The relationship between oxygen uptake kinetics and neuromuscular fatigue in high-intensity cycling exercise.
In theory, a slow oxygen uptake ([Formula: see text]) kinetics leads to a greater accumulation of anaerobic by-products, which can, in turn, induce more neuromuscular fatigue. However, the existence of this relationship has never been tested. After two sessions to measure peak [Formula: see text], peak power output (POpeak), and [Formula: see text] kinetics responses in the unfatigued state (τ [Formula: see text] MOD), 10 healthy young adults performed a 6-min cycling bout at 80% POpeak (INT6-min). [Formula: see text] kinetics responses were also measured during INT6-min. Neuromuscular fatigue was measured isometrically pre- and post-INT6-min (immediately post- and 15-s post-INT6-min) with an innovative cycle ergometer. Maximal voluntary contraction (MVC) force, high-frequency doublet amplitude, and the ratio of low- to high-frequency doublet amplitudes decreased by 34 ± 7, 43 ± 11, and 31 ± 13%, respectively (all P < 0.01). A significant Spearman's rank correlation was observed between the change in low-frequency doublet force (ΔDb10) immediately after INT6-min and both τ [Formula: see text] MOD and τ [Formula: see text] INT6-min (ρ = -0.68 and ρ = -0.67, both P < 0.05). When considering the largest responses from the two neuromuscular evaluations post-INT6-min, significant correlations were also found between τ [Formula: see text] MOD and ΔDb10 (ρ = -0.74; P < 0.05) and between τ[Formula: see text] INT6-min and both ΔDb10 and low-frequency fatigue (ρ = -0.70 and ρ = -0.66; both P < 0.05). The present results suggest that subjects with slow [Formula: see text] kinetics experience more peripheral fatigue, in particular more excitation-contraction coupling failure, likely due to a greater accumulation of protons and/or inorganic phosphates.


All-cause mortality risk of metabolically healthy abdominal obese individuals: the EPIC-MORGEN study.
It appears that a certain proportion of obese individuals have a normal metabolic profile despite having excess weight. Whether these so-called "metabolically healthy" obese express lower disease and mortality risks than "metabolically unhealthy" obese is still unclear. The mortality risk of "metabolically healthy" abdominal obese (MHAO) individuals was investigated. Prospective cohort study (EPIC-MORGEN) among 22,654 individuals aged 20-59 years followed for an average of 13.4 years (SD 2.3). MHAO was assessed at baseline (1993-1997) and defined as abdominal obesity (waist circumference ≥102 cm/≥88 cm (men/women)) with normal glucose, blood pressure, and plasma lipids. All-cause mortality risks adjusted for age and sex were estimated using Cox proportional hazards models. Individuals who were "metabolically healthy" nonabdominal obese (MHNAO) comprised the reference group. As compared to MHNAO, mortality risk for MHAO was around 40% higher (Hazard ratio (HR) 1.43; 95% confidence interval (CI): 1.00-2.04) and of the same magnitude as that for "metabolically unhealthy" nonabdominal obese (MUNAO) (HR 1.31; 95% CI: 1.08-1.59). The HR for MUAO was 1.99 (95% CI: 1.62-2.43). Mortality risk of MHAO individuals was significantly higher than that of MHNAO individuals and lower than, but not statistically significantly different from, that of MUAO individuals.


Differences and similarities between cancer and somatic stem cells: therapeutic implications.
Over the last decades, the cancer survival rate has increased due to personalized therapies, the discovery of targeted therapeutics and novel biological agents, and the application of palliative treatments. Despite these advances, tumor resistance to chemotherapy and radiation and rapid progression to metastatic disease are still seen in many patients. Evidence has shown that cancer stem cells (CSCs), a sub-population of cells that share many common characteristics with somatic stem cells (SSCs), contribute to this therapeutic failure. The most critical properties of CSCs are their self-renewal ability and their capacity for differentiation into heterogeneous populations of cancer cells. Although CSCs only constitute a low percentage of the total tumor mass, these cells can regrow the tumor mass on their own. Initially identified in leukemia, CSCs have subsequently been found in cancers of the breast, the colon, the pancreas, and the brain. Common genetic and phenotypic features found in both SSCs and CSCs, including upregulated signaling pathways such as Notch, Wnt, Hedgehog, and TGF-β. These pathways play fundamental roles in the development as well as in the control of cell survival and cell fate and are relevant to therapeutic targeting of CSCs. The differences in the expression of membrane proteins and exosome-delivered microRNAs between SSCs and CSCs are also important to specifically target the stem cells of the cancer. Further research efforts should be directed toward elucidation of the fundamental differences between SSCs and CSCs to improve existing therapies and generate new clinically relevant cancer treatments.


A study protocol for a feasibility study: Propofol Target-Controlled Infusion in Emergency Department Sedation (ProTEDS)-a multi-centre feasibility study protocol.
Procedural sedation is a core skill of the emergency physician. Bolus administration of propofol is widely utilised in UK emergency departments to provide procedural sedation. Bolus administration of propofol, titrated to an endpoint of sedation, has a rapid effect but can easily result in apnoea and loss of airway patency. The use of a target-controlled infusion of propofol allows for controlled titration to an effect site concentration and may reduce the rate of adverse incidents. Target-controlled infusion of propofol is not currently used in emergency departments.The primary aim of this feasibility study is to ensure that propofol target-controlled infusion (TCI) is acceptable to the patient and that recruitment rates are adequate to power a randomised controlled trial comparing propofol target-controlled infusion versus bolus administration. This study will recruit in four emergency departments in Scotland, UK. Patients aged 18-65 years with anterior shoulder dislocation, weighing ≥ 50 kg and fasted ≥ 90 min, will be screened. Recruited patients will undergo emergency reduction of a dislocated shoulder facilitated by procedural sedation utilising TCI of propofol.The widespread adoption of TCI propofol by emergency departments will require evidence that it is safe, potentially effective, patient centred and a timely method of providing procedural sedation. The primary endpoint will be acceptability measured by patient satisfaction. The secondary endpoints will include incidence and severity of adverse events, number of shoulder reduction attempts, nursing opinion of patient experience, patient's reported pain score and time from commencement of TCI propofol sedation to desired sedation level.The study will be open for recruitment from April 2017 to December 2018. If the study demonstrates patient acceptability with adequate recruitment, we will be in a position to determine the feasibility of progression to a randomised controlled clinical trial of TCI compared to bolus administration of propofol. ClinicalTrials.gov Identifier: NCT03442803. Registered retrospectively on 22 February 2018.


