Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.
Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families.


Dynamic measurement of myosin light-chain-domain tilt and twist in muscle contraction.
A new method is described for measuring motions of protein domains in their native environment on the physiological timescale. Pairs of cysteines are introduced into the domain at sites chosen from its static structure and are crosslinked by a bifunctional rhodamine. Domain orientation in a reconstituted macromolecular complex is determined by combining fluorescence polarization data from a small number of such labelled cysteine pairs. This approach bridges the gap between in vitro studies of protein structure and cellular studies of protein function and is used here to measure the tilt and twist of the myosin light-chain domain with respect to actin filaments in single muscle cells. The results reveal the structural basis for the lever-arm action of the light-chain domain of the myosin motor during force generation in muscle.


Cellular mechanism of the functional refractory period in ventricular muscle.
A premature action potential elicited in ventricular muscle during the functional refractory period of a preceding action potential requires an increased stimulus intensity for successful propagation. We measured the cellular basis for these relative decreases in tissue excitability during the recovery phase by performing parallel experiments on rabbit left papillary muscle and isolated rabbit ventricular cells in addition to conducting theoretical studies with numerical simulations of action potential initiation. For each experimental preparation, the pacing protocol consisted of a train of 10 stimuli (S1) at an S1-S1 interval of 500 msec with a premature stimulus (S2) of variable S1-S2 intervals following the tenth S1 action potential. The stimulus threshold for initiation of an S2 action potential (I2) was then measured as a function of the time of occurrence of the S2 stimulus relative to the time of 95% repolarization of the tenth S1 action potential (stimulus delay [SD] time). In the tissue preparation, the I2 increased sharply for SD times less than 0 msec to a value that was 100% above the S1 stimulus threshold for SD time = -5 +/- 2.4 msec (n = 8). Similar experiments on the isolated ventricular cell showed no increases in I2 as a function of SD time but rather significant decreases in both the action potential amplitude (APA) and the maximum rate of rise of the action potential upstroke (Vmax) of the S2 action potential. The APA and Vmax for the S2 action potential were decreased to 50% of the S1 action potential values for SD time = -5.2 +/- 2.1 msec and SD time = 0.3 +/- 1.6 msec, respectively (n = 8). Both parameters reached 100% recovery by SD time = 10 msec. These results and our numerical simulations are consistent with the hypothesis that the decreases in tissue excitability that occur with premature stimulation have a cellular mechanism as a result of a decrease in cellular responsiveness (APA, Vmax) rather than an intrinsic decrease in cellular excitability.


Enabling Large-Scale Condensed-Phase Hybrid Density Functional Theory Based Ab Initio Molecular Dynamics. 1. Theory, Algorithm, and Performance.
By including a fraction of exact exchange (EXX), hybrid functionals reduce the self-interaction error in semilocal density functional theory (DFT) and thereby furnish a more accurate and reliable description of the underlying electronic structure in systems throughout biology, chemistry, physics, and materials science. However, the high computational cost associated with the evaluation of all required EXX quantities has limited the applicability of hybrid DFT in the treatment of large molecules and complex condensed-phase materials. To overcome this limitation, we describe a linear-scaling approach that utilizes a local representation of the occupied orbitals (e.g., maximally localized Wannier functions (MLWFs)) to exploit the sparsity in the real-space evaluation of the quantum mechanical exchange interaction in finite-gap systems. In this work, we present a detailed description of the theoretical and algorithmic advances required to perform MLWF-based ab initio molecular dynamics (AIMD) simulations of large-scale condensed-phase systems of interest at the hybrid DFT level. We focus our theoretical discussion on the integration of this approach into the framework of Car-Parrinello AIMD, and highlight the central role played by the MLWF-product potential (i.e., the solution of Poisson's equation for each corresponding MLWF-product density) in the evaluation of the EXX energy and wave function forces. We then provide a comprehensive description of the exx algorithm implemented in the open-source Quantum ESPRESSO program, which employs a hybrid MPI/OpenMP parallelization scheme to efficiently utilize the high-performance computing (HPC) resources available on current- and next-generation supercomputer architectures. This is followed by a critical assessment of the accuracy and parallel performance (e.g., strong and weak scaling) of this approach when AIMD simulations of liquid water are performed in the canonical (NVT) ensemble. With access to HPC resources, we demonstrate that exx enables hybrid DFT-based AIMD simulations of condensed-phase systems containing 500-1000 atoms (e.g., (H2O)256) with a wall time cost that is comparable to that of semilocal DFT. In doing so, exx takes us one step closer to routinely performing AIMD simulations of complex and large-scale condensed-phase systems for sufficiently long time scales at the hybrid DFT level of theory.


Sex differences in sympathetic gene expression and cardiac neurochemistry in Wistar Kyoto rats.
The stellate ganglia are the predominant source of sympathetic innervation to the heart. Remodeling of sympathetic nerves projecting to the heart has been observed in several cardiovascular diseases, and sympathetic dysfunction contributes to cardiac pathology. Wistar Kyoto rats are a common model for the study of cardiovascular diseases, but we lack a profile of the baseline transcriptomic and neurochemical characteristics of their cardiac sympathetic neurons. Most studies of cardiovascular disease have used male animals only, but in the future both male and female animals will be used for these types of studies; therefore, we sought to characterize the transcriptome of male and female stellate ganglia and to correlate that with catecholamine and acetylcholine content in the heart. We have generated a dataset of baseline RNA expression in male and female Wistar Kyoto rat stellate ganglia using RNA-seq, and have measured neurotransmitter levels in heart and stellate ganglia using HPLC and mass spectrometry. We identified numerous gene expression differences between male and female stellates, including genes encoding important developmental factors, receptors and neuropeptides. Female hearts had significantly higher neurotransmitter content than male hearts; however, no significant differences were detected in expression of the genes encoding neurotransmitter synthetic enzymes. Similarly, no statistically significant differences were identified between the sexes in cardiac tyrosine hydroxylase levels.


Effects of local anesthetic concentration and dose on continuous interscalene nerve blocks: a dual-center, randomized, observer-masked, controlled study.
It is currently unknown if the primary determinant of continuous peripheral nerve block effects is simply total drug dose, or whether local anesthetic concentration and/or volume have an influence. We therefore tested the null hypothesis that providing ropivacaine at different concentrations and rates--but at an equal total basal dose--produces similar effects when used in a continuous interscalene nerve block. Preoperatively, an anterolateral interscalene perineural catheter was inserted using the anterolateral approach in patients undergoing moderately painful shoulder surgery. Subjects were randomly assigned to receive a postoperative perineural infusion of either 0.2% ropivacaine (basal 8 mL/h, bolus 4 mL) or 0.4% ropivacaine (basal 4 mL/h, bolus 2 mL) through the second postoperative day. Our primary endpoint was the incidence of an insensate hand/finger during the 24 hours beginning the morning following surgery. The incidence of an insensate hand/finger did not differ between the treatment groups (n = 50) to a statistically significant degree (0.2% ropivacaine, mean [SD] of 0.8 [1.3] times; 0.4% ropivacaine, mean 0.3 [0.6] times; estimated difference = 0.5 episodes, 95% confidence interval, -0.1 to 1.1 episodes; P = .080). However, this is statistically inconclusive given the confidence interval. In contrast, pain (P = .020) and dissatisfaction (P = .011) were greater in patients given 0.4% ropivacaine. For continuous interscalene nerve blocks, given the statistically inconclusive primary endpoint results and design limitations of the current study, further research on this topic is warranted. In contrast, providing a lower concentration of local anesthetic at a higher basal rate provided superior analgesia.


Buprenorphine assay and plasma concentration monitoring in HIV-infected substance users.
The availability of buprenorphine (BUP) provides an alternative approach to the treatment of opioid addiction with methadone, an agent that has many drug-drug interactions when combined with antiretroviral therapy (ART). However, due to limited long-term pharmacokinetic studies in HIV-infected patients, the clinical use of BUP, a CYP450-3A4 substrate, will require that studies be conducted to examine safety, tolerability and pharmacokinetics when these drugs are taken for chronic treatment. One clinical approach could include plasma concentration monitoring to avoid under- or overdosing BUP secondary to drug interactions with ART. The measurement of BUP and its active metabolite, norbuprenorphine (NBUP) facilitates the addition of BUP to ART in an attempt to avoid drug toxicity as described in a recent report by Bruce et al. Therefore, our objective was to validate a BUP assay and integrate its application into an ongoing antiretroviral (ARV) plasma concentration monitoring program. A chromatographic method for monitoring BUP and its active metabolite, NBUP was investigated. An assay was developed that would facilitate BUP and ARV measurement from a single 3 mL blood sample (0.75 mL plasma required) in conjunction with a previously validated multiple ARV HPLC method. The method measures BUP and NBUP over the range from 0.25 to 50 ng/mL with mass spectrometry detection. Inter- and intra-assay variation was <or=11%, across the concentration range. The method quantitates BUP and NBUP plasma concentrations within the range of expected values from current BUP dosing guidelines. Use of this combined BUP and ARV plasma concentration monitoring approach for a representative patient receiving BUP, atazanavir and efavirenz demonstrated its clinical application.


