cells using fluorescence microscopy. Efflux function of the new strain was studied by measuring its accumulation kinetics of ethidium bromide (EtBr, a pump substrate) using fluorescence spectroscopy, which was compared with cells (WT, ΔMexM, ΔABM, and nalB1) with various expression levels of MexAB-OprM. The new strain shows 6-fold lower accumulation rates of EtBr (15 μM) than ΔABM, 4-fold lower than ΔMexB, but only 1.1-fold higher than WT. As the EtBr concentration increases to 40 μM, the new strain has nearly the same accumulation rate of EtBr as ΔMexB, but 1.4-fold higher than WT. We observed the nearly same level of inhibitory effect of CCCP (carbonyl cyanide-m-chlorophenylhydrazone) on the efflux of EtBr by the new strain and WT. Antibiotic susceptibility study shows that the minimum inhibitory concentrations (MICs) of aztreonam (AZT) and chloramphenicol (CP) for the new strain are 6-fold or 3-fold lower than WT, respectively, and 2-fold higher than those of ΔMexB. Taken together, the results suggest that the fusion protein partially retains the efflux function of MexAB-OprM. The modeled structure of the fusion protein shows that the position and orientation of the N-terminal fused EGFP domain may either partially block the translocation pore or restrict the movement of the individual pump domains, which may lead to partially restricted efflux activity.


Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infection.
Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain the last available therapy for some patients with multi-resistant S. aureus infections. Using comparative and functional genomics we investigated the molecular determinants of resistance and SCV formation in sequential S. aureus isolates from a patient who had a persistent and recurrent S. aureus infection, after failed therapy with multiple antimicrobials, including linezolid. Two point mutations in key staphylococcal genes dramatically affected clinical behaviour of the bacterium, altering virulence and antimicrobial resistance. Most strikingly, a single nucleotide substitution in relA (SACOL1689) reduced RelA hydrolase activity and caused accumulation of the intracellular signalling molecule guanosine 3', 5'-bis(diphosphate) (ppGpp) and permanent activation of the stringent response, which has not previously been reported in S. aureus. Using the clinical isolate and a defined mutant with an identical relA mutation, we demonstrate for the first time the impact of an active stringent response in S. aureus, which was associated with reduced growth, and attenuated virulence in the Galleria mellonella model. In addition, a mutation in rlmN (SACOL1230), encoding a ribosomal methyltransferase that methylates 23S rRNA at position A2503, caused a reduction in linezolid susceptibility. These results reinforce the exquisite adaptability of S. aureus and show how subtle molecular changes cause major alterations in bacterial behaviour, as well as highlighting potential weaknesses of current antibiotic treatment regimens.


Beneficial impact of term labor: nonenzymatic antioxidant reserve in the human fetus.
Oxidative stress occurs when the production of damaging free radicals and other oxidative molecules exceeds the capacity of the body's antioxidant defenses. Oxidative stress is implicated in diseases that are associated with prematurity (such as retinopathy, cerebral palsy, intraventricular hemorrhage, and necrotizing enterocolitis). Nonenzymatic antioxidant reserve is the first line of defense against free radicals. We hypothesized that an in utero redox imbalance because of stress would diminish the fetal antioxidant reserve. We tested aspects of this hypothesis by investigating whether the presence of labor or gestational age at delivery (term vs preterm) alters the maternal/fetal nonenzymatic antioxidant reserve peripartum. Fetal redox consumption was calculated from the difference in the nonenzymatic antioxidant reserve that was measured in umbilical venous and arterial blood that was collected prospectively at delivery from 39 newborn infants. Eight women were delivered at term by elective cesarean delivery in the absence of labor; 31 women labored either at term (n = 20) or preterm (<37 weeks, n = 11). Maternal venous blood was collected on admission and within 1 hour of delivery. Nonenzymatic antioxidant reserve was measured in the plasma and red blood cells of each specimen by the quantitation of glutathione content (glutathione in red blood cell lysate) and the plasma total free radical-trapping antioxidant potential. Glutathione was measured with the use of a colorimetric assay and expressed in nanomoles per milligram of hemoglobin. The plasma total radical-trapping antioxidant potential was estimated with the use of a controlled, kinetic assay based on the time that was required to inhibit peroxyl-free radical generated under controlled conditions. The differences between both umbilical venous and umbilical arterial total radical-trapping antioxidant potential and glutathione were computed to estimate fetal nonenzymatic antioxidant reserve consumption. The differences between maternal total radical-trapping antioxidant potential and glutathione before and after delivery were computed to estimate maternal peripartal nonenzymatic antioxidant reserve consumption. Fetal red blood cell glutathione content was significantly greater than maternal red blood cell glutathione content, independent of delivery route. The calculation of the fetal nonenzymatic antioxidant reserve consumption and maternal peripartal nonenzymatic antioxidant reserve consumption revealed that women who labored at term experienced an up-regulation in red blood cell glutathione content, while their fetuses had significantly lower red blood cell glutathione consumption. In contrast, there was consumption of plasma antioxidants in preterm fetuses, as illustrated by a doubling of the fetal nonenzymatic antioxidant reserve consumption (elective cesarean delivery in the absence of labor, 0.9 +/- 0.5 min/microL; term labor, 1.0 +/- 0.1 min/microL; preterm labor, 2.0 +/- 0.4 min/microL; one-way analysis of variance; P =.04). This was mostly due to a lower umbilical arterial total radical-trapping antioxidant potential in preterm versus term fetuses (umbilical arterial, 3.3 min/microL versus umbilical venous 5.4 min/microL; paired t test; P =.001; power, 0.98). Generally, maternal total radical-trapping antioxidant potential remained unchanged peripartum. Term labor triggers a compensatory up-regulation of nonenzymatic antioxidant reserve in the fetal red blood cell compartment that may act to protect against the relative hyperoxia that is experienced by the newborn infant at birth. In contrast, the decreased nonenzymatic antioxidant reserve in the fetal red blood cell and plasma compartments after preterm labor and delivery would enhance the vulnerability to free radical damage of the preterm neonate. These findings suggest that the two compartments of nonenzymatic antioxidant reserve have distinct physiologic roles in the peripartal defense against free radicals and that their development is, in some fashion, ontogenes, in some fashion, ontogenetically regulated.


Self-Efficacy Among Caregivers of Children With Food Allergy: A Cohort Study.
The prevalence of pediatric food allergy (FA) is increasing and, due to early disease onset, requires significant caregiver management that is associated with psychosocial burden. Caregiver perception of how they cope and handle FA-related events (self-efficacy) has been linked to psychosocial outcomes in racially/geographically homogenous samples. This study explores FA-related caregiver self-efficacy and associations with FA-related caregiver quality of life (QoL) in a diverse cohort. Caregivers of children, diagnosed with IgE-mediated FA who identified as non-Hispanic Black or White, were recruited from U.S. academic allergy clinics. Caregivers completed demographic and medical questionnaires, the Food Allergy Self-Efficacy Scale for Parents (FASE-P), Food Allergy Independent Measure-Parent Form (FAIM), and the Food Allergy Quality of Life-Parental Burden (FAQL-PB). Bivariate and multivariate associations estimated relationships between study variables. Caregivers of 365 children (Mage = 5.8 years, 62.2% male, 31.1% Black) were enrolled. Caregivers reported high FA self-efficacy (M = 82.06/100), moderate perceptions of risk/FA severity (FAIM: M = 3.9/7), and some limitations on the FAQL-PB (M = 3.9/7). Self-efficacy was related to lower perceptions of risk/FA severity across all demographic groups (r = -.42, p < .001). Caregivers who reported higher self-efficacy reported better QoL, particularly Black caregivers (r = .67). In this sample of caregivers of children with FA, greater self-efficacy was related to improved QoL regardless of sociodemographic factors. Caregivers' perception of risk was lower for those with greater self-efficacy. Future research into the impact of FA management on QoL among diverse caregivers is needed.