The effects of volatile aromatic anesthetics on voltage-gated Na+ channels expressed in Xenopus oocytes.
Many inhaled anesthetics inhibit voltage-gated sodium channels at clinically relevant concentrations, and suppression of neurotransmitter release by these anesthetics results, at least partly, from decreased presynaptic sodium channel activity. Volatile aromatic anesthetics can inhibit N-methyl-D-aspartate (NMDA) receptor function and enhance gamma-amino butyric acid A receptor function, but these effects depend strongly on the chemical properties of the aromatic compounds. In the present study we tested whether diverse aromatic anesthetics consistently inhibit sodium channel function. We studied the effect of eight aromatic anesthetics on Na(v)1.2 sodium channels with beta(1) subunits, using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. All aromatic anesthetics inhibited I(Na) (sodium currents) at a holding potential which produce half-maximal current (V(1/2)) (partial depolarization); inhibition was modest with 1,3,5-trifluorobenzene (8% +/- 2%), pentafluorobenzene (13% +/- 2%), and hexafluorobenzene (13% +/- 2%), but greater with benzene (37% +/- 2%), fluorobenzene (39% +/- 2%), 1,2-difluorobenzene (48% +/- 2%), 1,4-difluorobenzene (31 +/- 3%), and 1,2,4-trifluorobenzene (33% +/- 1%). Such dichotomous effects were noted by others for NMDA and gamma-aminobutyric acid A receptors. Parallel, but much smaller inhibition, was found for I(Na) at a holding potential which produced near maximal current (-90 mV) (V(H-90)), and hexafluorobenzene caused small (6% +/- 1%) enhancement of this current. These changes in sodium channel function were correlated with effectiveness for inhibiting NMDA receptors, with lipid solubility of the compounds, with molecular volume, and with cation-pi interactions. Aromatic compounds vary in their actions on the kinetics of sodium channel gating and this may underlie their variable inhibition. The range of inhibition produced by minimum alveolar anesthetic concentration concentrations of inhaled anesthetics indicates that sodium channel inhibition may underlie the action of some of these anesthetics, but not others.


Densities and biomasses of non-fossorial southern African Savanna rodents during the dry season.
Dry season densities of small non-fossorial rodents in five different savanna habitats ranged from 11 to 41 animals ha-1 with corresponding live weights ranging from 310 g to 1557 g ha-1. Average biomasses of small frodents in two representative savanna types, Burkea and Acacia savanna, were 912 g ha-1 and 816 g ha-1 respectively. These biomasses were similar to or even exceeded biomasses of other important consumers (birds, cattle, impala, and grasshoppers) in the savanna. Due to allometric relationships 1 kg of small savanna rodents is equivalent in energy consumption to 8 kg of impala (Aepyceros melampus) or 12.7 kg of cattle. The potential effect of small rodents on the savanna is therefore much larger than previously thought and needs further investigation.


Bivalirudin during thrombolysis with catheter-directed tPA in a heparin-refractory patient: A case report.
Venous thromboembolism has increasing significance in hospitalized pediatric patients. Patients who have life-threatening or limb-threatening thrombotic events require thrombolysis in addition to anticoagulation. In patients who show signs of heparin resistance or heparin-induced thrombocytopenia, it is imperative to identify alternative therapeutic options. We present a child in whom bivalirudin was used for systemic anticoagulation during catheter-directed thrombolysis along with tissue plasminogen activator (Alteplase® ) for the treatment of a near-occlusive organ-threatening thrombus. We also review the currently available literature on the use of combination therapy of an intravenous direct thrombin inhibitor with alteplase.


Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years.
The minimum age to start specific immunotherapy with inhalant allergens in children has not been clearly established, and position papers discourage its use in children younger than 5 years. To assess the safety of high-dose sublingual-swallow immunotherapy (SLIT) in a group of children younger than 5 years. Sixty-five children (51 boys and 14 girls; age range, 38-80 months; mean +/- SD age, 60 +/- 10 years; median age, 60 months) were included in this observational study. They were treated with SLIT with a build-up phase of 11 days, culminating in a top dose of 300 IR (index of reactivity) and a maintenance phase of 300 IR 3 times a week. The allergens used were house dust mites in 42 patients, grass pollen in 11 patients, olive pollen in 5 patients, Parietaria pollen in 4 patients, and cypress pollen in 3 patients. All adverse reactions and changes in the treatment schedule were compared in 2 subgroups: children 38 to 60 months old and children 61. to 80 months old. The average cumulative dose of SLIT was 36,900 IR. Adverse reactions were observed in 11 children, none of them severe enough to require discontinuation of immunotherapy. Six reactions occurred in the 60 months or younger age group and 7 in the older than 60 months age group, with no differences between these 2 groups. High-dose immunotherapy in children younger than 5 years does not cause more adverse reactions than in children aged 5 to 7 years. There is no reason to forbear studies on safety and efficacy of these preparations in young children.


Optimization of the atrioventricular delay in conduction system pacing.
In patients receiving conduction system pacing (CSP), it is not well established how to program the sensed atrioventricular delay (sAVD), with respect to the type of capture obtained (selective, nonselective His-bundle [HB] capture or left bundle branch [LBB] capture). The aim of this study was to acutely assess the effectiveness of an electrophysiology (EP)-guided method for sAVD optimization by comparing it with the echocardiogram-guided optimization. Consecutive patients undergoing HB or LBB pacing were enrolled. The EP-guided sAVD was defined as the sAVD leading to a PR interval of 150 ms on surface electrocardiogram (ECG). In HB pacing patients, EP-guided sAVD was obtained subtracting the time from the onset of the P wave on ECG to the local atrial electrogram (EGM) recorded by the atrial lead (right atrial sensing latency, RASL) and the His-ventricular interval from 150 ms; in LBB pacing patients, subtracting RASL from 150 ms. Transmitral flow assessment by pulsed wave Doppler was used to find the echo-optimized sAVD by a modified iterative method. The discordance between the EP-guided and the echo-optimized sAVD was recorded. Seventy-one patients were enrolled: 12 with selective, 32 nonselective HB capture, and 27 LBB capture. Overall, the rate of concordance between the EP-guided and the echo-optimized sAVD was 71.8%, with no significant differences between the three groups. In CSP patients, an optimal sAVD can be programmed, in more than 70% of cases, considering only simple EGM intervals to obtain a physiological PR interval on surface ECG.


Fusarium species as pathogens of potato tubers during storage and their ability to produce mycotoxins.
During 1985 and 1986 seasons from potato tubers with dry not symptoms 50 cultures belonging to nineFusarium species were isolated and their ability to form mycotoxins has been examined. The dominating species were:F. sambucinum Fuckel-52%,F. avenaceum (Fr.) Sacc.-8%,F. crookwellense Burges, Nelson and Toussoun-8% andF. culmorum (W. G. Smith) Sacc.-8%. p ]In cultures growing on wheat kernels all 26 isolates ofF. sambucinum formed diacetoxyscirpenol (DAS) in the amount of 20-1000 mg/kg. F. culmorum isolates produced zearalenone (F-2), deoxynivalenol (DON) and 3-acetyldeoxynivalenol (3-AcDON),F. crookwellense- zearalenone,F. avenaceum andF. subglutinans Wollenw. and Reinking- moniliformin (1330 and 66 mg kg respectively). T-2 toxin, HT-2 toxin, nivalenol and fusarenon X were not produced by any of the examined isolates.