The role of resting state networks in focal neocortical seizures.
The role of resting state functional networks in epilepsy is incompletely understood. While some pathologic diagnoses have been shown to have maintained but altered resting state connectivity, others have implicated resting state connectivity in disease progression. However little is known about how these resting state networks influence the behavior of a focal neocortical seizure. Using data taken from invasively monitored patients with intractable focal neocortical epilepsy, we evaluated network connectivity (as determined by oscillatory covariance of the slow cortical potential (<0.5 Hz)) as it relates to neocortical seizure foci both in the interictal and ictal states. Similar to what has been shown in the past for sleep and anesthesia, electophysiologic resting state networks that are defined by this slow cortical potential covariance maintain their topographic correlation structure throughout an ictal event. Moreover, in the context of focal epilepsy in which the seizure has a specific site of onset, seizure propagation is not chaotic or random. Rather, the seizure (reflected by an elevation of high frequency power) preferentially propagates along the network that contains the seizure onset zone. Taken together, these findings further undergird the fundamental role of resting state networks, provide novel insights into the network-influenced behavior of seizures, and potentially identify additional targets for surgical disconnection including informing the location for the completion of multiple subpial transections (MSPTs).


Prevalence of and Associated Risk Factors for High Risk Human Papillomavirus among Sexually Active Women, Swaziland.
High risk human papillomavirus (hr-HPV) infection and the dual burden of HIV remains a huge challenge in some low-income countries (LICs) such as Swaziland with limited or no data. We estimated the prevalence and investigated determinants of hr-HPV, including HIV infection among sexually active women in Swaziland. A total of 655 women aged between 15 and 49 years from five health facilities were randomly enrolled using a cross-sectional study design. Cervical cells were tested for hr-HPV types using GeneXpert HPV Assays. The overall weighted hr-HPV prevalence was 46.2% (95%CI: 42.8-49.5). Of hr-HPV infected women, 12.4% (95%CI: 8.6-17.5) were HPV16-positive, 13.8% (95%CI:12.0-15.8) were positive for HPV18/45, 26.7% (95%CI: 24.2-29.3) for HPV31/33/35/52/58, 7.6% (95%CI: 7.6-11.9) for HPV51/59 and 11.0%, (95%CI: 7.9-15.3) for HPV39/56/66/68. Prevalence of hr-HPV decreased with increasing age. Overall HIV prevalence remained high (42.7%; 95%CI: 35.7-46.2). HIV infection was associated with hr-HPV infection (Adjusted OR = 4.9, 95%CI: 3.043-7.8, p<0.001). Overall hr-HPV/HIV co-infection was 24.4% (95%CI: 20.3-29.1) which was significantly higher among younger age groups (p<0.001). Prevalence of multiple group hr-HPV infection was significantly higher in HIV-positive versus -negative women (27.7% and 12.7% respectively, p<0.001). The presence, absence or unknown of history of STI with HIV did not appear to modify the relationship with hr-HPV (OR = 4.2, 95%CI: 2.6-7.1, OR = 4.6, 95%CI: 2.8-7.7, p<0.001, p<0.001 and OR = 4.1, 95%CI: 1.3-13.4, p<0.021 respectively). The prevalence of hr-HPV infection was high and significantly associated with HIV among sexually active women. Furthermore, the study has provided essential information about the HIV link with hr-HPV infections which may explain the high prevalence among HIV infected women. This can contribute to policy development and planning of prevention strategies incorporating HPV infection prevention especially among youth and HIV infected people.


The relationship between measured performance and satisfaction with care among clinically complex patients.
Recent work has shown that clinically complex patients are more likely to receive recommended care, but it is unknown whether higher achievement on individual performance goals results in improved care for complex patients or detracts from other important but unmeasured aspects of care, resulting in unmet needs and lower satisfaction with care. To examine the relationship between measured performance and satisfaction with care among clinically complex patients An observational analysis of a national sample of 35,927 veterans included in the External Peer Review Program in fiscal years 2003 and 2004. First, compliance with individual performance measures (breast cancer screening with mammography, colorectal cancer screening, influenza vaccination, pneumococcal vaccination, lipid monitoring, use of ACE inhibitor in heart failure, and diabetic eye examination), as well as overall receipt of recommended care, was estimated as a function of each patient's clinical complexity. Second, global satisfaction with care was estimated as a function of clinical complexity and compliance with performance measures. Higher clinical complexity was predictive of slightly higher overall performance (OR 1.13, 95% CI 1.09 to 1.18) and higher performance on most individual performance measures, an effect that was mediated by increased visit frequency. High measured performance was associated with higher satisfaction with care among patients with high clinical complexity. In fact, as complexity increased, the effect of achieving high performance on the odds of being satisfied with care also increased Not only was measured performance higher in clinically complex patients, but satisfaction with care was also higher among clinically complex patients with high measured performance, suggesting that compliance with performance measures in clinically complex patients does not crowd out unmeasured care.


Lycopene and bone: an in vitro investigation and a pilot prospective clinical study.
There are several effective therapies for osteoporosis but these agents might cause serious adverse events. Lycopene intake could prevent bone loss, however studies on its effects on bone are scarce. Our aim was to investigate the effects of lycopene on osteoblast cells as well as bone mineral density and bone turnover markers in postmenopausal women. We investigated the effect of lycopene on the Wnt/β-catenin and ERK 1/2 pathways, RUNX2, alkaline phosphatase, RANKL and COL1A of Saos-2. We also carried out a pilot controlled clinical study to verify the feasibility of an approach for bone loss prevention through the intake of a lycopene-rich tomato sauce in 39 postmenopausal women. Lycopene 10 µM resulted in higher β-catenin and phERK1/2 protein Vs the vehicle (p = 0.04 and p = 0.006). RUNX2 and COL1A mRNA was induced by both 5 and 10 µM doses (p = 0.03; p = 0.03 and p = 0.03; p = 0.05) while RANKL mRNA was reduced (p < 0.05). A significant bone density loss was not detected in women taking the tomato sauce while the control group had bone loss (p = 0.002). Tomato sauce intake resulted in a greater bone alkaline phosphatase reduction than the control (18% vs 8.5%, p = 0.03). Lycopene activates the WNT/β-catenin and ERK1/2 pathways, upregulates RUNX2, alkaline phosphatase, COL1A and downregulates RANKL Saos-2. These processes contributed to prevent bone loss in postmenopausal women.


The Role of the Trigemino Cervical Complex in Chronic Whiplash Associated Headache: A Cross Sectional Study.
To investigate signs of central sensitization in a cohort of patients with chronic whiplash associated headache (CWAH). Central sensitization is one of the mechanisms leading to chronicity of primary headache, and thus might contribute to CWAH. However, the pathophysiological mechanism of CWAH is poorly understood and whether it is simply an expression of the primary headache or has a distinct pathogenesis remains unclear. Thus, the factors involved in the genesis of CWAH require further investigation. Twenty-two patients with CWAH (20 females, 2 males; age 25-50 years, mean age 36.3 years) and 25 asymptomatic participants (13 females, 12 males; age 18-50 years, mean age 35.6 years) rated glare and light-induced discomfort in response to light from an ophthalmoscope. Hyperalgesia evoked by a pressure algometer was assessed bilaterally on the forehead, temples, occipital base, and the middle phalanx of the third finger. The number, latency, area under the curve, and recovery cycle of nociceptive blink reflexes elicited by a supraorbital electrical stimulus were also recorded. Eight and 6 CWAH patients had migrainous and tension-type headache (TTH) profiles, respectively; the remainder had features attributable to both migraine and TTH. Patients in the whiplash group reported significantly greater light-induced pain than controls (8.48 ± .35 vs 6.66 ± .43 on a 0-10 scale; P = .001). The CWAH patients reported significantly lower pressure pain thresholds at all sites. For stimuli delivered at 20 second intervals, whiplash patients were more responsive than controls (4.8 ± .6 blinks vs 3.0 ± .6 blinks in a block of 10 stimuli; P = .036). While R2 latencies and the area under the curve for the 20 second interval trials were comparable in both groups, there was a significant reduction of the area under the curve from the first to the second of the 2-second interval trials only in controls (99 ± 8% of baseline in whiplash patients vs 68 ± 7% in controls; P = .009). The recovery cycle was comparable for both groups. Our results corroborate previous findings of mechanical hypersensitivity and photophobia in CWAH patients. The neurophysiological data provide further evidence for hyperexcitability in central nociceptive pathways, and endorse the hypothesis that CWAH may be driven by central sensitization.


Association of healthy lifestyle with incident cardiovascular diseases among hypertensive and normotensive Chinese adults.
Whether lifestyle improvement benefits in reducing cardiovascular diseases (CVD) events extend to hypertensive patients and whether these benefits differ between hypertensive and normotensive individuals is unclear. This study aimed to investigate the associations of an overall healthy lifestyle with the subsequent development of CVD among participants with hypertension and normotension. Using data from the Suzhou subcohort of the China Kadoorie Biobank study of 51,929 participants, this study defined five healthy lifestyle factors as nonsmoking or quitting for reasons other than illness; nonexcessive alcohol intake; relatively higher physical activity level; a relatively healthy diet; and having a standard waist circumference and body mass index. We estimated the associations of these lifestyle factors with CVD, ischemic heart disease (IHD) and ischemic stroke (IS). During a follow-up of 10.1 years, this study documented 6,151 CVD incidence events, 1,304 IHD incidence events, and 2,243 IS incidence events. Compared to those with 0-1 healthy lifestyle factors, HRs for those with 4-5 healthy factors were 0.71 (95% CI: 0.62, 0.81) for CVD, 0.56 (95% CI: 0.42, 0.75) for IHD, and 0.63 (95% CI: 0.51, 0.79) for IS among hypertensive participants. However, we did not observe this association among normotensive participants. Stratified analyses showed that the association between a healthy lifestyle and IHD risk was stronger among younger participants, and the association with IS risk was stronger among hypertensive individuals with lower household incomes. Adherence to a healthy lifestyle pattern is associated with a lower risk of cardiovascular diseases among hypertensive patients, but this benefit is not as pronounced among normotensive patients.


Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1.
We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue cysteine 153 were associated with a milder phenotype and were seen in the familial cases in which the boys were still more severely affected compared to their mothers. We expect the mild end of the spectrum to significantly expand in the future. On the severe end of the spectrum we define reducing body myopathy as a progressive disease with early, but not necessarily congenital onset, distinguishing this condition from the classic essentially non-progressive congenital myopathies.


Complete revascularization reduces cardiovascular death in patients with ST-segment elevation myocardial infarction and multivessel disease: systematic review and meta-analysis of randomized clinical trials.
The aim of this work was to investigate the prognostic impact of revascularization of non-culprit lesions in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease by performing a meta-analysis of available randomized clinical trials (RCTs). Data from six RCTs comparing complete vs. culprit-only revascularization in STEMI patients with multivessel disease were analysed with random effect generic inverse variance method meta-analysis. The endpoints were expressed as hazard ratio (HR) with 95% confidence interval (CI). The primary outcome was cardiovascular death. Main secondary outcomes of interest were all-cause death, myocardial infarction (MI), and repeated coronary revascularization. Overall, 6528 patients were included (3139 complete group, 3389 culprit-only group). After a follow-up ranging between 1 and 3 years (median 2 years), cardiovascular death was significantly reduced in the group receiving complete revascularization (HR 0.62, 95% CI 0.39-0.97, I2 = 29%). The number needed to treat to prevent one cardiovascular death was 70 (95% CI 36-150). The secondary endpoints MI and revascularization were also significantly reduced (HR 0.68, 95% CI 0.55-0.84, I2 = 0% and HR 0.29, 95% CI 0.22-0.38, I2 = 36%, respectively). Needed to treats were 45 (95% CI 37-55) for MI and 8 (95% CI 5-13) for revascularization. All-cause death (HR 0.81, 95% CI 0.56-1.16, I2 = 27%) was not affected by the revascularization strategy. In a selected study population of STEMI patients with multivessel disease, a complete revascularization strategy is associated with a reduction in cardiovascular death. This reduction is concomitant with that of MI and the need of repeated revascularization.


Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial.
The optimal approach to airway management during out-of-hospital cardiac arrest is unknown. To determine whether a supraglottic airway device (SGA) is superior to tracheal intubation (TI) as the initial advanced airway management strategy in adults with nontraumatic out-of-hospital cardiac arrest. Multicenter, cluster randomized clinical trial of paramedics from 4 ambulance services in England responding to emergencies for approximately 21 million people. Patients aged 18 years or older who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017; follow-up ended in February 2018. Paramedics were randomized 1:1 to use TI (764 paramedics) or SGA (759 paramedics) as their initial advanced airway management strategy. The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred sooner. Modified Rankin Scale score was divided into 2 ranges: 0-3 (good outcome) or 4-6 (poor outcome; 6 = death). Secondary outcomes included ventilation success, regurgitation, and aspiration. A total of 9296 patients (4886 in the SGA group and 4410 in the TI group) were enrolled (median age, 73 years; 3373 were women [36.3%]), and the modified Rankin Scale score was known for 9289 patients. In the SGA group, 311 of 4882 patients (6.4%) had a good outcome (modified Rankin Scale score range, 0-3) vs 300 of 4407 patients (6.8%) in the TI group (adjusted risk difference [RD], -0.6% [95% CI, -1.6% to 0.4%]). Initial ventilation was successful in 4255 of 4868 patients (87.4%) in the SGA group compared with 3473 of 4397 patients (79.0%) in the TI group (adjusted RD, 8.3% [95% CI, 6.3% to 10.2%]). However, patients randomized to receive TI were less likely to receive advanced airway management (3419 of 4404 patients [77.6%] vs 4161 of 4883 patients [85.2%] in the SGA group). Two of the secondary outcomes (regurgitation and aspiration) were not significantly different between groups (regurgitation: 1268 of 4865 patients [26.1%] in the SGA group vs 1072 of 4372 patients [24.5%] in the TI group; adjusted RD, 1.4% [95% CI, -0.6% to 3.4%]; aspiration: 729 of 4824 patients [15.1%] vs 647 of 4337 patients [14.9%], respectively; adjusted RD, 0.1% [95% CI, -1.5% to 1.8%]). Among patients with out-of-hospital cardiac arrest, randomization to a strategy of advanced airway management with a supraglottic airway device compared with tracheal intubation did not result in a favorable functional outcome at 30 days. ISRCTN Identifier: 08256118.


Viral infections of the central nervous system in Spain: a prospective study.
The aim of the study was to determine the incidence of viruses causing aseptic meningitis, meningoencephalitis, and encephalitis in Spain. This was a prospective study, in collaboration with 17 Spanish hospitals, including 581 cases (CSF from all and sera from 280): meningitis (340), meningoencephalitis (91), encephalitis (76), febrile syndrome (7), other neurological disorders (32), and 35 cases without clinical information. CSF were assayed by PCR for enterovirus (EV), herpesvirus (herpes simplex [HSV], varicella-zoster [VZV], cytomegalovirus [CMV], Epstein-Barr [EBV], and human herpes virus-6 [HHV-6]), mumps (MV), Toscana virus (TOSV), adenovirus (HAdV), lymphocytic choriomeningitis virus (LCMV), West Nile virus (WNV), and rabies. Serology was undertaken when methodology was available. Amongst meningitis cases, 57.1% were characterized; EV was the most frequent (76.8%), followed by VZV (10.3%) and HSV (3.1%; HSV-1: 1.6%; HSV-2: 1.0%, HSV non-typed: 0.5%). Cases due to CMV, EBV, HHV-6, MV, TOSV, HAdV, and LCMV were also detected. For meningoencephalitis, 40.7% of cases were diagnosed, HSV-1 (43.2%) and VZV (27.0%) being the most frequent agents, while cases associated with HSV-2, EV, CMV, MV, and LCMV were also detected. For encephalitis, 27.6% of cases were caused by HSV-1 (71.4%), VZV (19.1%), or EV (9.5%). Other positive neurological syndromes included cerebellitis (EV and HAdV), seizures (HSV), demyelinating disease (HSV-1 and HHV-6), myelopathy (VZV), and polyradiculoneuritis (HSV). No rabies or WNV cases were identified. EVs are the most frequent cause of meningitis, as is HSV for meningoencephalitis and encephalitis. A significant number of cases (42.9% meningitis, 59.3% meningoencephalitis, 72.4% encephalitis) still have no etiological diagnosis.


A systematic review of factors predicting door to balloon time in ST-segment elevation myocardial infarction treated with percutaneous intervention.
Door to balloon time is important in the outcome of ST-elevation myocardial infarction treated with primary percutaneous intervention. This review summarizes prognostic factors for door to balloon time in STEMI patients presenting to a PCI capable hospital. NLM Gateway and Cochrane CENTRAL are the primary data sources. Searched reports were screened by title and abstract and full texts were located for potentially relevant articles. References from the selected articles and relevant background papers were hand searched for additional reports. Articles were reviewed and assessed for risk of bias. The results are summarized without meta-analysis. 90 papers are included in the review. Individual study quality was variable but was generally low. A number of patient characteristics, hospital characteristics, physician characteristics, care processes and "other" factors were associated with door to balloon time. Prognostic factors for longer times include: pre-hospital delay in presentation, cerebrovascular disease, absence of chest pain, lower PCI volume and specialization hospital, lower sum ST elevation, absence of Q waves and left bundle branch block. Shorter times were associated with: presentation during regular hours, PCI in a more recent year, 24 hour on site cardiology, pre-hospital ECG, single call to central page to activate the catheterization lab, ER physician activating the cath lab, lab staff arriving within 20 min of paging and culprit vessel PCI before full diagnostic angiography. Understanding prognostic factors for door to balloon time can likely lead to improved quality of care for STEMI.


Pregnancy detection and monitoring in cattle via combined foetus electrocardiogram and phonocardiogram signal processing.
Pregnancy testing in cattle is commonly invasive requiring manual rectal palpation of the reproductive tract that presents risks to the operator and pregnancy. Alternative non-invasive tests have been developed but have not gained popularity due to poor specificity, sensitivity and the inconvenience of sample handling. Our aim is to present the pilot study and proof of concept of a new non invasive technique to sense the presence and age (limited to the closest trimester of pregnancy) of the foetus by recording the electrical and audio signals produced by the foetus heartbeat using an array of specialized sensors embedded in a stand alone handheld prototype device. The device was applied to the right flank (approximately at the intercept of a horizontal line drawn through the right mid femur region of the cow and a vertical line drawn anywhere between lumbar vertebrae 3 to 5) of more than 2000 cattle from 13 different farms, including pregnant and not pregnant, a diversity of breeds, and both dairy and beef herds. Pregnancy status response is given "on the spot" from an optimized machine learning algorithm running on the device within seconds after data collection. Using combined electrical and audio foetal signals we detected pregnancy with a sensitivity of 87.6% and a specificity of 74.6% for all recorded data. Those values increase to 91% and 81% respectively by removing files with excessive noise (19%).Foetus ageing was achieved by comparing the detected foetus heart-rate with published tables. However, given the challenging farm environment of a restless cow, correct foetus ageing was achieved for only 21% of the correctly diagnosed pregnant cows. In conclusion we have found that combining ECG and PCG measurements on the right flank of cattle provides a reliable and rapid method of pregnancy testing. The device has potential to be applied by unskilled operators. This will generate more efficient and productive management of farms. There is potential for the device to be applied to large endangered quadrupeds in captive breeding programs where early, safe and reliable pregnancy diagnosis can be imperative but currently difficult to achieve.