Hyperthermia adds to chemotherapy.
The hallmarks of hyperthermia and its pleotropic effects are in favour of its combined use with chemotherapy. Preclinical research reveals that for heat killing and synergistic effects the thermal dose is most critical. Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential. The induction of genetically defined stress responses can deliver danger signals to activate the host's immune system. The positive results of randomised trials have definitely established hyperthermia in combination with chemotherapy as a novel clinical modality for the treatment of cancer. Hyperthermia targets the action of chemotherapy within the heated tumour region without affecting systemic toxicity. In specific clinical settings regional hyperthermia (RHT) or hyperthermic perfusion has proved its value and deserve a greater focus and investigation in other malignancies. In Europe, more specialised centres should be created and maintained as network of excellence for hyperthermia in the field of oncology.


Synthesis of a specific monolithic column with artificial recognition sites for L-glutamic acid via cryo-crosslinking of imprinted nanoparticles.
In this study, a new molecular imprinting (MIP)-based monolithic cryogel column was prepared using chemically crosslinked molecularly imprinted nanoparticles, to achieve a simplified chromatographic separation (SPE) for a model compound, L-glutamic acid (L-Glu). Cryogelation through crosslinking of imprinted nanoparticles forms stable monolithic cryogel columns. This technique reduces the leakage of nanoparticles and increases the surface area, while protecting the structural features of the cryogel for stable and efficient recognition of the template molecule. A non-imprinted monolithic cryogel column (NIP) was also prepared, using non-imprinted nanoparticles produced without the addition of L-Glu during polymerization. The molecularly imprinted monolithic cryogel column (MIP) indicates apparent recognition selectivity and a good adsorption capacity compared to the NIP. Also, we have achieved a significant increase in the adsorption capacity, using the advantage of high surface area of the nanoparticles.


Multiple variations in the branching pattern of the abdominal aorta.
We report on a unique clinically and surgically significant case of multiple abdominal aorta variations. Specifically, the left inferior phrenic, left gastric and splenic artery arose in common from the left aspect of the aorta constituting a common phrenogastrosplenic trunk, while the common hepatic artery originated separately from the midline of the anterior aspect of the aorta just inferiorly to the trunk. An accessory right hepatic artery arises from the right-anterior aspect of the abdominal aorta adjacent to superior mesenteric artery origin. On the left side, two renal arteries were observed. Moreover, the left gonadal artery exhibited a high origin, arising inferiorly to the upper left renal artery. We discuss about the embryological development of abdominal aorta arterial abnormalities and we attempt to sort the noticed variations according to existing classification in the literature. It is highlighted that the thorough knowledge of these arterial variations is important for the success of upper abdomen surgical operations such as liver and kidney transplantation, kidney preservation, abdominal aorta related vascular surgery, treatment of hepatocellular carcinoma by transcatheter arterial chemoembolizations as well as imaging interpretation of the region. Preoperative selective angiography or other abdominal aorta imaging studies are helpful for arterial variation demonstration and a precious tool for appropriate surgery planning.


Correlation between chromatin association and transcriptional regulation for the Act3p/Arp4 nuclear actin-related protein of Saccharomyces cerevisiae.
Actin-related proteins (Arps), which share a basal structure with actin but have distinct functions, have been found in a wide variety of organisms. While their functions are not yet clear, some Arps are localized in the nucleus and are suggested to contribute to the regulation of transcription. An essential gene of Saccharomyces cerevisiae, Act3p/Arp4, encodes the first identified nuclear Arp, which has been shown to bind to core histones in vitro. Here we have analyzed the in vivo function of Act3p/Arp4 on the his4-912delta promoter. Chromatin immunoprecipitation assays show that Act3p/Arp4 is bound to the entire his4-912delta promoter region. Conditional act3/arp4 mutations affect transcription from the his4-912delta promoter, where decreased Act3p/Arp4 binding and a change in nuclease sensitivity of chromatin were observed, showing the involvement of Act3p/Arp4 in the regulation of gene expression through the organization of chromatin structure. Taken together with the presence of Act3p/Arp4 in chromatin remodeling and histone acetyltransferase complexes, it is suggested that Act3p/Arp4 functions in transcriptional regulation to recruit chromatin remodeling and histone acetyltransferase complexes onto chromatin.


Drinking status and fatal crashes: which drinkers contribute most to the problem?
The object of this study was to estimate the relative contribution of various classes of drinkers (including those with alcohol-use disorders) to alcohol-related fatal motor vehicle crashes. Using the National Epidemiologic Survey on Alcohol and Related Conditions conducted in 2000, the percentage of state residents falling into six nonoverlapping alcohol-user categories-dependent drinkers, abusive drinkers, dependent and abusive drinkers, heavy episodic drinkers, current normative drinkers, and current nondrinkers- was determined based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, classifications. The percentage of residents in each state in each of these user categories and their relationships to the number of drinking drivers involved in fatal crashes in that state were determined through regression analysis using data from the Fatality Analysis Reporting System. The proportion of drinkers in a state in each of the six consumption categories was positively related to the number of drinking drivers in fatal crashes in that state. Conversely, the percentage of the state's population who were current nondrinkers was negatively related to the number of drinking road users in crashes. Although alcohol abusive and heavy episodic drinkers had substantially higher associations with impaired drivers in fatal crashes, half of such drivers were associated with the percentage of current nominative drinkers in the state. Despite the relevancy of these findings, they must be qualified by statistical limitations associated with the use of state as the unit of analysis.


Association of Distance from Transplantation Center and Place of Residence on Outcomes after Allogeneic Hematopoietic Cell Transplantation.
Regionalization of specialized health services can deliver high-quality care but may have an adverse impact on access and outcomes because of distance from the regional centers. In the case of hematopoietic cell transplantation (HCT), the effect of increased distance between the transplantation center and the rural/urban residence is unclear because of conflicting results from the existing studies. We examined the association between distance from primary residence to the transplantation center and rural versus urban residence with clinical outcomes after allogeneic HCT in a large cohort of patients. Overall mortality (OM), nonrelapse mortality (NRM), and relapse in all patients and those who survived for 200 days after HCT were assessed in 2849 patients who received their first allogeneic HCT between 2000 and 2010 at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance. Median distance from FHCRC was 263 miles (range, 0 to 2740 miles) and 83% of patients were urban residents. The association between distance and the hazard of OM varied according to conditioning intensity: myeloablative (MA) versus nonmyeloablative (NMA). Among MA patients, there was no evidence of an increased risk of mortality with increased distance, but for NMA patients, the results did show a suggestion of increased risk of mortality for some distances, although globally the difference was not statistically significant. In the subgroup of patients who survived 200 days, there was no evidence that the risks of OM, relapse, or NRM were increased with increasing distance. We did not find any association between longer distance from transplantation center and urban/rural residence and outcomes after MA HCT. In patients undergoing NMA transplantations, this relationship and how it is influenced by factors such as age, payers, and comorbidities needs to be further investigated.


Clustering of disability caused by unintentional injury among 15- to 60-year-old: a challenge in rapidly developing countries.
Little is known about disability caused by unintentional injury (accidents) worldwide. This study estimates the prevalence of disability caused by unintentional injury amongst people aged 15-60 years across different cities in the People's Republic of China with the aim of providing a scientific basis for developing prevention and control programmes. The prevalence of disability caused by unintentional injury in this target group in sampled cities across the country was estimated from data from the Second Chinese National Sample Survey on Disability. Using the statistical evolution tree approach, cities automatically clustered into a tree structure according to the level of social security and industrial structure. The Kruskal- Wallis test was applied to compare the prevalence in various types of city. The results show that the prevalence of disability due to unintentional injury in the target population group varied significantly across the 16 types of city investigated, but that it was particularly common among the unemployed and poor. With regard to occupational structure, cities with activities oriented towards transport and construction had the highest average prevalence despite access to local, relatively sound social security systems and adequate medical resources. It was also found that people struck by unintentional injury were treated in various ways depending on the availability of social assistance, medical care and job training, which differed widely between cities depending on each city's main occupational activity. High-risk cities areas were identified for that would benefit particularly by additional medical resource allocation as it would reduce their burden of unintentional injury.