Characteristics of growth and protein synthesis in skeletal muscles of normal and dystrophic chickens.
Several characteristics of cellular growth and protein synthesis were measured in vivo in the breast and leg muscles of normal (line 454) and hereditary muscular dystrophic (line 455) New Hampshire chickens at different ages. Fractional rates of protein synthesis (ks) were calculated from the rate of incorporation of labeled tyrosine administered continuously via a subcutaneous injection of an emulsion of L-[U-14C]tyrosine in sesame oil. Only the breast muscle showed signs of gross hypertrophy. The hypertrophy involved an abnormally rapid accumulation of protein, DNA and RNA. In dystrophic chickens, ks was at least 170% of the normal rates at 2, 5 and 52 weeks. The elevated ks was presumably a reflection of the higher DNA and RNA concentrations relative to those in normal birds. Because the RNA/DNA ratio and the activities of RNA and DNA were similar to values observed in normal birds, there may be no defect in the synthesis machinery per se.


Low-rank and sparse embedding for dimensionality reduction.
In this paper, we propose a robust subspace learning (SL) framework for dimensionality reduction which further extends the existing SL methods to a low-rank and sparse embedding (LRSE) framework from three aspects: overall optimum, robustness and generalization. Owing to the uses of low-rank and sparse constraints, both the global subspaces and local geometric structures of data are captured by the reconstruction coefficient matrix and at the same time the low-dimensional embedding of data are enforced to respect the low-rankness and sparsity. In this way, the reconstruction coefficient matrix learning and SL are jointly performed, which can guarantee an overall optimum. Moreover, we adopt a sparse matrix to model the noise which makes LRSE robust to the different types of noise. The combination of global subspaces and local geometric structures brings better generalization for LRSE than related methods, i.e., LRSE performs better than conventional SL methods in unsupervised and supervised scenarios, particularly in unsupervised scenario the improvement of classification accuracy is considerable. Seven specific SL methods including unsupervised and supervised methods can be derived from the proposed framework and the experiments on different data sets (including corrupted data) demonstrate the superiority of these methods over the existing, well-established SL methods. Further, we exploit experiments to provide some new insights for SL.


Catecholamine-induced cardiomyopathy: an endocrinologist's perspective.
Although many endocrine diseases can be associated with acquired cardiomyopathy and heart failure, conditions except hypothyroidism, hyperthyroidism, phaeochromocytoma-paraganglioma (PPGL), and primary hyperaldosteronism are rare. PPGL is a rare catecholamine-secreting neuroendocrine tumour arising from the adrenal gland in 80-85% or extra-adrenal chromaffin cells of the autonomic neural ganglia in the remainder. The annual incidence of PPGL is 3-8 cases per million per year in the general population. Catecholamine-induced cardiomyopathy (CICMP) has got a prevalence of 8-11% among patients with PPGL. Hypertension, either sustained or episodic, is present in the vast majority (95%) of PPGL patients. However, among patients with CICMP, hypertension is present only in 65% of cases and the classical triad of paroxysmal headache, sweating, and palpitation is present only in 4%. Based on the cardiac remodelling in response to endogenous catecholamine excess, PPGL patients might present with one of the three CICMPs, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or Takotsubo cardiomyopathy (TCM). Regardless of the subtypes, all CICMPs have many features in common - a dramatic clinical presentation, reversible cardiomyopathy, similar repolarisation electrocardiography changes, mild-moderate cardiac biomarker elevation, and normal coronary arteries on coronary angiography. CICMP should be suspected in patients with non-ischaemic, non-valvular forms of cardiomyopathy, even in those without definite features of catecholamine excess. PPGL associated TCM should be suspected in all acute coronary syndrome (ACS) patients exhibiting pronounced blood pressure variability with no culprit lesions on coronary angiography. This article will provide a review of the various CICMPs, their pathophysiology, clinical features, and the management options.


Interaction between fortilin and transforming growth factor-beta stimulated clone-22 (TSC-22) prevents apoptosis via the destabilization of TSC-22.
Yeast two-hybrid screening was conducted using a human ovary cDNA library to search for a novel binding protein using transforming growth factor-beta stimulated clone-22 (TSC-22). The selected protein was fortilin, which has been characterized as a nuclear anti-apoptotic protein. Overexpression of fortilin in ovarian carcinoma cells reversed TSC-22-mediated apoptosis, and the inhibition of fortilin expression via small interfering RNA (siRNA) resulted in an increase in the apoptosis of ovarian carcinoma cells. Moreover, fortilin overexpression promoted the degradation of TSC-22. Thus, an interaction between fortilin and TSC-22 prevents apoptosis via the destabilization of TSC-22 in ovarian carcinoma cells.


Variability in hand surface representations in areas 3b and 1 in adult owl and squirrel monkeys.
Detailed microelectrode maps of the hand representation were derived in cortical areas 3b and 1 from a series of normal adult owl and squirrel monkeys. While overlap relationships were maintained, and all maps were internally topographic, many map features varied significantly when examined in detail. Variable features of the hand representations among different monkeys included a) the overall shapes and sizes of hand surface representations; b) the actual and proportional areas of representations of different skin surfaces and the cortical magnifications of representations of specific skin surfaces, which commonly varied severalfold in area 3b and manyfold in area 1; c) the topographic relationships among skin surface representations, with skin surfaces that were represented adjacently in some monkeys represented in locations many hundreds of microns apart in others; d) the internal orderliness of representations; e) the completeness of representations of the dorsal hand surfaces; and f) the skin surfaces represented along the borders of the hand representation. Owl monkey maps were, in general, internally more strictly topographic than squirrel monkey maps. In both species, area 3b was more strictly topographic and less variable than was area 1. The degree of individual variability revealed in these experiments is difficult to reconcile with the hypothesis that details of cortical maps are ontogenetically specified during a period in early life. Instead, we propose that differences in the details of cortical map structure are the consequence of individual differences in lifelong use of the hands. This conclusion is consistent with earlier studies of the consequences of peripheral nerve transection and digital amputation, which revealed that cortical maps are dynamically maintained and are alterable as a function of use or nerve injury in these monkeys (Merzenich et al., '83a,b, '84a; Merzenich, '86; Jenkins et al., '84; Jenkins and Merzenich, '87).


Properties of poly(2-hydroxyethyl acrylate) networks.
Hydrogels, based on poly(2-hydroxyethyl acrylate) cross-linked with 1,4 butanediol dimethacrylate, were studied in respect to their swelling and mechanical behaviour. The determination of Young's modulus at r.t. permitted the calculation of average molecular weight between cross-links. This value could, in turn, be correlated with water-swelling data to give indicative values of the interaction parameter for the system poly(2-hydroxyethyl acrylate)-water.


An inhibitor of prostaglandin biosynthesis from human decidua: partial purification and properties.
An inhibitor of prostaglandin synthetase which catalyzes the conversion of arachidonic acid into prostaglandin E2 was partially purified from the 105,000 x g supernatant fraction of the human decidual cell homogenate. By means of ammonium sulfate fractionation, Mono Q ion-exchange chromatography, and gel filtration chromatography, the inhibitor was purified about 15-fold, giving a preparation with a molecular weight of 55-60 KDa. The 50% inhibitory concentration of the purified substance was approximately 0.2 mg/ml. The inhibitor may play a role in suppression of prostaglandin production by decidua in early pregnancy.