Androgen receptor expression is associated with adverse pathological features in ureteral but not in pelvicalyceal urothelial carcinomas of the upper urinary tract.
This study aims to determine the significance of androgen receptor (AR) expression in urothelial carcinoma of the upper urinary tract (UTUC). AR expression was assessed on tissue microarrays containing specimens of 737 patients with UTUC who underwent radical nephroureterectomy with curative intent. AR expression was correlated with clinical and pathological tumor features as well as recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Overall, AR was expressed in 11 % of tumors. AR expression was significantly associated with tumor necrosis as well as sessile and multifocal tumor growth but not with RFS, CSS or OS. AR was detected nearly twice as often in tumors of the ureter than of the pelvicalyceal system (p = 0.005). Subgroup analyses showed that the significant associations of AR with unfavorable pathologic features were exclusively attributable to tumors located in the ureter. However, in both ureteral and pelvicalyceal tumors, AR status was independent of RFS, CSS and OS. In this cohort of patients treated with RNU, AR expression was found in approximately 10 % of UTUCs, twice as often in ureteral than in pelvicalyceal tumors. While AR expression had no impact on postoperative prognosis, it was significantly associated with unfavorable pathologic features in ureteral tumors. Steroid hormone signaling might be relevant for future investigations of differences between ureteral and pelvicalyceal tumors.


Voices unheard: barriers to expressing dissatisfaction to health plans.
Consumers dissatisfied with their health plan can either "exit" (switch service providers) or "voice" (complain to the current provider). Policymakers' efforts to help consumers voice their dissatisfaction to health plans or external mediators have been disappointing, in part because little is known about the determinants of voice. This article represents the first comprehensive assessment of voicing in response to problematic experiences with health plans. A national consumer survey from 1999 is used to test hypotheses about characteristics of problems, patients, and settings that might inhibit voice and assess state regulations intended to enhance voice. Although problems associated with plans led to more voice than exit, voice is circumscribed by several factors: certain groups, such as racial minorities, do not express their grievances as often; episodes with severe health consequences for patients are not reported as regularly. The findings suggest that even though regulatory initiatives have not increased the frequency of voice, they have made grievances more effective, at least in jurisdictions where citizens know about the laws.


The eye lens: age-related trends and individual variations in refractive index and shape parameters.
The eye lens grows throughout life by cell accrual on its surface and can change shape to adjust the focussing power of the eye. Varying concentrations of proteins in successive cell layers create a refractive index gradient. The continued growth of the lens and age-related changes in proteins render it less able to alter shape with loss of capacity by the end of the sixth decade of life. Growth and protein ageing alter the refractive index but as accurate measurement of this parameter is difficult, the nature of such alterations remains uncertain. The most accurate method to date for measuring refractive index in intact lenses has been developed at the SPring-8 synchrotron. The technique, based on Talbot interferometry, has an X-ray source and was used to measure refractive index in sixty-six human lenses, aged from 16 to 91 years. Height and width were measured for forty-five lenses. Refractive index contours show decentration in some older lenses but individual variations mask age-related trends. Refractive index profiles along the optic axis have relatively flat central sections with distinct micro-fluctuations and a steep gradient in the cortex but do not exhibit an age-related trend. The refractive index profiles in the equatorial aspect show statistical significance with age, particularly for lenses below the age of sixty that had capacity to alter shape in vivo. The maximum refractive index in the lens centre decreases slightly with age with considerable scatter in the data and there are age-related variations in sagittal thickness and equatorial height.


Modulation of costimulation by CD28 and CD154 alters the kinetics and cellular characteristics of corneal allograft rejection.
To examine the effect of modulating the lymphocyte costimulation pathways through CD28 and CD154 (CD40 ligand) in a model of corneal allograft rejection, with particular interest in changes in the observed features of rejection. CD28 knock-out (CD28KO) and wild-type BALB/c control mice received corneal grafts from fully major histocompatibility complex (MHC)-mismatched C3H donors and were treated with CTLA4-Ig and/or anti-CD154 Ab on days 0, 2, and 4 after transplantation. Proliferation of BALB/c and CD28KO T cells in response to C3H stimulators was examined in a mixed lymphocyte reaction (MLR) in the presence of CTLA4-Ig or anti-CD154 Ab. Corneal allograft survival in wild-type BALB/c mice (median survival time [MST] 14 days) was significantly prolonged by blockade of the costimulatory pathways with CTLA4-Ig or anti-CD154 Ab (MST 21 days and 25 days respectively). MST in recipients treated with CTLA4-Ig and anti-CD154 Ab in combination was 29 days, not significantly longer than graft survival in single-treatment groups. MST in CD28KO recipients was 46 days and was not prolonged after treatment with anti-CD154 Ab (MST, 43 days). A similar result was found in the MLR, in which anti-CD154 Ab had no effect on proliferation of CD28KO compared with wild-type T cells. In CTLA4-Ig-treated CD28KO, grafts were rejected at an accelerated tempo, similar to that in wild-type BALB/c recipients (MST 16 days). More severe graft injury after the onset of rejection in untreated allograft recipients was accompanied by a higher number of graft-infiltrating CD45(+) cells, but similar proportions of CD4(+) and CD8(+) cells. CD28- and CD154-mediated costimulation have significant functional roles in corneal allograft rejection. Agents that modulate CD28 and CD154 pathways delay onset and reduce the severity of observed allograft rejection. However, their use in combination did not have an additive effect, MLR data indicating that the CD40-CD154 system depends on a functioning CD28 costimulatory pathway.


Occupational respiratory cancer in Korea.
Malignant mesothelioma and lung cancer are representative examples of occupational cancer. Lung cancer is the leading cause of cancer death, and the incidence of malignant mesothelioma is expected to increase sharply in the near future. Although information about lung carcinogen exposure is limited, it is estimated that the number of workers exposed to carcinogens has declined. The first official case of occupational cancer was malignant mesothelioma caused by asbestos exposure in the asbestos textile industry in 1992. Since then, compensation for occupational respiratory cancer has increased. The majority of compensated lung cancer was due to underlying pneumoconiosis. Other main causative agents of occupational lung cancer included asbestos, hexavalent chromium, and crystalline silica. Related jobs included welders, foundry workers, platers, plumbers, and vehicle maintenance workers. Compensated malignant mesotheliomas were associated with asbestos exposure. Epidemiologic studies conducted in Korea have indicated an elevated risk of lung cancer in pneumoconiosis patients, foundry workers, and asbestos textile workers. Occupational respiratory cancer has increased during the last 10 to 20 yr though carcinogen-exposed population has declined in the same period. More efforts to advance the systems for the investigation, prevention and management of occupational respiratory cancer are needed.


Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP.
POEMS syndrome (the acronym reflects the common features: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a paraneoplastic disorder with a 'demyelinating' peripheral neuropathy that is often mistaken for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The nerve conduction study (NCS) and electromyography (EMG) attributes that might differentiate POEMS from CIDP and lead to earlier therapeutic intervention were explored. NCS/EMG of POEMS patients identified through retrospective review from 1960 to 2007 were compared with matched CIDP controls. 138 POEMS patients and 69 matched CIDP controls were compared. POEMS patients demonstrated length dependent reduction in compound muscle action potentials, low conduction velocities, prolonged distal latencies and prolonged F wave latencies. Compared with CIDP controls, POEMS patients demonstrated: (1) greater reduction of motor amplitudes, (2) greater slowing of motor and sensory conduction velocities, (3) less prolonged motor distal latencies, (4) less frequent temporal dispersion and conduction block, (5) no sural sparing, (6) greater number of fibrillation potentials in a length dependent pattern and (7) higher terminal latency indices (TLI). TLI ≥0.38 in the median nerve demonstrated a sensitivity of 70% and specificity of 77% in discriminating POEMS from CIDP. NCS/EMG of POEMS syndrome suggests both axonal loss and demyelination. Compared with CIDP, there is greater axonal loss (reduction of motor amplitudes and increased fibrillation potentials), greater slowing of the intermediate nerve segments, less common temporal dispersion and conduction block, and absent sural sparing. These findings imply that the pathology of POEMS syndrome is diffusely distributed (uniform demyelination) along the nerve where the pathology of CIDP is probably predominantly proximal and distal. Median motor TLI may be useful in clinically distinguishing these disorders.


Regulating the retention of T-cell receptor alpha chain variants within the endoplasmic reticulum: Ca(2+)-dependent association with BiP.
Immunoglobulin heavy chain binding protein (BiP, GRP 78) coprecipitates with soluble and membrane-associated variants of the T-cell antigen receptor alpha chain (TCR-alpha) which are stably retained within the ER. Chelation of Ca2+ during solubilization of cells leads to the dissociation of BiP from the TCR-alpha variants, which is dependent upon the availability of Mg2+ and hydrolyzable ATP; this suggests that Ca2+ levels can serve to modulate the association/dissociation of these proteins with BiP. In vivo treatment of cells expressing either the soluble or membrane-anchored TCR-alpha variants with the Ca2+ ionophore, A23187, or an inhibitor of an ER Ca(2+)-ATPase, thapsigargin, or the membrane-permeant Ca2+ chelator BAPTA-AM, results in the redistribution of these proteins out of the ER and their subsequent secretion or cell surface expression. Under the same assay conditions, no movement of BiP out of the ER is observed. Taken together, these observations indicate that decreased Ca2+ levels result in the dissociation of a protein bound to BiP, leading to its release from ER retention. These data suggest that the intracellular fate of newly synthesized proteins stably associated with BiP can be regulated by Ca2+ levels in the ER.