Autoimmune pancreatitis accompanied with recurrence of bladder cancer: difficulty in diagnosis and management of systemic lesions in a case with autoimmune pancreatitis.
A case of autoimmune pancreatitis develops a hepatic metastasis of bladder cancer resected over 5 years before, mimicking a pseudotumor of the liver. A 71-year-old man with a surgical history of bladder cancer (pT4, G2>3, N (+)) later developed autoimmune pancreatitis. Diagnosis of autoimmune pancreatitis was not problematic; however, a variety of systemic disorders appeared after the onset of autoimmune pancreatitis, possibly associated with autoimmune disorder or steroid therapy. These included pancreatic stone attack, septic shock due to ureteral stenosis, and bloody phlegm due to a lung aspergilloma. These events were not easily controlled but were managed with clinical efforts. In the following course, pelvic lymph nodes gradually enlarged and a hepatic mass occurred at 5 years and 6 months after total cystectomy. Several candidates were considered for the hepatic lesion including inflammatory pseudotumor, cholangiocellular carcinoma, and hepatic adenoma. However, percutaneous biopsy confirmed metastasis of the bladder cancer. In general, recurrence after 5 years following cystectomy is extremely rare in cases of pT4 bladder cancer with lymph node metastasis. Patients of autoimmune pancreatitis display various problematic scenarios in diagnosis and long-term management, not only for their pancreatic lesions but also for systemic lesions.


Effects of ractopamine hydrochloride and zilpaterol hydrochloride supplementation on carcass cutability of calf-fed Holstein steers.
Effects of ractopamine hydrochloride (RH) and zilpaterol hydrochloride (ZH) on saleable yield of carcass sides from calf-fed Holstein steers were evaluated using steers implanted with a progesterone (100 mg) plus estradiol benzoate (10 mg) implant followed by a terminal trenbolone acetate (200 mg) plus estradiol (40 mg) implant. Steers were blocked by weight into pens (n = 32) randomly assigned to one of four treatments: control, RH fed at 300 mg•steer(-1)/d(-1) (RH 300) or RH fed at 400 mg•steer(-1)/d(-1) (RH 400) the final 31 d of finishing, and ZH fed at 60 to 90 mg•steer(-1)/d(-1) (7.56 g/ton on a 100% DM basis) for 21 d with a 5 d withdrawal before harvest. Eight to nine carcass sides were randomly selected from each pen; carcass sides with excessive hide pulls, fat pulls or bruises were avoided. Cutout data were collected within a commercial facility using plant personnel to fabricate sides at a rate of one every 3 to 4 min into items typically merchandised by the facility. All lean, fat and bone were weighed and summed back to total chilled side weight with a sensitivity of ± 2% to be included in the data set. Compared to controls, β-agonists increased saleable yield of whole-muscle cuts by 0.61%, 0.86% and 1.95% for RH 300, RH 400 and ZH, respectively (P < 0.05). Percent fat was less in carcasses from the ZH treatment compared to controls (P < 0.05); however, this difference was not observed between RH treatments and controls (P > 0.05). Percent bone was less in the ZH treatment due to increased muscle (P < 0.05). The percent of chilled side weight comprised of trimmings was unchanged between treatments, but on a 100% lean basis, RH 400 and ZH increased trim yields (P < 0.05). Analysis of saleable yield by primal showed a fundamental shift in growth and development. Beta-agonists caused a shift in proportion of saleable yield within individual primals, with a greater portion produced from the hindquarter relative to the forequarter, specifically in those muscles of the round (P < 0.05). Beta-agonists increased saleable yield, but these effects were not constant between all major primals. The cutout value gained by packers as a result of β-agonist use may be influenced more by reduced fatness and increased absolute weight if musculature is primarily increased in the lower priced cuts of the carcass.


Increased rate of significant findings on brain MRI during the early stage of the COVID-19 pandemic.
To assess the effect of the COVID-19 pandemic on the proportion of abnormal paediatric neuroimaging findings as a surrogate marker for potential underutilisation. Consecutive paediatric brain MRIs performed between March 27th and June 19th 2019 (Tbaseline) and March 23rd and June 1st 2020 (Tpandemic) were reviewed and classified according to presence or absence and type of imaging abnormality, and graded regarding severity on a 5-point Likert scale, where grade 4 was defined as abnormal finding requiring non-urgent intervention and grade 5 was defined as acute illness prompting urgent medical intervention. Non-parametric statistical testing was used to assess for significant differences between Tpandemic vs. Tbaseline. Fewer paediatric MRI brains were performed during Tpandemic compared to Tbaseline (12.2 vs 14.7 examinations/day). No significant difference was found between the two time periods regarding sex and age (Tbaseline: 557 females (44.63%), 7.95 ± 5.49 years, Tpandemic: 385 females (44.61%), 7.64 ± 6.11 years; p = 1 and p = .079, respectively). MRI brain examinations during Tpandemic had a higher likelihood of being abnormal, 41.25% vs. 25.32% (p<.0001). Vascular abnormalities were more frequent during Tpandemic (11.01% vs 8.01%, p = .02), congenital malformations were less common (8.34% vs 12.34%, p = .004). Severity of MRI brain examinations was significantly different when comparing group 4 and group 5 individually and combined between Tbaseline and Tpandemic (p = .0018, p < .0001, and p <.0001, respectively). The rate of abnormality and severity found on paediatric brain MRI was significantly higher during the early phase of the pandemic, likely due to underutilisation.


Fibroblast growth factor 23 and new-onset chronic kidney disease in the general population: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.
Fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone that increases early in the course of chronic kidney disease (CKD), is associated with disease progression in patients with established CKD. Here we aimed to investigate the association between plasma FGF23 and new-onset CKD in the general population. We included 5253 individuals without CKD who participated in the Prevention of Renal and Vascular Endstage Disease study, a prospective, population-based cohort. Multi-variable Cox regression was used to study the association of plasma C-terminal FGF23 with new-onset CKD, defined as a combined endpoint of estimated glomerular filtration rate (eGFR) <60 mL/min/ 1.73 m2, urinary 24-h albumin excretion (UAE) >30 mg/24 h or both, or with all-cause mortality. The median baseline FGF23 was 68 [interquartile range (IQR) 56-85] RU/mL, eGFR was 95 ± 13 mL/min/1.73 m2 and UAE was 7.8 (IQR 5.8-11.5) mg/24 h. After follow-up of 7.5 (IQR 7.2-8.0) years, 586 participants developed CKD and 214 participants died. A higher FGF23 level was associated with new-onset CKD, independent of risk factors for kidney disease and parameters of bone and mineral homoeostasis {fully adjusted hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.10-1.44] per doubling of FGF23; P = 0.001}. In secondary analyses, FGF23 was independently associated with new-onset eGFR <60 mL/min/1.73 m2 [adjusted HR 1.28 (95% CI 1.00-1.62); P = 0.048] or with UAE >30 mg/24 h [adjusted HR 1.24 (95% CI 1.06-1.45); P = 0.01] individually. A higher FGF23 level was also associated with an increased risk of all-cause mortality [fully adjusted HR 1.30 (95% CI 1.03-1.63); P = 0.03]. High FGF23 levels are associated with an increased risk of new-onset CKD and all-cause mortality in this prospective population-based cohort, independent of established CKD risk factors.


Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC.
Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.