Mild acute ischaemic stroke--the case for thrombolytic therapy.
The incidence of acute ischaemic stroke with mild neurological deficits (called mild ischaemic stroke [MIS]) is increasing, and studies show that a large percentage of untreated patients have poor long-term outcomes. Many physicians do not, however, routinely treat patients with MIS with intravenous recombinant tissue plasminogen activator (rtPA)--the only thrombolytic therapy currently approved by the FDA. Here, we discuss the reasons why physicians do not treat patients with MIS and we review the studies published to date regarding the potential risks and benefits of administering rtPA in this patient population. We then provide our perspective on why patients with MIS should be treated with intravenous rtPA and we highlight the need for a randomized clinical trial to address treatment of MIS.


Heart disease, cancer and vehicle travel.
A new concept as to the cause of heart disease, cancers and diabetes is put forward in this paper. It is established that there is a mathematical relationship between motor vehicle use, from 1920 to 1975, and deaths due to the abovementioned diseases. This relationship has been established by an extensive statistical study of vehicle usage and deaths due to these diseases.


Immunomodulation following chemotherapy.
In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancer in some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B16 melanoma in a murine model. This combination generated cells with MHC-unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the nontransplant setting to induce an antitumor immune response following cytoreductive chemotherapy.


Characterization of HCV-infected people who inject drugs (PWID) in the setting of clinical care in Canada (CAPICA): A retrospective study.
People who use drugs (PWUD) are among the highest risk category for becoming infected with the hepatitis C virus (HCV) in Canada. There is a need for more information on the demographics of HCV-infected PWUD/PWID who have recently injected drugs or who are actively injecting drugs. CAPICA was a multicentre, retrospective database/chart review conducted from October 2015 to February 2016 that was designed to characterize HCV-infected people who inject drugs (PWID) and are enrolled in clinical care in Canada. The aim was to identify factors of health care engagement essential in the design systems of HCV care and treatment in this population. The study enrolled 420 patients with a history of injection drug use within the last 12 months who had been diagnosed with chronic viremic HCV infection and had been participants in an outpatient clinical care setting in the past 12 months. Patients who were co-infected with HIV/HCV were excluded. Harm reduction programs were in place at 92% (11/12) of the sites, and 75% (9) of these sites offered opioid agonist therapy (OAT), with 48% of the patients currently taking OAT. HCV genotype 1a was most prevalent (56%), followed by G3 (34%), and the most common fibrosis score was F1 (34%). The average reinfection rate was about 5%. Seventeen percent of the patients were undergoing HCV treatment or had recently failed therapy, while 83% were not being treated. In a multivariate analysis, the following factors were significantly associated with treatment: increasing age (OR 1.10), a fibrosis score of F4 (OR 4.91), moderate alcohol consumption (OR 3.70), and not using a needle exchange program (OR 6.95).


Dioxins in breast milk of Chinese mothers: A survey 40 years after the e-waste recycling activities.
In the past two decades, numerous studies on dioxin concentrations in breast milk have been conducted in China. However, information concerning dioxin concentrations in breast milk from women living in e-waste recycling sites remains limited. Thus, this study aimed to evaluate health risk owing dioxin intake in e-waste recycling areas in China. In 2015, 42 mothers were recruited from an e-waste recycling site, and the same number of mothers were recruited from a reference site. We collected 10-mL breast milk samples from each participant. Breast milk concentrations of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzofurans (PCDFs) were significantly higher in the exposed group than in the reference group. The total toxic equivalents (TEQ) of PCDDs/DFs were 9.68 pg/g lipid in the exposed group, a value two times higher than those in the reference group (4.18 pg/g lipid). The estimated daily intake (EDI) of PCDD/DFs was calculated to assess the risk of dioxins through breastfeeding. The infant EDI level was two times higher in the exposed group (54.21 pg TEQ/kg body wt/day) than in the reference group (23.41 pg TEQ/kg body wt/day). Our findings suggest that mothers and their breastfeeding infants living in an e-waste recycling site were exposed to higher dioxin concentrations than those living in a reference site.


Products, kinetics, and substrate specificity of homogeneous thromboxane synthase from human platelets: development of a novel enzyme assay.
Homogeneous thromboxane synthase from human platelets converted prostaglandin H2 (PGH2) to thromboxane A2 (measured as thromboxane B2, TxB2), 12(L)-hydroxy-5,8,10-heptadecatrienoic acid (HHT), and malondialdehyde (MDA) in equimolar amounts under a variety of experimental conditions. PGG2 was transformed to MDA and corresponding 15- and 12-hydroperoxy products. PGH1 was enzymatically transformed into 12(L)-hydroxy-8,10-heptadecadienoic acid (HHD) and PGH3 into TxB3 and 12(L)-hydroxy-5,8,10,14-heptadecatetraenoic acid (delta 14-HHT) as earlier reported for solubilized and partially purified thromboxane synthase preparations. The ratio of thromboxane to C17 hydroxy fatty acid formation was 1:1 with PGG2, PGH2, and PGH3 as substrates. These results confirm and extend earlier observations with partially purified enzyme that the three products are formed in a common enzymatic pathway (Diczfalusy, U., Falardeau, P., and Hammarström, S. (1977) FEBS Lett. 84, 271-274). A convenient spectrophotometric assay for thromboxane synthase activity measuring the ultraviolet light absorption of the C17 hydroxy acid formed (e.g., HHT) was developed. The validity of the assay was determined employing specific inhibitors for thromboxane synthase. The substrate specificity of thromboxane synthase was determined using this assay. PGG2 and PGH3 showed Vmax and KM values similar to those of PGH2. The KM value of PGH1 was also identical to that of PGH2 but the Vmax value PGH1 was more than twice as high as that of PGH2.


The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.
Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.


Accurate recognition of colorectal cancer with semi-supervised deep learning on pathological images.
Machine-assisted pathological recognition has been focused on supervised learning (SL) that suffers from a significant annotation bottleneck. We propose a semi-supervised learning (SSL) method based on the mean teacher architecture using 13,111 whole slide images of colorectal cancer from 8803 subjects from 13 independent centers. SSL (~3150 labeled, ~40,950 unlabeled; ~6300 labeled, ~37,800 unlabeled patches) performs significantly better than the SL. No significant difference is found between SSL (~6300 labeled, ~37,800 unlabeled) and SL (~44,100 labeled) at patch-level diagnoses (area under the curve (AUC): 0.980 ± 0.014 vs. 0.987 ± 0.008, P value = 0.134) and patient-level diagnoses (AUC: 0.974 ± 0.013 vs. 0.980 ± 0.010, P value = 0.117), which is close to human pathologists (average AUC: 0.969). The evaluation on 15,000 lung and 294,912 lymph node images also confirm SSL can achieve similar performance as that of SL with massive annotations. SSL dramatically reduces the annotations, which has great potential to effectively build expert-level pathological artificial intelligence platforms in practice.