The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial.
The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.


Compact two-photon fluorescence microscope based on a single-mode fiber coupler.
We present a two-photon fluorescence microscope based on a three-port single-mode optical fiber coupler. It is found that the coupler behaves as a low-pass filter that can deliver an ultrashort-pulsed laser beam of as much as 150 mW of power in the wavelength range from 770 to 870 nm as well as collect a two-photon fluorescence signal in the visible range. As a result of using the fiber coupler, the new two-photon imaging system exhibts a number of advantages, including a compact arrangement, freedom from vibration from lasers and electronic devices, self-alignment, reduction of multiple scattering, and an enhanced optical sectioning effect. The effectiveness of the new instrument is demonstrated with a set of three-dimensional images of biological samples. This instrument may make two-photon fluorescence endoscopy possible for in vivo medical applications.


Sibling recurrence and the genetic epidemiology of autism.
Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings. The authors report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register, with at least one child clinically affected by an autism spectrum disorder and at least one full biological sibling. A traditionally defined autism spectrum disorder in an additional child occurred in 10.9% of the families. An additional 20% of nonautism-affected siblings had a history of language delay, one-half of whom exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale supported previously reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multiple-incidence families and a relative absence of quantitative autistic traits among siblings in single-incidence families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts. These data suggest that, depending on how it is defined, sibling recurrence in autism spectrum disorder may exceed previously published estimates and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism and advance current understanding of the genetic epidemiology of autism spectrum conditions.


Effect of fatty acids on lipid and apoprotein secretion and association in hepatocyte cultures.
Increasing availability of free fatty acids (FFA) to liver results in enhanced rates of secretion of triglycerides in lipoproteins. However, as FFA uptake increases, triglyceride secretory rates reach a plateau and esterified fatty acids accumulate intracellularly, suggesting that something is limiting lipid transport out of the liver. One possibility could be the limited availability of apoproteins. To test this hypothesis, primary rat hepatocytes in culture were incubated with increasing amounts of FFA (0-2.1 mumol/dish) and the amounts of lipids and apoproteins inside the cells and in culture media were measured; the latter by specific radioimmunoassays. Media also were fractionated on Sepharose 2B and 6B columns and the elution profiles of apoproteins were obtained. With exposure to increasing amounts of free fatty acids, hepatocytes took up more fatty acids and intracellular levels of triglycerides rose (from 71 to 146 micrograms/mg cell protein). Concomitantly, media triglycerides nearly doubled (31 to 51 micrograms/mg). Incorporation of [3H]glyceride into cellular and media triglyceride also rose. However, levels of apoproteins A-I, B, C-III3, and E in cells and media were unchanged. The increasing amounts of triglycerides in media were present in larger particles, as demonstrated on gel permeation chromatography. The elution profiles of apoproteins B, C-III3, and E were altered in that a greater proportion of the apoproteins eluted with larger particles. Similar results were obtained when hepatocytes were preloaded with increasing amounts of FFA over 12 h and analyses of cells and media were carried out 8 and 22 h after removal of fatty acids from the media. During loading of cells, accumulation of cellular triglycerides was directly related to media FFA concentrations. During unloading, triglyceride secretory rates were related to cellular triglyceride levels. At higher triglyceride secretory rates larger particles were secreted and a greater proportion of apoproteins was associated with the larger particles, but total amounts of apoproteins in the system did not change. These data lead us to suggest that enhanced rates of apoprotein synthesis need not occur in the response to acute changes in hepatic lipid transport, rather, increased secretion of lipid is brought about by augmented intracellular lipid apoprotein association.


Effect of travel distance and rurality of residence on initial surveillance for hepatocellular carcinoma in VA primary care patient with cirrhosis.
To determine the relationship between travel distance and surveillance for hepatocellular carcinoma among veterans with cirrhosis. Veterans Health Administration (VHA) inpatient and outpatient administrative data were linked to geocoded enrollee files. CMS-VHA merged data were used to assess receipt of Medicare-financed non-VA imaging. A retrospective cohort of US veterans diagnosed with cirrhosis between 2009 and 2015 was examined. First available abdominal imaging following the diagnosis of cirrhosis was analyzed separately as a function of travel distance to the nearest VA medical center (VAMC) and to the patient's assigned VA primary care provider. Veterans with dual use of Medicare and VA services were also examined for receipt of imaging outside of the VA. Veterans who resided more than 30 miles from the nearest VAMC were less likely to receive any imaging for HCC surveillance. Among dual users, increased travel distance between the patient's residence and nearest VAMC was associated with an increased likelihood of receiving any abdominal imaging at non-VA facilities. Increased travel distance to the nearest VA medical center reduces the likelihood of receiving imaging for HCC surveillance in cirrhotic veterans. Future efforts should focus on reducing geographic barriers to HCC surveillance.


Impact of variability in adherence to HIV antiretroviral therapy on the immunovirological response and mortality.
Several previous studies have shown relationships between adherence to HIV antiretroviral therapy (ART) and the viral load, the CD4 cell count, or mortality. However, the impact of variability in adherence to ART on the immunovirological response does not seem to have been investigated yet. Monthly adherence data (November 1999 to April 2009) from 317 HIV-1 infected patients enrolled in the Senegalese ART initiative were analyzed. Latent-class trajectory models were used to build typical trajectories for the average adherence and the standardized variance of adherence. The relationship between the standardized variance of adherence and each of the change in CD4 cell count, the change in viral load, and mortality were investigated using, respectively, a mixed linear regression, a mixed logistic regression, and a Cox model with time-dependent covariates. All the models were adjusted on the average adherence. Three latent trajectories for the average adherence and three for the standardized variance of adherence were identified. The increase in CD4 cell count and the increase in the percentage of undetectable viral loads were negatively associated with the standardized variance of adherence but positively associated with the average adherence. The risk of death decreased significantly with the increase in the average adherence but increased significantly with the increase of the standardized variance of adherence. The impacts of the level and the variability of adherence on the immunovirological response and survival justify the inclusion of these aspects into the process of patient education: adherence should be both high and constant.


Distinguishing Anuran species by high-resolution melting analysis of the COI barcode (COI-HRM).
Taxonomic identification can be difficult when two or more species appear morphologically similar. DNA barcoding based on the sequence of the mitochondrial cytochrome c oxidase 1 gene (COI) is now widely used in identifying animal species. High-resolution melting analysis (HRM) provides an alternative method for detecting sequence variations among amplicons without having to perform DNA sequencing. The purpose of this study was to determine whether HRM of the COI barcode can be used to distinguish animal species. Using anurans as a model, we found distinct COI melting profiles among three congeners of both Lithobates spp. and Hyla spp. Sequence variations within species shifted the melting temperature of one or more melting domains slightly but do not affect the distinctness of the melting profiles for each species. An NMDS ordination plot comparing melting peak profiles among eight Anuran species showed overlapping profiles for Lithobates sphenocephala and Gastrophryne carolinensis. The COI amplicon for both species contained two melting domains with melting temperatures that were similar between the two species. The two species belong to two different families, highlighting the fact that COI melting profiles do not reveal phylogenetic relationships but simply reflect DNA sequence differences among stretches of DNA within amplicons. This study suggests that high-resolution melting analysis of COI barcodes (COI-HRM) may be useful as a simple and rapid method to distinguish animal species that appear morphologically similar.


Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen?
Second primary cancers are a serious late occurrence for patients surviving Hodgkin's disease (HD). In addition to previously described risk factors such as age, gender, clinical stage, and treatment modalities, splenectomy was found to correlate with an increase in risk for secondary acute leukemia. We assumed that splenic irradiation inducing functional hyposplenia and splenectomy could have similar consequences on second cancer risk. We studied a series of 892 continuously disease-free HD adult patients treated at a single institution between 1960 and 1984. The risk of second cancer was analyzed (1) relative to the general population and (2) between risk subgroups using the Cox proportional hazards model. Fifty-six patients developed a second cancer (8 acute leukemias, 3 myelodysplastic syndromes, 8 non-Hodgkin's lymphomas, and 37 solid tumors; basal cell and in situ cervix carcinomas were excluded). The 15-year cumulative incidence rate (with 95% confidence limits) was 13.2% (9.3% to 17.2%). Relative to the general population incidence data, the risk of second cancer was multiplied by 4.68 (3.51 to 6.12; P < .001); it was multiplied by 2.80 (1.63 to 4.48; P < .001) in patients whose spleen was not treated and multiplied by 6.87 (4.81 to 9.51; P < .001) in splenectomized patients or patients whose spleen was irradiated. Multivariate regression analysis that controlled for confounding variables (age, gender, clinical stage, extent of radiation therapy, and chemotherapy regimen) showed that, in addition to age above 40 years (relative risk [RR] = 3.72; P < .001), combination of MOPP chemotherapy and regional irradiation (RR = 4.99; P = .015) and combination of MOPP chemotherapy and extended irradiation (RR = 10.86; P < .001), splenic irradiation (RR = 3.67; P = .003), and splenectomy (RR = 2.54; P = .018) also significantly correlated with an increased risk. The results of this hospital-based registry study strongly suggest that splenic irradiation and splenectomy might increase the risk for treatment-related second cancer. These findings, if confirmed, have to be considered in future HD treatment policies.


Regiospecific formal [3 + 2] annulation of tert-propargyl alcohols with acyclic 1,3-diketones via the cycloisomerization of homoallenyl ketones.
A one-pot, regiospecific synthesis of dihydrofurans bearing a quaternary centre and tetrasubstituted furans is developed from the formal [3 + 2] annulation of tert-propargyl alcohols and 1,3-diketones under Ca(ii)/DBU conditions. The reaction proceeds through the SN2I mechanism to form homoallenyl ketone and a subsequent cycloisomerization to yield novel and new chemical entities of privileged scaffolds.