Co-Administration of Clomiphene Citrate and Letrozole in Mild Ovarian Stimulation Versus Conventional Controlled Ovarian Stimulation Among POSEIDON Group 4 Patients.
This retrospective study assessed the effect of the co-administration of clomiphene citrate (CC) and letrozole in mild ovarian stimulation, compared to conventional regimens, among Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) Group 4 patients. There were 114 POSEIDON Group 4 patients undergoing in vitro fertilization treatments with 216 stimulation cycles recruited from a Taiwan's reproductive center during 2016-2020. Main outcomes were the numbers, quality of retrieved oocytes and embryo development. Pregnancy outcomes were assessed after embryo transfers. Per stimulation cycle, patients receiving mild stimulation with a combination of CC and letrozole (study group) versus those with COS (control group) had lower numbers of pre-ovulatory follicles (2.00 ± 1.23 vs. 2.37 ± 1.23, p=0.0066) and oocytes retrieved (1.83 ± 1.17 vs. 2.37 ± 1.23, p=0.0017), and lower follicular output rate (58.6% vs. 68.38%, p=0.0093) and mature oocyte output rate (44.29% vs. 52.88%, p=0.0386) but a higher top-quality metaphase II oocyte ratio (66.7% vs. 54.59%, p=0.0444) and a similar fertilization rate (91.67% vs. 89.04%, p=0.4660). With adjustment for significant between-group baseline differences using multivariable logistic generalized estimating equation model analyses, there was no statistical difference in oocytes retrieved and embryo development between the study and control groups, and insignificant increases in successful pregnancies in the study group were found compared to the control group (i.e., odds ratios [95% CIs]: 1.13 [0.55, 232] and 1.50 [0.65, 3.49] for ongoing pregnancy and live birth, respectively). For POSEIDON Group 4 patients, cotreatment of CC and letrozole in mild stimulation may increase the high-quality oocyte ratio and yield comparable fertilization rate and pregnancy outcomes.


Catalytic cyclization of o-alkynylbenzaldehyde acetals and thioacetals. Unprecedented activation of the platinum catalyst by olefins. Scope and mechanism of the reaction.
A general protocol for the synthesis of functionalized indenes from o-alkynylbenzaldehyde acetals and thioacetals has been elaborated. Acetals uniformly give cyclization products having the alkyl group from the starting acetylene migrated to the alpha-position, whereas the cyclization of the corresponding thioacetals proceeds without alkyl migration. Optimization of the catalytic system for the cyclization of o-alkynylbenzaldehyde acetals revealed an unknown activation effect: PtCl(2) was found to be a better catalyst for the cyclization of acetals in the presence of olefins than without. A similar catalytic system (PtCl(2)/benzoquinone) has been found to be appropriate for the cyclization of cyclic acetals, whereas the optimal catalyst for the reaction of thioacetals is PdI(2). NMR monitoring of two reactions, acetal 3a + Pd(CH(3)CN)Cl(2) in CD(3)CN and thioacetal 5j + PdI(2) in CD(2)Cl(2), revealed that in both reactions similar cationic species are formed at the early stage of the transformation. Computational data (B3LYP/SDD level of theory) suggest that the difference in the reaction pathways for acetals and thioacetals can be rationalized by taking into account the relative stabilities of the corresponding vinylpalladium intermediates (22 vs 20 and 19 vs 21), which suggests a reversible thermodynamically controlled alkyl migration in the intermediate vinylcationic species.


Influence of dietary zinc on semen traits and seminal plasma antioxidant enzymes and trace minerals of beetal bucks.
Zinc (Zn) is a potent antioxidant and plays a key role in scavenging free radicals. We hypothesized that supplementation of Zn would reduce the oxidative damage, which is linked with poor sperm quality. Sixteen bucks of similar average age (2 years) and body weight (41 kg) were randomly divided into four groups viz., 1, 2, 3 and 4 supplemented with zinc sulphate into the diet at the rate of 0, 50, 100 and 200 mg/buck/day, respectively, for 3 months. At the end of the experiment, semen samples were collected and assessed. Seminal plasma was separated to find the concentration of superoxide dismutase (SOD), glutathione peroxidase (GPx), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and trace minerals (Zn, Cu, Mn and Fe). The results revealed that semen volume (1.85 ± 0.01 ml) and sperm motility (88.23 ± 5.77%) increased significantly (p < 0.05) in supplemented groups compared with the control specifically in group 3. SOD (10.66 ± 0.23 inhibition rate %) and GPx (23.55 ± 0.49 mU/ml) increased significantly (p < 0.05) in group 3 with no effect on AST and ALT. Among seminal plasma trace elements, no significant change (p > 0.05) was observed. From the present results, we concluded that zinc sulphate at the rate of 100 mg/buck/day improved semen traits and seminal plasma antioxidant capacity in Beetal bucks.


Operationalizing treatment as prevention in Los Angeles County: antiretroviral therapy use and factors associated with unsuppressed viral load in the Ryan White system of care.
Despite extensive prevention efforts, an estimated 21% of individuals with HIV/AIDS in the United States are unaware of their status, placing them at greater risk for spreading the virus to others. HIV treatment as prevention (TasP) is rapidly becoming an important public health strategy to reduce HIV transmission at the population level. Data for this study were collected on a sample of 11,397 HIV-positive individuals in the Ryan White system, a publicly funded system of care for HIV-positive individuals in Los Angeles County who are uninsured, in 2009 to examine two components of TasP: baseline rates and factors associated with antiretroviral therapy (ART) use and viral load (VL) suppression in a publicly funded system of care. ART coverage among our sample was 90%. In multivariate analyses, those with a higher odds of having unsuppressed VL included: females compared to males (adjusted odds ratio [AOR]=1.25; 95% confidence interval [CI]=1.06, 1.47); African Americans compared to whites (AOR=1.42; 95% CI=1.24, 1.62); men who have sex with men compared to heterosexuals (AOR=1.15; 95% CI=1.00, 1.32); recent substance abusers compared to nonsubstance abusers (AOR=1.35; 95% CI=1.17, 1.55); those recently incarcerated or ever incarcerated compared to those never incarcerated (AOR=1.37; 95% CI=1.15, 1.63; and AOR=1.28; 95% CI=1.09, 1.50); and those retained in care compared to those not retained in care (AOR=1.98; 95% CI=1.76, 2.22). Understanding the key sociodemographic, geographic and behavioral factors associated with ART use as well as HIV VL suppression will be useful for informing the development and deployment of targeted programming and policies that may further enhance the implementation of the TasP approach in communities across the United States.


[Diffuse thickening of the gallbladder wall. Clinical significance].
This article presents an analysis of the causes thickening of the gallbladder wall. It was shown that thickening of the wall of the gallbladder may be primary and secondary. Submitted by illustrations showing the thickening of the wall of the gall bladder in various diseases of the gallbladder.


Investigating PUM1 mutations in a Taiwanese cohort with cerebellar ataxia.
Mutations in the PUM1 gene were recently identified to cause spinocerebellar ataxia type 47 (SCA47). However, their role in cerebellar ataxia in various populations remains elusive. The aim of this study was to elucidate the frequency and spectrum of PUM1 mutations in a cohort of Taiwanese patients with molecularly undetermined cerebellar ataxia. Mutational analyses of PUM1 were performed by Sanger sequencing in a cohort of 248 unrelated patients with cerebellar ataxia of unknown cause, including 108 with autosomal-dominantly inherited cerebellar ataxia, 45 with autosomal-recessively inherited cerebellar ataxia, and 95 with apparently sporadic cerebellar ataxia. Among them, the genetic causes of ataxia remained unknown after excluding mutations responsible for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, 19/22, 23, 26, 27, 28, 31, 35, 36, dentatorubral-pallidoluysian atrophy and Friedreich's ataxia. Two heterozygous missense PUM1 variants were identified in two patients with apparently sporadic cerebellar ataxia, including a known disease-causing mutation (p.R1139W) and a variant of uncertain significance (p.K151R). The patient carrying the p.R1139W mutation had a slowly progressive, relatively pure cerebellar ataxia, presenting with gait unsteadiness, limb dysmetria, ataxic dysarthria and saccadic pursuit. Our findings support the pathogenic role of PUM1 mutations in cerebellar ataxia and emphasize the importance of considering PUM1 mutations as a possible etiology of cerebellar ataxia.