Risk assessment of excessive CO2 emission on diatom heavy metal consumption.
Diatoms are the dominant group of phytoplankton in the modern ocean, accounting for approximately 40% of oceanic primary productivity and critical foundation of coastal food web. Rising dissolution of anthropogenic CO2 in seawater may directly/indirectly cause ocean acidification and desalination. However, little is known about dietary diatom-associated changes, especially for diatom heavy metal consumption sensitivity to these processes, which is important for seafood safety and nutrition assessment. Here we show some links between ocean acidification/desalination and heavy metal consumption by Thalassiosira weissflogii. Excitingly, under desalination stress, the relationships between Cu, Zn, and Cd were all positively correlated, especially between Cu and Zn (r=0.989, total intracellular concentration) and between Zn and Cd (r=0.962, single-cell intracellular concentration). Heavy metal consumption activity in decreasing order was acidification<acidification+desalination<desalination for Zn, acidification<desalination<acidification+desalination for Cu and Cd, i.e., heavy metal uptake (or release) were controlled by environmental stress. Our findings showed that heavy metal uptake (or release) was already responded to ongoing excessive CO2 emission-driven acidification and desalination, which was important for risk assessment of climate change on diatom heavy metal consumption, food web and then seafood safety in future oceans.


Biological evaluation of 2-aryl-2-fluoropropionic acids as possible platforms for new medicinal agents.
We investigated the cyclooxygenase (COX) inhibitory and anticancer activities of 2-aryl-2-fluoropropionic acids 1a-e. These fluorinated compounds showed lower inhibitory activity toward COX-1 than the corresponding non-fluorinated compounds 2a-e with retained inhibitory activity against COX-2 resulting in modification of the balance of COX-1/COX-2 inhibitions, and they showed little anticancer activity. Interesting differences of the activities between (S)- and (R)-enantiomers were observed in some cases.


Genetic diversity of Chikungunya virus, India 2006-2010: evolutionary dynamics and serotype analyses.
The genetic diversity of Chikungunya virus (CHIKV) causing recurring outbreaks in India since 2006 was studied. The 2006 epidemic was caused by a virus strain of the East, Central and South African (ECSA) genotype with 226A in the E1 glycoprotein. The variant strain with E1-A226V mutation caused outbreaks since 2007 in the state of Kerala where Aedes albopictus is the abundant mosquito vector. Molecular epidemiology data since 2007 is scarce from other regions of the country. RT-PCR, sequencing and phylogenetic analyses of CHIKV isolates from the 2009 to 2010 epidemics in the States of Tamil Nadu and Andhra Pradesh placed them in a separate clade within the ECSA lineage. The isolates of the study had 226A in the E1 glycoprotein. The isolates had a novel E1-K211E mutation that was under significant positive selection. E1-211E is highly conserved in the Asian genotype of the virus circulated by Aedes aegypti. Unique mutations in E2 glycoprotein were identified. The two sub-lineages of ECSA genotype circulating in India parallel the abundance of Ae. albopictus and Ae. aegypti. Novel mutations in the envelope glycoproteins suggest adaptive evolution of the virus to local vector abundance. Cross neutralization of the virus isolates from recurring Indian epidemics indicated that no distinct serotypes had evolved. The study has provided insights into the origin, distribution and evolutionary adaptation of the virus to local vector abundance in the region that has reportedly, the highest incidence of CHIKV infection in the world.


[Dependence from age of reaction time by acoustical stimulation (author's transl)].
The reaction time by optical and acoustical stimulation decreases until 20 years, and ascends then. The acoustical reaction time is shorter than the optical, with the exception of some unexplicable falls in the senium.


Gene cloning and seamless site-directed mutagenesis using single-strand annealing (SSA).
The full length of interested genes can be usually cloned by assembling exons or RACE products through overlap PCR. However, the procedure requires multiple PCR steps, which are prone to random mutagenesis. Here, we present a novel SSA-based method for gene cloning and seamless site-directed mutagenesis. We firstly cloned the full-length coding sequence of Cashmere goat (Capra hircus) Hoxc13 gene by assembling exons amplified from genomic DNA. Secondly, we created a Hoxc13 loss-function mutant seamlessly and further illustrated that direct repeat length of 25 bp is enough to trigger the SSA repair in routine E. coli strains including DH5α, Trans1t1, JM109, and Top10. Moreover, we cloned another full-length mutant of Foxn1 gene from Cashmere goat cDNA using further shortened direct repeats of 19 bp. In summary, our study provided an alternative method to overcome the difficulties during overlap PCR in some particular cases for gene cloning.


A comparison of two hyperbaric oxygen regimens: 2.0 ATA for 120 minutes to 2.4 ATA for 90 minutes in treating radiation-induced cystitis Are these regimens equivalent?
Hyperbaric oxygen dosing variations exist in radiation cystitis treatment. The objectives of this study were to compare response and safety rates among patients with radiation cystitis treated with different protocols: 2.0 ATA (atmospheres absolute) for 120 minutes at the University of Pennsylvania; and 2.4 ATA for 90 minutes at Hennepin Healthcare. Retrospective chart review of radiation cystitis patients treated with hyperbaric oxygen at the University of Pennsylvania (January 2010-December 2018) and Hennepin Healthcare Minnesota (January 2014-December 2018). Primary outcome was response to treatment. Complications were limited to hyperbaric-related conditions. Regression analysis was performed with ordinal logistic regression and binary logistic regression. 126 patients were included in the analysis (2.0 ATA: 66, 2.4 ATA: 60). Overall response rate was 75.4% (good) and was not significantly different between protocols (good response: 2.0 ATA 72.7% vs. 2.4 ATA 78.3% p=0.74). The 2.0 ATA group required additional treatments [2.0 ATA: 45.45 ± 14.5 vs. 2.4 ATA: 40.03 ± 9.7, p<0.05]. 6.1% (2.0 ATA) and 13.3% (2.4 ATA) required tympanostomy tube placement or needle myringotomy for otic barotrauma (p=0.22). Transfusion was associated with poorer outcomes (p<0.05). Both groups - 2.0 ATA and 2.4 ATA - had similar response and complication rates. Blood transfusion is a negative prognostic factor for treatment outcome.


Magnetic source imaging in non-lesional neocortical epilepsy: additional value and comparison with ICEEG.
To investigate the utility of magnetic source imaging (MSI) for localizing the epileptogenic zone (EZ) and predicting epilepsy surgery outcome in non-lesional neocortical focal epilepsy (NLNE) patients. Data from 18 consecutive patients with NLNE who underwent presurgical evaluation including intracranial electroencephalography (ICEEG) and MSI were studied. Follow-up after epilepsy surgery was ≥24 months. Intracranial electroencephalography and MSI results were classified using a sublobar classification. Sublobar ICEEG focus was completely resected in 15 patients; seizure-free rate was 60%. Eight patients showed sublobar-concordant ICEEG/MSI results and complete resection of both regions; seizure-free rate was 87.5%. Seizure-free rate in cases not matching these criteria was only 30% (p=0.013). Magnetoencephalography is a useful tool to localize the EZ and determine the site of surgical resection in NLNE patients. When sublobar concordance with ICEEG is observed, MSI increases the predictive value for a seizure-free epilepsy surgery outcome in these patients.