History, geography and population structure influence the distribution and heritability of blood and anthropometric quantitative traits in nine Sardinian genetic isolates.
Isolated founder populations which exhibit great genetic and environmental homogeneity provide an attractive setting for the study of quantitative traits (QTs). Geneticists have repeatedly turned to population isolates and the past successes have prompted increased interest among medical researchers. We studied nine small isolated villages of a secluded area of Sardinia (Ogliastra), all of them characterized by a few founders, high endogamy rates, slow population expansion and a distinct genetic makeup. Anthropometric and blood parameters, 43 QTs in all, were analysed in about 9000 voluntary subjects for whom extended genealogical information was available. We explored the distribution and examined mean differences of each trait among villages by analysis of variance (ANOVA). A heritability analysis with the variance component (VC) method was performed. Results show significant differences in the distribution of most traits between groups of villages located in two distinct geographical areas already identified by a previous population structure analysis, thus supporting the existence of differentiation among sub-populations in the same region. Heritability estimates range between 30 and 89%, demonstrating that genetic effects substantially contribute to phenotypic variation of all investigated traits and that this population provides excellent research conditions for gene-mapping projects. Results suggest that history, geographic location and population structure may have influenced the genetic and phenotypic features of these isolates. Our findings may be useful for the ongoing linkage and association studies in these isolates and suggest that a thorough characterization of population is valuable to better identify genes or variants that may be rare in the population at large and peculiar to single villages.


Turkish Thoracic Society Experts Consensus Report: Recommendations for Pulmonary Function Tests During and After COVID 19 Pandemic.
The recommendation of conducting pulmonary function tests (PFTs) from different societies during and after the coronavirus disease (COVID-19) pandemic was rated by the experts of the Turkish Thoracic Society (TTS) and presented as the TTS experts consensus report. Information about the topic has been provided.Globally, as of mid-May 2020, there have been over 4.4 million confirmed cases of COVID-19. There are two main routes of transmission of COVID-19: respiratory droplets and contact transmission. PFTs are non-invasive tests that are commonly performed in routine assessment and follow-up of patients in the pulmonology units. However, PFTs may generate aerosols and require sharing common surfaces. With regard to the high prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the community, PFTs should not be performed routinely in confirmed or suspected patients with COVID-19 during the pandemic. Because of the risk of human-to-human transmission of COVID-19, PFTs should be restricted to a small patient population with selected indications. Triage for COVID-19 should be performed prior to testing. Only essential PFTs such as spirometry, diffusion capacity of the lungs for carbon monoxide (DLCO), arterial blood gas analysis, or pulse oximetry should be performed in the selected cases. Tests should be scheduled to allow sufficient time for donning and doffing of the technical personnel with the full personal protective equipment (PPE) (gown, a filtering respirator mask, goggles or full-face shield, and disposable gloves), ventilation of the room, and application of post-test cleaning and disinfection procedures of the equipment and the testing room.


How is active transport associated with children's and adolescents' physical activity over time?
As few longitudinal studies have examined how active transport is associated with physical activity among children and adolescents over time, and how active transport tracks through childhood and adolescence, it is important to understand whether physically active children retain their activity patterns through adolescence. This study aimed to examine (a) tracking of active transport and of moderate-to-vigorous physical activity (MVPA) across childhood and adolescence in two age cohorts; and (b) associations between active transport and MVPA at three distinct time-points, over five years. This longitudinal study of two cohorts aged 5-6 years (n = 134) and 10-12 years (n = 201) at baseline (T1), in Melbourne, Australia, gathered follow-up data at three (T2) and five years (T3). Walking/cycling to local destinations was survey-reported; while MVPA was recorded using accelerometers and mean time spent daily in MVPA on week days and on weekends was computed. Tracking of these behaviours was examined over five years using General Estimating Equations. Linear regression analyses were performed to examine associations between active transport and MVPA at each time-point. Active transport tracked moderately among children (boys, βs = 0.36; girls, βs = 0.51) but not among adolescents. Physical activity tracked moderately (βs value range: 0.33-0.55) for both cohorts. Active transport was not associated with children's MVPA at any time-point, but was associated with adolescent boys' MVPA on week days at T1 (B = 1.37 (95% CI: 0.15, 2.59)), at T2 (B = 1.27 (95% CI: 0.03, 2.51)) and at T3 (B = 0.74 (95% CI: 0.01, 1.47)), and with adolescent girls' MVPA on week days (B = 0.40 (95% CI: 0.04, 0.76)) and on weekends (B = 0.54 (95% CI: 0.16, 0.93)) at T3 only. Active transport was associated only with boys' MVPA during early adolescence and with boys' and girls' MVPA during late adolescence. While active transport should be encouraged among all school-aged children, it may provide an important source of habitual physical activity for adolescent girls, in particular, among whom low and declining physical activity levels have been reported world-wide.


Recent national trends in Salvia divinorum use and substance-use disorders among recent and former Salvia divinorum users compared with nonusers.
CONTEXT: Media and scientific reports have indicated an increase in recreational use of Salvia divinorum. Epidemiological data are lacking on the trends, prevalence, and correlates of S. divinorum use in large representative samples, as well as the extent of substance use and mental health problems among S. divinorum users. OBJECTIVE: To examine the national trend in prevalence of S. divinorum use and to identify sociodemographic, behavioral, mental health, and substance-use profiles of recent (past-year) and former users of S. divinorum. DESIGN: Analyses of public-use data files from the 2006-2008 United States National Surveys on Drug Use and Health (N = 166,453). SETTING: Noninstitutionalized individuals aged 12 years or older were interviewed in their places of residence. MAIN MEASURES: Substance use, S. divinorum, self-reported substance use disorders, criminality, depression, and mental health treatment were assessed by standardized survey questions administered by the audio computer-assisted self-interviewing method. RESULTS: Among survey respondents, lifetime prevalence of S. divinorum use had increased from 0.7% in 2006 to 1.3% in 2008 (an 83% increase). S. divinorum use was associated with ages 18-25 years, male gender, white or multiple race, residence of large metropolitan areas, arrests for criminal activities, and depression. S. divinorum use was particularly common among recent drug users, including users of lysergic acid diethylamide (53.7%), ecstasy (30.1%), heroin (24.2%), phencyclidine (22.4%), and cocaine (17.5%). Adjusted multinomial logistic analyses indicated polydrug use as the strongest determinant for recent and former S. divinorum use. An estimated 43.0% of past-year S. divinorum users and 28.9% of former S. divinorum users had an illicit or nonmedical drug-use disorder compared with 2.5% of nonusers. Adjusted logistic regression analyses showed that recent and former S. divinorum users had greater odds of having past-year depression and a substance-use disorder (alcohol or drugs) than past-year alcohol or drug users who did not use S. divinorum. CONCLUSION: S. divinorum use is prevalent among recent or active drug users who have used other hallucinogens or stimulants. The high prevalence of substance use disorders among recent S. divinorum users emphasizes the need to study health risks of drug interactions.


Barriers to access to visceral leishmaniasis diagnosis and care among seasonal mobile workers in Western Tigray, Northern Ethiopia: A qualitative study.
Ethiopia bears a high burden of visceral leishmaniasis (VL). Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist. The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death. Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs. In 2017, 50 interviews and 11 focus group discussions were conducted with MWs, mobile residents, VL patients and caretakers, community leaders and healthcare workers in Kafta Humera District, Tigray. Participants reported high vulnerability to VL among MWs and residents engaged in transitory work. Multiple visits to health facilities were consistently needed to access VL diagnosis. Inadequate healthcare worker training, diagnostic test kit unavailability at the primary healthcare level, lack of VL awareness, insufficient finances for care-seeking and prioritization of income-generating activities were significant barriers to diagnosis and care. Social (decision-making and financial) support strongly and positively influenced care-seeking; workers unable to receive salary advances, compensation for partial work, or peer assistance for contract completion were particularly disadvantaged. Participants recommended the government/stakeholders intervene to ensure: MWs access to bed-nets, food, shelter, water, and healthcare at farms or sick leave; decentralization of diagnostic tests to primary healthcare facilities; surplus medications/staff during the peak season; improved referral/feedback/reporting/training within the health system; free comprehensive healthcare for all VL-related services; and community health education. Contrary to what health policy for VL dictates in this endemic setting, study participants reported very poor access to diagnosis and, consequently, significantly delayed access to treatment. Interventions tailored to the socio-economic and health needs of MWs (and other persons suffering from VL) are urgently needed to reduce health disparities and the VL burden.


[Hemodialysis case in which RCC was identified after disappearance of perirenal hematoma following spontaneous renal rupture treated by transcatheter arterial embolization].
A 55-year-old man who had been undergoing hemodialysis for 9 years visited our institution after the sudden onset of severe left flank pain. He presented with hypotension and was admitted immediately because computed tomography (CT) revealed a massive perirenal hematoma. Renal arteriography showed contrast media leakage at the lower branch of the left renal artery, and spontaneous renal rupture was diagnosed. Five months after the bleeding was stopped by selective transcatheter embolization of the branch of renal artery, CT showed an enhanced mass at the upper pole of left kidney and renal cell carcinoma (RCC) was suspected. Radical nephrectomy was performed, the pathological diagnosis was clear cell carcinoma, and the man has not experienced recurrence within 36 months after the surgery. RCC did not appear to be the cause of the original hemorrhage because there was a small residual hematoma in the middle of the renal parenchyma that was separated from the RCC. In cases of spontaneous renal rupture, re-evaluation by imaging studies is mandatory after disappearance of perirenal hematoma because imaging studies at the time of the rupture sometimes do not reveal the cause of the hemorrhage.


Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells.
The small, water soluble molecule Dichloroacetate (DCA) is recently arousing lively interests in the field of cancer therapy for it has been shown to be able to inhibit the growth of human tumors acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells. Neuroblastoma was one of the tumor types on which DCA was considered ineffective as it is composed of cells with few recognized mitochondrial anomalies. Neuroblastoma, however, is composed of different cell types in terms of metabolism, phenotype and malignant potential. Despite the above prediction, in this work, we show that (i) DCA exhibits an unexpected anticancer effect on NB tumor cells and (ii) this effect is selectively directed to very malignant NB cells, whereas the more differentiated/less malignant NB cells are refractory to DCA treatment. This result supports the need of a detailed investigation of DCA anticancer properties against this tumor type with the final aim of its possible use as therapeutic agent.


Genetic Instability in Lymphocytes is Associated With Blood Plasma Antioxidant Levels in Health Care Workers Occupationally Exposed to Ionizing Radiation.
Earlier reports have suggested that exposure to radiation at workplace may induce cytogenetic abnormalities. However, the association between plasma antioxidants and the cytogenetic abnormalities in these patients has not been elucidated till now. Hence, the present study was undertaken to determine the relationship between the cytogenetic abnormalities, plasma antioxidant system, and the radiation exposure levels in men who were occupationally exposed to ionizing radiation. The study included 134 male volunteers, among whom 83 were occupationally exposed to ionizing radiation. Incidence of micronuclei and chromosomal aberration was assessed in lymphocytes. Total and reduced glutathione (GSH), total antioxidant capacity (TAC), superoxide dismutase (SOD), and lipid peroxidation were assessed in the plasma. The micronuclei frequency and chromosomal aberrations were significantly higher in the exposed group in comparison to the nonexposed group (P < 0.01-0.0001). Similarly, GSH, TAC, and SOD in the blood plasma were significantly higher in the exposed group than the nonexposed group (P < 0.01-0.0001). However, the level of malondialdehyde, which is an indicator of lipid peroxidation, did not differ significantly between both the groups. Importantly, radiation absorbed dose exhibited a positive correlation with the incidence of micronuclei in blood lymphocytes but not with chromosomal aberrations. This study shows that the susceptibility of peripheral blood lymphocytes to chromosomal damage is associated with plasma antioxidant levels. Furthermore, increased levels of blood plasma GSH, TAC, and SOD in occupationally exposed individuals could be an adaptive measure in response to oxidative stress to protect somatic cell genetic integrity.


Behaviour/emotional problems in male juvenile delinquents and controls in Russia: the role of personality traits.
Recent studies based on the psychobiological theory of personality by Cloninger postulate a relationship between certain personality traits and various psychopathological manifestations. To test this theory, we administered the Temperament and Character Inventory and the Youth Self-Report to 188 male delinquents from a juvenile correction centre in Northern Russia, and to 111 age-matched male controls recruited from among schoolchildren. As assumed by previous studies, psychological symptoms were primarily positively correlated with harm avoidance and negatively correlated with self-directedness. At the same time, the higher levels of aggressive and delinquent behaviour were positively correlated with novelty-seeking and negatively correlated with co-operativeness. The possible mechanisms underlying these findings are discussed.


InWiM: knowledge management for insurance medicine.
Suva (Swiss National Accident Insurance Fund) is the most important carrier of obligatory accident insurance in Switzerland. Its services not only comprise insurance but also prevention, case management and rehabilitation. Suva's medical division supports doctors in stationary and ambulatory care with comprehensive case management and with conciliar advice. Two Suva clinics provide stationary rehabilitation. Medicine in general, including insurance medicine, faces the problem of a diversity of opinions about the facts of a case. One of the reasons is a diversity of knowledge. This is the reason why Suva initiated a knowledge management project called InWiM. "InWiM" is the acronym for "Integrierte Wissensbasen der Medizin" which can be translated as "Integrated Knowledge Bases in Medicine". The project is part of an ISO 9001 certification program and comprises the definition and documentation of all processes in the field of knowledge management as well as the development of the underlying ITC infrastructure. The knowledge representation model used for the ICT implementation considers knowledge as a multidimensional network of interlinked units of information. In contrast to the hyperlink technology in the World Wide Web, links between items are bidirectional: the target knows the source of the link. Links are therefore called cross-links. The model allows annotation for the narrative description of the nature of the units of information (e.g. documents) and the cross-links as well. Information retrieval is achieved by means of a full implementation of the MeSH Index, the thesaurus of the United States National Library of Medicine (NLM). As far as the authors are aware, InWiM is currently the only implementation worldwide - with the exception of the NLM and its national representatives - which supports all MeSH features for in-house retrieval.


Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E.
One strategy to improve therapies in advanced prostate cancer (PC) involves targeting genes that are activated by androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. Heat shock protein 27 (Hsp27) expression becomes highly upregulated in PC cells after androgen withdrawal or chemotherapy, in which it functions as a cytoprotective chaperone to confer broad-spectrum treatment resistance. The purpose of this study is to elucidate anti-apoptotic pathways regulated by Hsp27 that are activated during PC progression. Using two-hybrid experiment, we found that Hsp27 was having a major role in the protein translational initiation process. Furthermore, using complementary DNA (cDNA) microarray analysis, 4E binding protein 1 was identified as being proportionately and highly regulated by Hsp27. These data led us to analyze the protein synthesis initiation pathway, which is a prerequisite for cell growth and proliferation. Using northern and western blot analysis, we found that Hsp27 downregulation decreased eukaryotic translation initiation factor 4E (eIF4E) expression at the protein, but not mRNA, level. The cytoprotection afforded by Hsp27 overexpression was attenuated by eIF4E knockdown using specific eIF4E short interfering RNA (siRNA). Co-immunoprecipitation and co-immunofluorescence confirmed that Hsp27 colocalizes and interacts directly with eIF4E. Hsp27-eIF4E interaction decreases eIF4E ubiquitination and proteasomal degradation. By chaperoning eIF4E, Hsp27 seems to protect the protein synthesis initiation process to enhance cell survival during cell stress induced by castration or chemotherapy. Forced overexpression of eIF4E induces resistance to androgen-withdrawal and paclitaxel treatment in the prostate LNCaP cells in vitro. These findings identify Hsp27 as a modulator of eIF4E and establish a potential mechanism for the eIF4E-regulated apoptosis after androgen ablation and chemotherapy. Targeting Hsp27-eIF4E interaction may serve as a therapeutic target in advanced PC.


Perspective on lead toxicity, a comparison between the United States and Iran.
Lead is a pervasive toxin that has been implicated in human poisonings throughout history. Exposure mitigation strategies in the United States and worldwide have led to a decline in symptomatic poisonings and population blood lead levels; however, lead remains a major health hazard. In this article, we review the history of lead toxicity, clinical manifestations ranging from subclinical and subtle features to life-threatening complications, and the subsequent public health interventions in the US. In addition, we explore common routes of lead exposure and the unique differences between the US and Iran. Although the US has made significant strides with regard to this public health issue, lead poisoning in both countries continues to be a health hazard in the adult and pediatric populations. It is also critical to consider natural disasters and reconstruction efforts as potential sources of lead contamination. In conclusion, we make recommendations that both the US and Iranian authorities can implement to eradicate lead as a public health hazard.


The H*1 hematology analyzer. Its performance characteristics and value in the diagnosis of infectious disease.
The performance characteristics and the value of data provided by the H*1 Automated Blood Cell Analyzer in the diagnosis of infectious disease are assessed. Data produced by the machine are precise over a wide range of complete blood cell counts and differential white blood cell (WBC) parameters. It is capable of accurately quantifying WBCs greater than 4000/mm3 (4 X 10(9)/L); red blood cells (RBCs), greater than 2.5 X 10(6)/mm3 (2.5 X 10(12)/L); and platelets greater than 1 X 10(3)/mm3 (1 X 10(9)/L). There is good agreement between the neutrophils and lymphocytes quantified by the standard microscopic count and the automated system; however, cells that are generally present in low incidence, namely, monocytes, basophils, and eosinophils, are less well correlated. The microscopic band cell count provides the greatest test efficiency in the diagnosis of infection. None of the unique parameters generated by the H*1 differential analyzer proved to have neither a test efficiency nor a diagnostic index greater than that of the absolute WBC count in the diagnosis of infection. The "left shift" in the leukocyte differential count as detected by the H*1 relates poorly to the presence of band neutrophils in the specimen. It is concluded that the state-of-the-art automated leukocyte differential count can dramatically reduce workload, but offers no advantage over the traditional differential WBC count in the diagnosis of infectious disease. Its potential value in the diagnosis of other conditions, particularly hematologic diseases, and in the sequential monitoring of infections in individual patients were not addressed by the present study.