Dodine as a protein denaturant: the best of two worlds?
Traditional denaturants such as urea and guanidinium ion unfold proteins in a cooperative "all-or-none" fashion. However, their high working concentration in combination with their strong absorption in the far ultraviolet region make it impossible to measure high quality circular dichroism or infrared spectra, which are commonly used to detect changes in protein secondary structure. On the other hand, detergents such as dodecyl sulfate destabilize native protein conformation at low millimolar concentrations and are UV transparent, but they denature proteins more gradually than guanidinium or urea. In this work, we studied the denaturation properties of the fungicide dodecylguanidinium acetate (dodine), which combines both denaturants into one. We show that dodine unfolds some small proteins at millimolar concentrations, facilitates temperature denaturation, and is transparent enough at its working concentration, unlike guanidinium, to measure full range circular dichroism spectra. Our results also suggest that dodine allows fine-tuning of the protein's unfolded state, unlike traditional "all-or-none" denaturants.


The influences of metabotropic receptor activation on cellular signaling and synaptic function in amacrine cells.
Amacrine cells receive glutamatergic input from bipolar cells and GABAergic, glycinergic, cholinergic, and dopaminergic input from other amacrine cells. Glutamate, GABA, glycine, and acetylcholine (ACh) interact with ionotropic receptors and it is these interactions that form much of the functional circuitry in the inner retina. However, glutamate, GABA, ACh, and dopamine also activate metabotropic receptors linked to second messenger pathways that have the potential to modify the function of individual cells as well as retinal circuitry. Here, the physiological effects of activating dopamine receptors, metabotropic glutamate receptors, GABAB receptors, and muscarinic ACh receptors on amacrine cells will be discussed. The retina also expresses metabotropic receptors and the biochemical machinery associated with the synthesis and degradation of endocannabinoids and sphingosine-1-phosphate (S1P). The effects of activating cannabinoid receptors and S1P receptors on amacrine cell function will also be addressed.


The cost of reducing unplanned water supply interruptions: A parametric shadow price approach.
Water companies are responsible for supplying water to customers 24 h per day. However, due to extreme natural events and/or anthropogenic actions, water companies suffer from unplanned water supply interruptions, which directly impact customers and incur expenses by the companies. In this study, for the first time, we estimated the shadow price (or implicit cost) of unplanned water supply interruptions using stochastic frontier techniques for a sample of 21 Chilean water companies over the period of 2007-2017. The results indicate that, on average, the Chilean water company needed to spend an extra 2.547€ in operating expenditures to avoid 1 h of interruption. Average shadow price of unplanned water supply interruptions was higher for concessionary and full private companies than public ones. These findings demonstrate that the regulatory agency may need to promote effective policies and incentives to ensure and improve the continuity of the water supply. This is very relevant to the Chilean water industry, where there is an ongoing policy debate regarding the use of penalties and compensations as an incentive to avoid unplanned water supply interruptions.


Thoracic involvement in systemic primary vasculitis: radiological patterns and follow-up.
Systemic primary vasculitides are rare idiopathic diseases causing an inflammatory injury to the vessel walls. A pulmonary involvement is frequent, and chest-CT is the imaging technique of reference in its assessment. An extremely wide variety of parenchymal, vascular and airways abnormalities, has been described and diagnosis can be challenging: knowledge of clinical data and a close cooperation with the referring physician is often crucial. The aim of this work is to describe the most common typical and atypical CT features of pulmonary vasculitis and their possible changes over time and therapy, focusing on the differential diagnosis with other inflammatory/infectious or neoplastic diseases.


Phospholipid and triacylglycerol profiles modified by PLD suppression in soybean seed.
Phospholipase D (PLD) is capable of hydrolyzing membrane phospholipids, producing phosphatidic acid. To alter phospholipid profiles in soybean seed, we attenuated PLD enzyme activity by an RNA interference construct using the partial sequence from a soybean PLDα gene. Two transgenic soybean lines were established by particle inflow gun (PIG) bombardment by co-bombarding with pSPLDi and pHG1 vectors. The lines were evaluated for the presence and expression of transgenes thoroughly through the T(4) generation. PLD-suppressed soybean lines were characterized by decreased PLDα enzyme activity and decreased PLDα protein both during seed development and in mature seeds. There was no change in total phospholipid amount; however, the PLD-attenuated transgenic soybean seed had higher levels of di18:2 (dilinoleoyl)-phosphatidylcholine (PC) and -phosphatidylethanolamine (PE) in seeds than the non-transgenic lines. The increased polyunsaturation was at the expense of PC and PE species containing monounsaturated or saturated fatty acids. In addition to increased unsaturation in the phospholipids, there was a decrease in unsaturation of the triacylglycerol (TAG) fraction of the soybean seeds. Considering recent evidence for the notion that desaturation of fatty acids occurs in the PC fraction and that the PC→DAG (diacylglycerol)→TAG pathway is the major route of TAG biosynthesis in developing soybean seed, the current data suggest that PLDα suppression slows the conversion of PC to TAG. This would be consistent with PLD playing a positive role in that conversion. The data indicate that soybean PLD attenuation is a potentially useful approach to altering properties of edible and industrial soybean lecithin.


Cognitive impairment in MS: impact of white matter integrity, gray matter volume, and lesions.
To investigate whether extent and severity of white matter (WM) damage, as measured with diffusion tensor imaging (DTI), can distinguish cognitively preserved (CP) from cognitively impaired (CI) multiple sclerosis (MS) patients. Conventional MRI and DTI data were acquired from 55 MS patients (35 CP, 20 CI) and 30 healthy controls (HC). Voxelwise analyses were used to investigate fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity of a WM skeleton. Regional gray matter volume was quantified and lesion probability maps were generated. Compared to HCs, decreased FA was found in 49% of the investigated WM skeleton in CP patients and in 76% of the investigated WM in CI patients. Several brain areas that showed reduced FA in both patient groups were significantly worse in CI patients, i.e, corpus callosum, superior and inferior longitudinal fasciculus, corticospinal tracts, forceps major, cingulum, and fornices. In CI patients, WM integrity damage was additionally seen in cortical brain areas, thalamus, uncinate fasciculus, brainstem, and cerebellum. These findings were independent of lesion location and regional gray matter volume, since no differences were found between the groups. CI patients diverged from CP patients only on DTI metrics. WM integrity changes were found in areas that are highly relevant for cognition in the CI patients but not in the CP patients. These WM changes are therefore thought to be related to the cognitive deficits and suggest that DTI might be a powerful tool when monitoring cognitive impairment in MS.


Revealing the importance of meristems and roots for the development of hypersensitive responses and full foliar resistance to Phytophthora infestans in the resistant potato cultivar Sarpo Mira.
The defence responses of potato against Phytophthora infestans were studied using the highly resistant Sarpo Mira cultivar. The effects of plant integrity, meristems, and roots on the hypersensitive response (HR), plant resistance, and the regulation of PR genes were analysed. Sarpo Mira shoots and roots grafted with the susceptible Bintje cultivar as well as non-grafted different parts of Sarpo Mira plants were inoculated with P. infestans. The progress of the infection and the number of HR lesions were monitored, and the regulation of PR genes was compared in detached and attached leaves. Additionally, the antimicrobial activity of plant extracts was assessed. The presented data show that roots are needed to achieve full pathogen resistance, that the removal of meristems in detached leaves inhibits the formation of HR lesions, that PR genes are differentially regulated in detached leaves compared with leaves of whole plants, and that antimicrobial compounds accumulate in leaves and roots of Sarpo Mira plants challenged with P. infestans. While meristems are necessary for the formation of HR lesions, the roots of Sarpo Mira plants participate in the production of defence-associated compounds that increase systemic resistance. Based on the literature and on the presented results, a model is proposed for mechanisms involved in Sarpo Mira resistance that may apply to other resistant potato cultivars.