[Extradural hematoma of the posterior fossa. Report of 7 cases].
Hematomas of the posterior fossa are an uncommon complication of head injury. Almost invariably they occur after trauma of the occiput, and are associated with skull fracture. Their diagnosis and management have been greatly improved by CT scanning. In the present series, the majority of patients had acute evolution indicating the potential hazard of conservative treatment. Our results (29% mortality) are similar to those previously reported in other series.


Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma.
In lung cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitizing mutations co-existing with rare minor EGFR mutations are known as compound mutations. These minor EGFR mutations can lead to acquired resistance after EGFR tyrosine kinase inhibitor treatment, so determining the mutation status of patients is important. However, using amplicon-based targeted deep sequencing based on next-generation sequencing to characterize mutations is prone to sequencing error. We therefore assessed the benefit of incorporating molecular barcoding with high-throughput sequencing to investigate genomic heterogeneity in treatment-naïve patients who have undergone resection of their non-small cell lung cancer (NSCLC) EGFR mutations. We performed amplicon-based targeted sequencing with the molecular barcoding system (MBS) to detect major common EGFR mutations and uncommon minor mutations at a 0.5% allele frequency in fresh-frozen lung cancer samples. Profiles of the common mutations of EGFR identified by MBS corresponded with the results of clinical testing in 63 (98.4%) out of 64 cases. Uncommon mutations of EGFR were detected in seven cases (10.9%). Among the three types of major EGFR mutations, patients with the G719X mutation had a significantly higher incidence of compound mutations than those with the L858R mutation or exon 19 deletion (p = 0.0052). This was validated in an independent cohort from the Cancer Genome Atlas dataset (p = 0.018). Our findings demonstrate the feasibility of using the MBS to establish an accurate NSCLC patient genotype. This work will help understand the molecular basis of EGFR compound mutations in NSCLC, and could aid the development of new treatment modalities.


Ultra-rare complement factor 8 coding variants in families with age-related macular degeneration.
Genome-wide association studies have uncovered 52 independent common and rare variants across 34 genetic loci, which influence susceptibility to age related macular degeneration (AMD). Of the 5 AMD-associated complement genes, complement factor H (CFH) and CFI exhibit a significant rare variant burden implicating a major contribution of the complement pathway to disease pathology. However, the efforts for developing AMD therapy have been challenging as of yet. Here, we report the identification of ultra-rare variants in complement factors 8A and 8B, two components of the terminal complement membrane attack complex (MAC), by whole exome sequencing of a cohort of AMD families. The identified C8 variants impact local interactions among proteins of C8 triplex in vitro, indicating their effect on MAC stability. Our results suggest that MAC, and not the early steps of the complement pathway, might be a more effective target for designing treatments for AMD.


Prazosin: effect on psychomotor-stimulant cues and locomotor activity in mice.
Mice trained to discriminate 1 mg/kg d-amphetamine from saline, or the selective norepinephrine uptake inhibitor, nisoxetine, from saline, cross-generalized to the alternate drug. They also generalized to 5.6 mg/kg cocaine. The cues produced by amphetamine were antagonized by the selective alpha 1-adrenoceptor antagonist, prazosin, and slightly potentiated by the selective alpha 2-adrenoceptor antagonist, yohimbine. The nisoxetine cue was also antagonized by prazosin. In contrast, the peripherally acting sympathomimetics, p-hydroxyamphetamine and phenylpropranolamine, failed to substitute for, and pimozide and propranolol failed to block, either drug cue. In addition, prazosin, at a dose that did not affect either saline-associated locomotor behavior in mice or the locomotor-activity increase produced by the dopamine uptake inhibitor, bupropion, also antagonized the locomotor stimulation produced by amphetamine and cocaine. Thus, in mice, both the cues and locomotor stimulation produced by amphetamine and cocaine appear to be at least partially mediated by central alpha 1-adrenoceptor activation secondary to increased central synaptic concentrations of norepinephrine.


Effects of cigarette smoking on resting EEG, visual evoked potentials and photic driving.
The effects of smoking a cigarette (1.3 mg nicotine delivery) versus sham smoking were studied using EEG, visual evoked potentials (VEP), photic driving (PD) and heart rate (HR) in thirty young healthy male and female habitual cigarette smokers. Heart rate (HR) and exhaled carbon monoxide (CO) level were significantly increased by real as opposed to sham smoking. Real versus sham smoking significantly increased relative power in the beta bands, reduced alpha and theta activity to a small but significant extent, but had no effect on delta activity. Dominant EEG alpha frequency was significantly increased by real as opposed to sham smoking. Smoking produced no significant mean change in PD or VEP. However, correlational analysis indicated that variables such as basal CO level, residual butt filter nicotine, basal electrocortical response level and personality, predicted to varying degrees the magnitude and direction of the effect of smoking on VEP, PD and EEG.


Selection of aptamers against pathogenic bacteria and their diagnostics application.
Aptamers are short nucleotide sequences which can specifically bind to a variety of targets with high affinity. They are identified and selected via systematic evolution of ligands by exponential enrichment (SELEX). Compared to antibodies, aptamers offer several advantages including easy labeling, high stability and lower cost. Those advantages make it possible to be a potential for use as a recognition probe to replace antibody in the diagnostic field. This article is intended to provide a comprehensive review, which is focused on systemizing recent advancements concerning SELEX procedures, with special emphasis on the key steps in SELEX procedures. The principles of various aptamer-based detections of pathogenic bacteria and their application are discussed in detail, including colorimetric detection, fluorescence detection, electrochemical detection, lateral flow strip test, mass sensitive detection and PCR-based aptasensor. By discussing recent research and future trends based on many excellent publications and reviews, we attempt to give the readers a comprehensive view in the field of aptamer selection against pathogenic bacteria and their diagnostics application. Authors hope that this review will promote lively and valuable discussions in order to generate new ideas and approaches towards the development of aptamer-based methods for application in pathogenic bacteria diagnosis.


The relationship between follicle development and progesterone receptor membrane component-1 expression in women undergoing in vitro fertilization.
To determine the relationship between progesterone receptor membrane component-1 (PGRMC1) expression and the outcome of IVF treatment. A prospective study in which PGRMC1 messenger RNA (mRNA) levels, methylation status of the Pgrmc1 promoter, and the presence of point mutations within Pgrmc1 were obtained from granulosa (GC)/luteal cells of women undergoing controlled ovarian hyperstimulation (COH). Fertility center/basic science laboratory. Eighty-five patients undergoing IVF treatment and 10 women who were undergoing COH for the purpose of oocyte donation were included in this study. None. The PGRMC1 measurements were correlated with clinical outcomes, such as number of follicles, number of retrieved oocytes, and ongoing pregnancy rates (PR). The PGRMC1 mRNA levels within GC/luteal cells of 18% of IVF patients were >2.25-fold higher than those of oocyte donors. Individuals with elevated PGRMC1 mRNA levels had 30% fewer large follicles and fewer oocytes retrieved. The elevated PGRMC1 mRNA levels were associated with an increase in the methylation of Pgrmc1 promoter. In patients with elevated PGRMC1 mRNA levels, gonadotropin-induced follicle development is attenuated, although sufficient numbers of follicles develop to allow for ET and subsequent pregnancy.