Association of insulin resistance with overactive bladder in female patients.
Metabolic syndrome and obesity have been advocated to be risk factors for the development of overactive bladder (OAB). Additionally, insulin resistance is the underlying mechanism of metabolic syndrome. We aimed to investigate the association of insulin resistance with overactive bladder in female patients. We prospectively conducted the study in our urology department. Female patients aged between 30 and 76 years old applied to our policlinics with or without OAB symptoms were enrolled. One hundred and twenty-two patients with OAB and 62 age-matched controls without OAB were included into the study. Fasting serum insulin, glucose, high-density lipoprotein (HDL-c), and triglycerides levels were measured. Insulin resistance value was obtained via the homeostasis model assessment of insulin resistance (HOMA-IR) calculator. The chi-square and Mann-Whitney U tests were used to compare differences in variables. Serum insulin level was found higher in female patients with OAB (11.5±6.2 µU/mL) relative to controls (6.4±2.1 µU/mL), statistically significant (P=0.036). In addition, HOMA-IR was significantly found higher in the OAB group, 2.86 (0.76 to 17.04) in comparison to controls, 1.32 (0.67 to 224), P=0.018. High-density lipoprotein cholesterol levels (HDL-c) were significantly found lower in females with OAB. Insulin resistance can be associated to overactive bladder and may play significant role in pathogenesis.


The liver: a special case in transplantation tolerance.
Liver transplants are not often rejected in patients weaned from immunosuppression and are spontaneously accepted in some animal models. We review past and recent findings of liver transplantation and propose a unified model in which several mechanisms act in concert to induce and maintain tolerance in both naïve and effector T cell compartments. First, passenger leukocytes migrate to lymphoid tissues and induce apoptosis of alloreactive naïve T cells. Second, antigen-specific activation and subsequent deletion of naïve and effector cells within the liver itself purge the repertoire of alloreactive T cells. Other mechanisms such as microchimerism and migration of donor dendritic cells to the thymus may play a predominant role in maintaining tolerance, and soluble major histocompatibility complex molecules, donor peptides, and regulatory T cells may participate in the induction and maintenance phases. Thus, the major challenge in liver transplantation will be to favor these tolerogenic processes while developing strategies that specifically inhibit alloreactive memory T cells.


Effects of organic farming and genotype on alimentary and nutraceutical parameters in tomato fruits.
In recent years there has been growing interest in the influence of sustainable cultivation systems on the biochemical quality of vegetables. In this study, two genotypes of tomato, Giulianova and Perbruzzo, were grown in both organic (Or) and conventional (Conv) systems for three years and harvested at commercial ripening in each year. The Conv system was established according to traditional techniques and the Or system according to current EU regulations. Samples were evaluated for volatile substances, sugars, organic acids, dry matter, pH and lycopene. During the three years, volatile substances increased in Or samples of Giulianova, while this response was less evident in Perbruzzo. Other parameters of both genotypes were not influenced by Or cultivation. Lycopene content in both Conv-cultivated genotypes was constant during the whole experimental period. In Or samples, lycopene content was lower than in Conv samples during the first and second years. In the last year, lycopene content in Or samples of Giulianova was similar to that in Conv samples, while lycopene content in Or samples of Perbruzzo was higher than that in Conv samples. Changes in biochemical parameters of tomato fruits could be affected by both cultivation system and genotype, with a significant increase in both volatile substances and lycopene in the 2010 crop.


Signed words in the congenitally deaf evoke typical late lexicosemantic responses with no early visual responses in left superior temporal cortex.
Congenitally deaf individuals receive little or no auditory input, and when raised by deaf parents, they acquire sign as their native and primary language. We asked two questions regarding how the deaf brain in humans adapts to sensory deprivation: (1) is meaning extracted and integrated from signs using the same classical left hemisphere frontotemporal network used for speech in hearing individuals, and (2) in deafness, is superior temporal cortex encompassing primary and secondary auditory regions reorganized to receive and process visual sensory information at short latencies? Using MEG constrained by individual cortical anatomy obtained with MRI, we examined an early time window associated with sensory processing and a late time window associated with lexicosemantic integration. We found that sign in deaf individuals and speech in hearing individuals activate a highly similar left frontotemporal network (including superior temporal regions surrounding auditory cortex) during lexicosemantic processing, but only speech in hearing individuals activates auditory regions during sensory processing. Thus, neural systems dedicated to processing high-level linguistic information are used for processing language regardless of modality or hearing status, and we do not find evidence for rewiring of afferent connections from visual systems to auditory cortex.


Isoform-specific tethering links the Golgi ribbon to maintain compartmentalization.
Homotypic membrane tethering by the Golgi reassembly and stacking proteins (GRASPs) is required for the lateral linkage of mammalian Golgi ministacks into a ribbon-like membrane network. Although GRASP65 and GRASP55 are specifically localized to cis and medial/trans cisternae, respectively, it is unknown whether each GRASP mediates cisternae-specific tethering and whether such specificity is necessary for Golgi compartmentalization. Here each GRASP was tagged with KillerRed (KR), expressed in HeLa cells, and inhibited by 1-min exposure to light. Significantly, inactivation of either GRASP unlinked the Golgi ribbon, and the immediate effect of GRASP65-KR inactivation was a loss of cis- rather than trans-Golgi integrity, whereas inactivation of GRASP55-KR first affected the trans- and not the cis-Golgi. Thus each GRASP appears to play a direct and cisternae-specific role in linking ministacks into a continuous membrane network. To test the consequence of loss of cisternae-specific tethering, we generated Golgi membranes with a single GRASP on all cisternae. Remarkably, the membranes exhibited the full connectivity of wild-type Golgi ribbons but were decompartmentalized and defective in glycan processing. Thus the GRASP isoforms specifically link analogous cisternae to ensure Golgi compartmentalization and proper processing.


The role of past in the simulation of autobiographical future episodes.
Human beings' ability to envisage the future has been recently assumed to rely on the reconstructive nature of episodic memory (Schacter & Addis, 2007). In the present research, young adults mentally reexperienced and preexperienced temporally close and distant autobiographical episodes, and rated their phenomenal characteristics as well as their novelty. Additionally, they performed a delayed recognition task including remember-know judgments on new, old-remember, and old-imagine words. Results showed that past and future temporally close episodes included more phenomenal details than distant episodes, in line with earlier studies. However, future events were occasionally rated as already occurred in the past. Furthermore, in the recognition task, participants falsely attributed old-imagine words to remembered episodes. While partially in line with previous results, these findings call for a more subtle analysis in order to discriminate representations of past episodes from true future events simulations.


Prevention of mosquitoes (Diptera: Culicidae) and house flies (Diptera: Muscidae) from entering simulated aircraft with commercial air curtain units.
Commercially available air curtain units were used to create air barriers to prevent mosquitoes and house flies from entering a simulated aircraft doorway together with passengers. Two assemblies of simulated passenger bridge and aircraft were constructed, and airflow measurements were recorded to confirm airflow characteristics for several combinations of commercial units. Three mosquito species were selected for different host-seeking characteristics, and house flies were selected to represent a large, strong-flying insect. Batches of 20 or 200 insects of four species were released into the passenger bridge just before 25 persons passed through the assembly, then insects that entered the aircraft cabin were recovered. Results showed that horizontal plus vertical or vertical-mounted air curtain units with the airflow directed at a 45 degrees angle into the passenger bridge excluded 95-99% of the mosquitoes and 95-100% of the house flies, respectively. Airflows were measured and estimated to be effective if the mean was > 4 m/s in the critical area in the center of the converging airflows. The study validates the concept that air barriers can effectively prevent the passage of flying insects into an aircraft.


The paradoxes of asthma management: time for a new approach?
Poor adherence to maintenance pharmacotherapy is a reality in asthma. Studies confirm that when symptoms worsen, most patients increase short-acting β2-agonist (SABA) use, instead of using controller medication. This behaviour might be attributable to several paradoxes in the current treatment approach. These paradoxes include the recommended use of a SABA bronchodilator alone at Global Initiative for Asthma (GINA) step 1, despite the fact that asthma is a chronic inflammatory disease. At step 1, the patient has autonomy and their perception of need and disease control is accepted, but at higher asthma treatment steps a fixed-dose approach is recommended, irrespective of symptom severity. The unintended consequence is the establishment of a pattern of early over-reliance on SABA. New approaches that avoid these paradoxes are needed, such as patient-adjusted therapy, in which patients adopt a symptom-driven approach using a combination reliever/controller. We propose that SABA reliever monotherapy should be replaced by a combination of inhaled corticosteroid (ICS) and formoterol, or similar rapid-onset bronchodilator, as reliever therapy for patients at GINA steps 1 or 2. This will ensure early and more regular administration of a controller medication. However, a significant body of clinical data will be needed before this approach can be approved by regulatory authorities.


"It Doesn't Make Sense for Us Not to Have One"-Understanding Reasons Why Community Sports Organizations Chose to Participate in a Funded Automated External Defibrillator Program.
Implementation of automated external defibrillators (AEDs) in community sports settings is an important component of emergency medical planning. This study aimed to understand motivations for why sports organizations participated in a government-funded program that provided AEDs and associated first-aid training. Face-to-face interviews. Community sports organizations in Victoria, Australia. Representatives from 14 organizations who participated in a government-funded AED program. Motivations to participate in the AED program were explored using a qualitative descriptive approach. Two overarching themes emerged: awareness of the program and decision to apply. Awareness was gained indirectly through grant advertising in newsletters/emails/web sites and directly through their sporting associations. For most organizations, there was no decision process per se, rather, the opportunity to apply was the key determinant for participating in the program. A duty of care also emerged as a key driving factor, with recognition of AEDs as a valuable asset to communities broadly, not just the participants' immediate sports setting. Reflecting on participation in the program, these participants identified that it was important to increase awareness about AED ownership and use. The program benefits were clearly summed up as being best prepared for a worst-case scenario. This study provides new understanding of why community sports organizations apply for an AED and training. The strongest reason was simply the opportunity to acquire this at no cost. Therefore, for wider implementation of AEDs, additional funding opportunities, targeted awareness of these opportunities, and continued promotion of AED importance are recommended.