Across the Indian Ocean: A remarkable example of trans-oceanic dispersal in an austral mygalomorph spider.
The Migidae are a family of austral trapdoor spiders known to show a highly restricted and disjunct distribution pattern. Here, we aim to investigate the phylogeny and historical biogeography of the group, which was previously thought to be vicariant in origin, and examine the biogeographic origins of the genus Moggridgea using a dated multi-gene phylogeny. Moggridgea specimens were sampled from southern Australia and Africa, and Bertmainus was sampled from Western Australia. Sanger sequencing methods were used to generate a robust six marker molecular dataset consisting of the nuclear genes 18S rRNA, 28S rRNA, ITS rRNA, XPNPEP3 and H3 and the mitochondrial gene COI. Bayesian and Maximum Likelihood methods were used to analyse the dataset, and the key dispersal nodes were dated using BEAST. Based on our data, we demonstrate that Moggridgea rainbowi from Kangaroo Island, Australia is a valid member of the otherwise African genus Moggridgea. Molecular clock dating analyses show that the inter-specific divergence of M. rainbowi from African congeners is between 2.27-16.02 million years ago (Mya). This divergence date significantly post-dates the separation of Africa from Gondwana (95 Mya) and therefore does not support a vicariant origin for Australian Moggridgea. It also pre-dates human colonisation of Kangaroo Island, a result which is further supported by the intra-specific divergence date of 1.10-6.39 Mya between separate populations on Kangaroo Island. These analyses provide strong support for the hypothesis that Moggridgea colonised Australia via long-distance trans-Indian Ocean dispersal, representing the first such documented case in a mygalomorph spider.


PKCγ, role in lens differentiation and gap junction coupling.
To determine the role of PKCγ in the regulation of gap junction coupling in the normal lens, we have compared the properties of coupling in lenses from wild type (WT) and PKC-γ knockout (KO) mice. Western blotting, confocal immunofluorescence microscopy, immunoprecipitation, RT-PCR and quantitative real time PCR were used to study gap junction protein and message expression; gap junction coupling conductance and pH gating were measured in intact lenses using impedance studies. There were no gross differences in size, clarity, or expression of full-length Cx46 or Cx50 in lenses from WT and PKCγ KO mice. However, total Cx43 protein expression was ~150% higher in the KO lenses. In WT lenses, Cx43 was found only in epithelial cells whereas in KO lenses, its expression continued into the fiber cells. Gap junction coupling conductance in the differentiating fibers (DF) of PKCγ KO lenses was 34% larger than that of WT. In the mature fiber (MF), the effect was much larger with the KO lenses having an 82% increase in coupling over WT. pH gating of the DF fibers was not altered by the absence of PKCγ. PKCγ has a major role in the regulation of gap junction expression and coupling in the normal lens.


The impact of diurnal sleep on the consolidation of a complex gross motor adaptation task.
Diurnal sleep effects on consolidation of a complex, ecological valid gross motor adaptation task were examined using a bicycle with an inverse steering device. We tested 24 male subjects aged between 20 and 29 years using a between-subjects design. Participants were trained to adapt to the inverse steering bicycle during 45 min. Performance was tested before (TEST1) and after (TEST2) training, as well as after a 2 h retention interval (TEST3). During retention, participants either slept or remained awake. To assess gross motor performance, subjects had to ride the inverse steering bicycle 3 × 30 m straight-line and 3 × 30 m through a slalom. Beyond riding time, we sophisticatedly measured performance accuracy (standard deviation of steering angle) in both conditions using a rotatory potentiometer. A significant decrease of accuracy during straight-line riding after nap and wakefulness was shown. Accuracy during slalom riding remained stable after wakefulness but was reduced after sleep. We found that the duration of rapid eye movement sleep as well as sleep spindle activity are negatively related with gross motor performance changes over sleep. Together these findings suggest that the consolidation of adaptation to a new steering device does not benefit from a 2 h midday nap. We speculate that in case of strongly overlearned motor patterns such as normal cycling, diurnal sleep spindles and rapid eye movement sleep might even help to protect everyday needed skills, and to rapidly forget newly acquired, interfering and irrelevant material.


Imaging of the acute scrotum.
The scrotum is a superficial structure and clinical examination is frequently not enough for making a specific diagnosis. In acute scrotal pain US can confirm the presumptive clinical diagnosis and provide additional relevant information. In testicular torsion, color-Doppler imaging has a central role since it has become possible to identify it at early stage by showing absence of perfusion in the affected testis before any gray-scale abnormality. Scintigraphy remains a satisfactory alternative in evaluating testicular torsion and should be used when color Doppler is inadequate, raising doubts about the suspected torsion. Diagnosis of torsion of testicular appendages is particularly difficult. Ischemic infarction shows a characteristic pattern at gray-scale and color Doppler imaging, whereas hemorrhagic ischemia may require MRI. Inflammatory diseases of the scrotum can be easily investigated by echo color Doppler and conventional radiography, and CT can be particularly useful in the detection of gas bubbles. In scrotal trauma, scrotal hematoma, hematocele, intratesticular hematoma, and testicular rupture can be identified using gray-scale US with very good reliability. Magnetic resonance imaging is indicated when a small tear of tunica albuginea is suspected but not visualized on US.


Acral melanoma foot lesions. Part 1: epidemiology, aetiology, and molecular pathology.
Acral melanoma (AM) is a rare subtype of cutaneous malignant melanoma (MM) found on acral skin, primarily on the soles of the feet. Although rare, it is the most common subtype of MM found in patients of African or East Asian ethnicity and has a poor prognosis, often because of the more advanced stage of presentation at diagnosis. The pathogenesis of AM is unclear, but genetic alterations, including mutations in BRAF, NRAS, and KIT have been implicated. Early diagnosis of AM is important for a better prognosis, but its identification is often challenging, leading to easy misdiagnosis. In the first of this two-part review, we review the history, epidemiology, aetiology and molecular pathology of AM; in part 2 we will review diagnosis and management.


Pharmacotherapy and the neurobehavioural sequelae of traumatic brain injury.
Recent advances in clinical neuropharmacology are likely to improve the treatment and rehabilitation of traumatic brain injury (TBI) patients. Treatment may be directed to alleviate specific symptoms, to improve function in certain areas, or even to enhance the cortical recovery process. The author reviews pertinent issues in clinical neuropharmacology for the following drug classes: stimulants, other dopamine agonists, antidepressants, lithium, cholinergics, neuroleptics, anticonvulsants, beta-blockers, calcium channel blockers, nootropes, opiates and neuropeptides. Since the relevant research literature in TBI is so sparse, information and recommendations are extrapolated from some other patient groups, especially developmentally handicapped children and adults, and patients with dementia.