Corticofugal regulation of auditory sensitivity in the bat inferior colliculus.
Under free-field stimulation conditions, corticofugal regulation of auditory sensitivity of neurons in the central nucleus of the inferior colliculus of the big brown bat, Eptesicus fuscus, was studied by blocking activities of auditory cortical neurons with Lidocaine or by electrical stimulation in auditory cortical neuron recording sites. The corticocollicular pathway regulated the number of impulses, the auditory spatial response areas and the frequency-tuning curves of inferior colliculus neurons through facilitation or inhibition. Corticofugal regulation was most effective at low sound intensity and was dependent upon the time interval between acoustic and electrical stimuli. At optimal inter-stimulus intervals, inferior colliculus neurons had the smallest number of impulses and the longest response latency during corticofugal inhibition. The opposite effects were observed during corticofugal facilitation. Corticofugal inhibitory latency was longer than corticofugal facilitatory latency. Iontophoretic application of gamma-aminobutyric acid and bicuculline to inferior colliculus recording sites produced effects similar to what were observed during corticofugal inhibition and facilitation. We suggest that corticofugal regulation of central auditory sensitivity can provide an animal with a mechanism to regulate acoustic signal processing in the ascending auditory pathway.


Chlamydia pneumoniae in an ex vivo human artery culture model.
The role of the obligate intracellular pathogen Chlamydia pneumoniae in the development of atherosclerosis could not be completely clarified. Reasons are the highly discrepant results obtained in the hitherto existing studies and the lack of an experimental system allowing the direct examination of chlamydial effects in the human vasculature. We established a human ex vivo organ culture model for the characterization of vascular chlamydial infection. Ninety sections of renal arteries, obtained from nephrectomies, were inoculated with Chlamydia pneumoniae. Using a monoclonal FITC-conjugated antibody, chlamydial LPS was broadly detected in inoculated arteries during the entire observation period of 35 days. However, recultivation of viable organisms from the artery vessel wall was impossible, indicating that productive infection in human arteries did not occur even under optimized conditions. This was substantiated by low recovery rates of Chlamydia pneumoniae, low amounts of detectable chlamydial 16S rRNA and ultramorphological presence of polymorph multilamellar bodies in experimentally infected smooth muscle cells originating from aortas, coronary and renal arteries. We could demonstrate that the complex environment of a human artery did not support the growth of Chlamydia pneumoniae although the presence of chlamydial LPS in the artery vessel wall following experimental infection was a common event. The presence of chlamydial LPS in the absence of viable organisms within the artery vessel wall may explain the failure of antibiotic treatment strategies for atherosclerosis.


Reglucosylation of glycoproteins and quality control of glycoprotein folding in the endoplasmic reticulum of yeast cells.
Proteins entering the secretory pathway may be glycosylated upon transfer of an oligosaccharide (Glc3Man9GlcNAc2) from a dolichol-P-P derivative to nascent polypeptide chains in the lumen of the endoplasmic reticulum (ER). Oligosaccharides are then deglucosylated by glucosidases I and II (GII). Also in the ER, glycoproteins acquire their final tertiary structures, and species that fail to fold properly are retained and eventually degraded in the proteasome. It has been proposed that in mammalian cells the monoglucosylated oligosaccharides generated either by partial deglucosylation of the transferred compound or by reglucosylation of glucose-free oligosaccharides by the UDP-Glc:glycoprotein glucosyltransferase (GT) are recognized by ER resident lectins (calnexin and/or calreticulin). GT is a sensor of glycoprotein conformation as it only glucosylates misfolded species. The lectin-monoglucosylated oligosaccharide interaction would retain glycoproteins in the ER until correctly folded, and also facilitate their acquisition of proper tertiary structures by preventing aggregation. GII would liberate glycoproteins from the calnexin/calreticulin anchor, but species not properly folded would be reglucosylated by GT, and so continue to be retained by the lectins. Only when the protein becomes properly folded would it cease to be retained by the lectins. This review presents evidence suggesting that a similar quality control mechanism of glycoprotein folding is operative in Schizosaccharomyces pombe and that the mechanism in Saccharomyces cerevisiae probably differs substantially from that occurring in mammalian and Sch. pombe cells.


A high fidelity model for single-incision laparoscopic cholecystectomy.
Single-incision laparoscopic surgery (SILS) is a safe approach for cholecystectomy, with the potential to minimise the iatrogenic trauma sustained from the operation. However, a number of reports show SILS to be technically challenging and as such there is expected to be a significant learning curve for expert surgeons adopting the new technique, as well as for junior surgical trainees. There are inherent risks to patient safety associated with practicing and developing new skills in a real-life theatre environment. However, thus far, there have been no realistic SILS training models available. We tested the feasibility of conducting SILS cholecystectomies on a cadaveric porcine model with standard operating equipment, which may provide a platform to facilitate safe training and assessment protocols. In this paper we provide an account of the training model technique, and review the literature surrounding SILS training and performance evaluation.


Tumour-associated CD204+ microglia/macrophages accumulate in perivascular and perinecrotic niches and correlate with an interleukin-6-enriched inflammatory profile in glioblastoma.
Glioblastomas are heterogeneous tumours with a rich tumour microenvironment particularly comprised of tumour-associated microglia/macrophages (TAMs), but also containing a population of dedifferentiated/stem-like glioblastoma cells. Both cell populations contribute to tumour aggressiveness and immune evasion through the actions of various signalling molecules. The scavenger and pattern recognition receptor CD204 is associated with a pro-tumourigenic phenotype of TAMs and has a negative prognostic value. Our objective was to investigate the possible interaction between TAMs and dedifferentiated glioblastoma cells and characterise the myeloid phenotype of CD204-enriched glioblastomas. Double immunohistochemistry and cell counting was performed on eight glioblastoma samples to estimate the expression and interaction level between dedifferentiated/stem-like tumour cells and TAMs. Using the NanoString technology, myeloid transcriptome profiling was performed on 46 glioblastomas, which had been selected based on their protein expression levels of CD204 and ionised calcium-binding adaptor molecule-1 (IBA1). The results were validated by immunohistochemistry and in silico gene expression analyses. TAMs especially CD204+ TAMs accumulated in perivascular and perinecrotic niches in close proximity to podoplanin+ glioblastoma cells. Gene profiling revealed that CD204-enriched glioblastoma has a unique signature with upregulation of genes related to hypoxia, angiogenesis and invasion, including interleukin-6. The gene signature favoured a poor prognosis in patients with glioblastoma. This is the first study to characterise the role of CD204 in the myeloid microenvironment of glioblastoma. Our results support the unfavourable prognostic impact of CD204 and suggest that CD204 and interleukin-6 could serve as targets for re-education of TAMs and potentiation of current anti-glioma therapy.