Bioactivity of peptide analogs of the neutrophil chemoattractant, N-acetyl-proline-glycine-proline.
The release of N-acetyl-proline-glycine-proline (PGP), a chemoattractant resulting from direct alkaline hydrolysis of corneal proteins, is believed to be the initial trigger for neutrophil invasion into the alkali-injured cornea. The purpose of this study is twofold: (1) to compare the activity of N-acetyl-PGP with the bioactivities of other similar synthetic peptides in an effort to uncover information about this chemoattractant molecule, and (2) to test these peptide analogs as potential antagonists of N-acetyl-PGP. The polarization assay was used to measure the potential chemotactic response of human neutrophils to peptides. Bioactivity was expressed as the peptide concentration required to produce 50% neutrophil polarization (EC50). Antagonist activity was expressed as the peptide concentration required to produce 50% inhibition (ID50) of polarization activated by N-acetyl-PGP. Peptide bioactivities (EC50) were ranked as follows: APGPR (0.34 mM) > N-acetyl-PGP (0.5 mM) > N-(PGP)4-PGLG (3 mM) = t-Boc-PGP (3 mM) > N-acetyl-PG (3.4 mM) > N-methyl-PGP (15 mM) = PGP (15 mM) > peptides without detectable activity (t-Boc-PGP-OMe, N-acetyl-P, PG, PGG, GP, GG and gly-pro-hyp). Peptides with no detectable bioactivity were tested as potential antagonists of neutrophil polarization induced by N-acetyl-PGP. Gly-Pro-Hyp inhibited N-acetyl-PGP activation of polarization at 20 mM (ID50). No other synthetic peptide demonstrated a capacity for inhibition. The minimum requirement to elicit bioactivity was the presence of PGP alone or derivatives of PG in which the N-terminal proline is blocked. Using this approach, active and inactive mimetic peptides of N-acetyl-PGP were produced. The most active peptide, APGPR, was equal to or slightly greater than N-acetyl-PGP, suggesting that more potent analogs might be designed. Gly-pro-hyp was the only inactive peptide analog to inhibit the chemoattractant.


Recent classifications systems for gastroenteropancreatic neuroendocrine tumors A single-center experience.
In this study, we aimed to review the demographic histopathological and clinical findings and long-term results of our GEP-NET cases, as well as to re-evaluate our cases according to the new classification systems. 46 patients diagnosed as GEPNETs were presented. Immunohistochemical studies were performed in all cases. The cases were divided into 3 groups according to their embryogenic origin (Foregut, Midgut and Hindgut). All cases re-evaluated according to recent WHO (2019) and AJCC (2017) TNM calcification. Investigation was made to find differences between the embryonic origins and to find correlation between stage and grading systems with each other. The most common localization was appendix (52.3%) The distribution of cases according to embryologic origin were as follows: foregut tumors 13 cases (27.7%), midgut tumors 27 cases (57.4%) and hindgut tumors in 6 cases (12.8%). The Ki-67 ratio was evaluated in all patients, with a mean of 6.34%±2.51 (range: 1-80). The Ki-67 ratio was less than 3% in 82.6% of patients. Mitotic count was less than 2 per/10 HPF in 76% of patients. According to WHO 2019 most of patients were Grade 1 Neuroendocrine Tumor (65.2%) and there were only 2 Neuroendocrine Carcinoma (NEC) cases. According to AJCC 2017 most cases were Stage 1 (52.1%) and only 4 cases were Stage 4. The grades and stages of our cases were statistically significantly correlated. Overall survival did not differ significantly with regard to embryologic origin (log-rank test, p=0.062). The median overall survival was 106±7.4 months. The 5-year cumulative survival rate was 84.1±5.6 years. Seven patients died during this time with a median time of 5 months (range: 1-31 months). In the Cox regression analysis, the percentage of Ki- 67 was found to have a statistically significant effect on overall survival (p=0.000) CONCLUSION: Correlation was noticed between WHO 2019 and AJCC 2017 classification for grade and stage and controlled trials must be undertaken to develop a single diagnostic algorithm and to change the future management of such patients. Neuroendocrine Tumors, Gastroenteropancreatic neuroendocrine tumor.


Search for haplotype interactions that influence susceptibility to type 1 diabetes, through use of unphased genotype data.
Type 1 diabetes is a T-cell-mediated chronic disease characterized by the autoimmune destruction of pancreatic insulin-producing beta cells and complete insulin deficiency. It is the result of a complex interrelation of genetic and environmental factors, most of which have yet to be identified. Simultaneous identification of these genetic factors, through use of unphased genotype data, has received increasing attention in the past few years. Several approaches have been described, such as the modified transmission/disequilibrium test procedure, the conditional extended transmission/disequilibrium test, and the stepwise logistic-regression procedure. These approaches are limited either by being restricted to family data or by ignoring so-called "haplotype interactions" between alleles. To overcome this limit, the present study provides a general method to identify, on the basis of unphased genotype data, the haplotype blocks that interact to define the risk for a complex disease. The principle underpinning the proposal is minimal entropy. The performance of our procedure is illustrated for both simulated and real data. In particular, for a set of Dutch type 1 diabetes data, our procedure suggests some novel evidence of the interactions between and within haplotype blocks that are across chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 15, 16, 17, 19, and 21. The results demonstrate that, by considering interactions between potential disease haplotype blocks, we may succeed in identifying disease-predisposing genetic variants that might otherwise have remained undetected.


Incidence of Malignancies in a Cohort of Psoriatic Arthritis Patients Taking Traditional Disease Modifying Antirheumatic Drug and Tumor Necrosis Factor Inhibitor Therapy: An Observational Study.
Psoriatic arthritis (PsA) is an inflammatory arthropathy, associated with skin and/or nail psoriasis. As suggested in 2012 by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), studies devoted to assess cancer in the PsA population are still limited and need to be increased. Therefore, the aim of this study was to determine the incidence of malignancies in patients with PsA who are taking conventional and biologic therapies. A cohort of patients with PsA was followed prospectively. At first visit, as well as at each 3-4 month followup visit, according to standardized clinical practice, medical history, and physical and laboratory findings were recorded. Information on the presence of comorbidities, as well as malignancies, was collected. At each visit, data were recorded on radiography and pathology, confirming malignancy diagnosis, when present. A total of 618 patients with PsA were included in the study. In particular, 296 were taking anti-tumor necrosis factor-α (anti-TNF) agents and 322 were taking disease-modifying antirheumatic drugs (DMARD). During the observation period, in the total group, 44 patients (7.1%) had a diagnosis of malignancy. Of them, 14 (4.7%; 95% CI 2.8-7.8; 0.52/100 patient-yrs) received anti-TNF therapy and 30 (9.3%; 95% CI 6.6-13.0; 1.03/100 patient-yrs) received traditional DMARD (p = 0.019). However, after adjusting for major demographic and clinical characteristics, the difference between the 2 treatments was no longer significant (p = 0.480), and the only predictor of malignancy occurrence was age (HR 1.04, 95% CI 1.009-1.073, p = 0.012). Data from this study confirm that biological therapies do not lead to any increased risk for cancer development, when adequately administered and with proper followup.


Comparing the attitudes of four groups of stakeholders from Quebec, Canada, toward extending medical aid in dying to incompetent patients with dementia.
The Canadian province of Quebec has recently legalized medical aid in dying (MAID) for competent patients who satisfy strictly defined criteria. The province is considering extending the practice to incompetent patients. We compared the attitudes of four groups of stakeholders toward extending MAID to incompetent patients with dementia. We conducted a province-wide postal survey in random samples of older adults, informal caregivers of persons with dementia, nurses, and physicians caring for patients with dementia. Clinical vignettes featuring a patient with Alzheimer's disease were used to measure the acceptability of extending MAID to incompetent patients with dementia. Vignettes varied according to the stage of the disease (advanced or terminal) and type of request (written or oral only). We used the generalized estimating equation (GEE) approach to compare attitudes across groups and vignettes. Response rates ranged from 25% for physicians to 69% for informal caregivers. In all four groups, the proportion of respondents who felt it was acceptable to extend MAID to an incompetent patient with dementia was highest when the patient was at the terminal stage, showed signs of distress, and had written a MAID request prior to losing capacity. In those circumstances, this proportion ranged from 71% among physicians to 91% among informal caregivers. We found high support in Quebec for extending the current MAID legislation to incompetent patients with dementia who have reached the terminal stage, appear to be suffering, and had requested MAID in writing while still competent.


Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial.
Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 microg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 microg of bFGF (n=8), 100 microg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0+/-6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-microg bFGF group had angina, whereas all patients in the 100-microg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7+/-3.7% to 23.8+/-5.7%, P=0.06), no significant change in the 10-microg bFGF group, and significant improvement in the 100-microg bFGF group (19.2+/-5.0% to 9.1+/-5.9%, P=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-microg bFGF group (10.7+/-3.9% to 3. 7+/-6.3%, P=0.06). This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.


Systemic Negligence: Why It Is Morally Important for Developing World Bioethics.
In the context of clinical and non-clinical biomedical practices, negligence is usually understood as a lapse of a specific professional duty by a healthcare worker or by a medical facility. This paper tries to delineate systemic negligence as another kind of negligence in the context of health systems, particularly in developing countries, that needs to be recognized and addressed. Systemic negligence is not just a mere collection of stray incidences of medical errors and system failures in a health system, but is proposed in this paper as a more pervasive kind of neglect. Several non-medical factors, such as lack of social and political will, also contribute to it and hence is more difficult to address in a health system. This paper argues that recognizing systemic negligence and including it research agenda have special moral importance for researchers in developing world bioethics, public health ethics and for health activists in the developing world. For, it can be a potent health system barrier, and can seriously impair efforts to ensure patient safety, particularly in the weaker health systems. As it erodes accountability in a health system, addressing it is also important for the twin goals of ensuring patient safety and improving health system performance. Above all, it needs to be addressed because the tolerance of its persistence in a health system seems to undervalue health as a social good.


Per and polyfluoroalkylated substances (PFAS) target and EOF analyses in ski wax, snowmelts, and soil from skiing areas.
Per and polyfluoroalkylated substances (PFAS) are common additives in ski waxes for their water repellent characteristic. Abrasion of ski wax leaves PFAS on the snow surface, however, little is known about the distribution and concentration of PFAS in snow and soil due to skiing. In this study we analysed different ski waxes, snowmelts and soil from family skiing areas from Alpine locations using targeted high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to understand more about PFAS distribution in the environment. In general, we found a very diverse PFAS pattern in the analysed media. PFAS level was higher in skiing areas compared to the non-skiing ones that were used as control. ∑target PFAS ranged between <1.7 ng L-1 and 143 ng L-1 in snowmelt, <0.62 ng g-1 and 5.35 ng g-1 in soil and <1.89 and 874 ± 240 ng g-1 in ski wax samples. Snowmelt was dominated by short-chained PFAS, while soil and wax contained both short and long-chained PFAS. Extractable organic fluorine (EOF) was several orders of magnitude higher for waxes (0.5-2 mg g-1) than for soils (up to 0.3 μg g-1), while total fluorine (TF) content of the waxes was even higher, up to 31 210 ± 420 μg g-1. We also showed that the ∑ target PFAS accounts for up to 1.5% in EOF content, showing that targeted LC-MS/MS gives a limited measure of the pollution originated from ski waxes and non-targeted analysis and EOF is necessary for a better overview on PFAS distribution.


Synthesis and characterization of an anti-apoptotic immunosuppressive compound for improving the outcome of islet transplantation.
Mycophenolic acid (MPA) is a commonly used immunosuppressive drug for human islet transplantation. However, it is toxic to transplanted islets, causing primary nonfunction. We recently synthesized a quinic acid derivative, 1,3,4,5-tetrahydroxy-N-propylcyclohexanecarboxamide (KZ41), which has anti-inflammatory and anti-apoptotic effects. We hypothesized that the conjugate (E)-2,3,5-trihydroxy-5-(propylcarbamoyl) cyclohexyl 6-(4-ethoxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (JP-3-110), which is composed of KZ41 and MPA through esterification, can suppress the immune rejection while inducing less toxicity. Early characterization showed that the solubility of JP-3-110 was significantly higher than that of MPA, though JP-3-110 was still poorly water-soluble. The ester bond connecting KZ41 and MPA is stable for a limited duration (<4 weeks). Pharmacological studies demonstrated that JP-3-110 induced significantly less activated caspase 3 and apoptotic cell death of human islets than MPA, while maintaining an equally potent immunosuppressive effect. A similar immunosuppressive effect of JP-3-110 and MPA in humanized NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NOD scid gamma, NSG) mice with adoptively transferred human immunity was observed. Taken together, our results demonstrated that JP-3-110 can be a safer immunosuppressive agent for human islet transplantation.


Efficacy of dihydroartemisinin/piperaquine in patients with non-complicated Plasmodium falciparum malaria in Yaoundé, Cameroon.
Dihydroartemisinin/piperaquine is increasingly used for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. The efficacy of this combination in Cameroon is poorly documented, while resistance to dihydroartemisinin/piperaquine readily spreads in Southeast Asia. This study evaluated the clinical efficacy of dihydroartemisinin/piperaquine in Cameroon, as well as the molecular profile and phenotypic susceptibility of collected isolates to dihydroartemisinin and piperaquine. Dihydroartemisinin/piperaquine efficacy in 42 days was followed-up for 138 patients presenting non-complicated falciparum malaria. Piperaquine concentration was determined at day 7 for 124 patients. kelch13 gene polymorphisms (n = 150) and plasmepsin2 gene amplification (n = 148) were determined as molecular markers of resistance to dihydroartemisinin and piperaquine, respectively. Parasite susceptibility to dihydroartemisinin and piperaquine was determined using validated in vitro survival assays. The efficacy of dihydroartemisinin/piperaquine treatment was 100% after PCR correction. The reinfections were not associated with a variation of piperaquine concentration at day 7. Ninety-six percent (144/150) of the samples presented a WT allele of the kelch13 gene. Two percent (3/150) presented the non-synonymous mutation A578S, which is not associated with resistance to dihydroartemisinin. No duplication of the plasmepsin2 gene was observed (0/148). All the samples tested in vitro by survival assays (n = 87) were susceptible to dihydroartemisinin and piperaquine. Dihydroartemisinin/piperaquine has demonstrated excellent therapeutic efficacy with no evidence of emerging artemisinin or piperaquine resistance in Yaoundé, Cameroon. This observation suggests that dihydroartemisinin/piperaquine could be a sustainable therapeutic solution for P. falciparum malaria if implemented in areas previously free of artemisinin- and piperaquine-resistant parasites, unlike Southeast Asia.


A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer.
Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences contain multiple regulatory motifs and hence are capable of influencing expression of host genes. TEs are known to be released from epigenetic repression and can become transcriptionally active in cancer. Such activation could also lead to lineage-inappropriate activation of oncogenes, as previously described in lymphomas. However, there are few reports of this mechanism occurring in non-blood cancers. Here, we re-analyzed whole transcriptome data from a large cohort of patients with colon cancer, compared to matched normal colon control samples, to detect genes or transcripts ectopically expressed through activation of TE promoters. Among many such transcripts, we identified six where the affected gene has described role in cancer and where the TE-driven gene mRNA is expressed in primary colon cancer, but not normal matched tissue, and confirmed expression in colon cancer-derived cell lines. We further characterized a TE-gene chimeric transcript involving the Interleukin 33 (IL-33) gene (termed LTR-IL-33), that is ectopically expressed in a subset of colon cancer samples through the use of an endogenous retroviral long terminal repeat (LTR) promoter of the MSTD family. The LTR-IL-33 chimeric transcript encodes a novel shorter isoform of the protein, which is missing the initial N-terminus (including many conserved residues) of Native IL-33. In vitro studies showed that LTR-IL-33 expression is required for optimal CRC cell line growth as 3D colonospheres. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in colon cancer.