An epidemic of opium dependence among Asian refugees in Minnesota: characteristics and causes.
After several decades absence, opium smoking has reappeared in the U.S. Introduced by Indochinese refugees in the early 1980's, it has spread to several regions of the country. In this report the characteristics of refugee opium addicts is described. In addition, the factors contributing to a fertile situation for opium addiction are presented. Finally, implications of these findings and remedial recommendations are suggested.


Sub chronic exposure to crude oil, dispersed oil and dispersant induces histopathological alterations in the gills of the juvenile rabbit fish (Siganus canaliculatus).
There is little existing information on the sub-lethal effects of experimental exposure of Arabian Gulf fish to oil pollution. This study investigated the potential sub-lethal effects of the water accommodated fraction (WAF) of light Arabian crude oil, dispersed oil and dispersant (Maxi Clean 2) on the gills of the juvenile rabbit fish (Siganus canaliculatus), observing several histopathological biomarkers at different time points and different doses. These laboratory exposures simulated a range of possible oil pollution events. Significant alterations in four health categories (circulatory, proliferative, degenerative and inflammatory) were identified and form the basis for understanding the short-term response of fish to oil. Evaluations of histopathological lesions in gill tissue were carried out following 3, 6, 9, 12, 15, 18 and 21 days of exposure. The main lesions observed and quantified were lamellar capillary aneurysms, vasodilatation of lamellae, hemorrhage, edema, lifting of lamellar and filamentary epithelium and epithelium necrosis, epithelial and chloride cell hypertrophy and hyperplasia, fusion of adjacent lamellae, epitheliocystis and inflammatory infiltration. Exposure of juvenile fish to WAF, dispersant oil and dispersant caused significant changes in the gill lesions and reaction patterns. Dispersed oil caused the most significant effect followed by WAF and then dispersant. The present study is one of the first which explores the relationship between oil pollution and epitheliocystis and reports that exposure to crude oil and dispersed oil increases the prevalence of epitheliocystis formation under controlled laboratory conditions.


Factors affecting peak shape in comprehensive two-dimensional gas chromatography with non-focusing modulation.
In the case of a non-focusing modulator for comprehensive two-dimensional gas chromatography (GC×GC), the systematic distortions introduced when the modulator loads the second-dimension column give rise to a characteristic peak shape. Depending on the operating conditions this systematic distortion can be the dominant component of the second-dimension elution profiles in the GC×GC peak. The present investigation involved a systematic investigation of peak shape in pulsed-flow modulation (PFM)-GC×GC. It is shown that low flow ratio can lead to significant peak skewing and increasing the flow ratio reduces the magnitude of peak skewing. Validation of the peak shape model is made by comparison with experimental data. The residuals from the fitting process (normalised to the maximum detector response) vary between -1.5% and +2.6% for an isothermal model and between -1.0% and +3.0% for a temperature-programmed model.


A human experimental capsaicin model for trigeminal sensitization. Gender-specific differences.
Migraine is much more common in women (18%) than in men (6%). Menstrual migraine in female migraineurs also varies from 7 to 19%. The main goals of the present study were (1) to investigate gender specific differences in an experimental capsaicin model of trigeminal sensitization (a proposed mechanism of migraine) and (2) to explore the influence of menstrual cycle phases. Twenty-eight healthy female and male volunteers were studied. Capsaicin (100 microg/0.1 ml) was injected intradermally to the forehead. Pain intensity and distribution together with the visual flare and allodynic area (central sensitization) were assessed for females (during their menstrual and luteal phases) and for males. Pain area significantly changed across the menstrual cycle with 19.2+/-2.0 cm x min at menstrual and 16.4+/-0.9 cm x min at luteal phase (P<0.001). The area was significantly larger in both phases for females compared to males (14.2+/-1.3 cm x min, P<0.0001). Flare area at menstrual phase (69.2+/-4.2 cm(2)) was significantly (P<0.0001) larger than luteal phase (58.6+/-2.1 cm(2)). Females, in both phases, showed larger flare area compared to males (44.9+/-3.6 cm(2), P<0.0001). Area of brush-evoked allodynia was also larger at the menstrual phase compared to the luteal phase (P<0.0001) and males (P<0.0001). A significant difference was found in the capsaicin-evoked pain distribution with a greater response in menstrual phase compared to the luteal phase (P<0.01) and men (P<0.0001). Capsaicin induced trigeminal sensitization and evoked gender specific sensory and vaso-motor responses, with menstruating females generally showing the strongest manifestations. The model may be further applied to explore mechanisms of human trigeminal sensitization.


Ultrastructural and immunocytochemical study of the uptake and distribution of bacterial lipopolysaccharide in human monocytes.
Interaction of bacterial lipopolysaccharide (LPS) with monocytes stimulates production of a variety of mediators that are involved in the pathogenesis of septic shock and wound repair. We report here the mechanisms of LPS uptake and intracellular distribution of LPS in human monocytes. Ficoll-Hypaque-purified peripheral mononuclear cells (PBMC) were exposed to LPS from rough Escherichia coli (J5) or to biotin-conjugated LPS (biotin-LPS) from smooth E. coli (0111:B4), or to fluorescein isothiocyanate-conjugated LPS of E. coli (055:B5) at 37 degrees C for various times and processed for electron microscopy, immunocytochemistry, and flow cytometry. Monocytes were identified by the presence of numerous cytoplasmic peroxidase-positive granules or by monoclonal antibodies against monocyte. LPS micelles were identified by their specific bilayer structure, staining of horseradish peroxidase reaction product, or colloidal gold using biotin-LPS or a monoclonal antibody to LPS. Binding of LPS to cell surface was observed 5 min after incubation with LPS. Intracellular localization of LPS micelles was found 30 min following exposure to LPS. Prolonged incubation with LPS increased intracellular LPS. Intracellularly, LPS micelles were found in large membrane-bound vacuoles, in small vesicles, and in the cytoplasm and nucleus. They were also observed in association with the cytomembrane of various organelles. The overall results indicate that LPS may be taken up by monocytes by direct passive diffusion through ruptures of plasma membrane, pinocytosis, and phagocytosis, involving specific and/or nonspecific binding, and suggest that peripheral blood monocytes play an important role in clearance of LPS; that LPS may have broad effects on cell functions; and that the nonspecific binding to various cytomembranes may be destructive to cell organelles and cells in general.


Are CT angiography source images accurate for evaluating infarct volume?
Noncontrast computed tomography (NCCT) has been considered the standard test for determining eligibility for thrombolysis from the beginning of the thrombolytic era. CT angiography (CTA) reveals the cranio-cervical vessel and the occlusion site. Furthermore, the source image (SI) of the CTA (CTA-SI) reflects cerebral blood volume and can detect the infarct core as hypoattenuated areas with higher sensitivity than ischemic changes on NCCT. However, it was recently reported that the CTA-SI using fast acquisition protocol significantly overestimated the infarct core mostly on the basis of the poor collaterals. On the other hand, CTA-SI using standardized protocol was reported to be good predictor for final infarct extension. Imaging used in the setting of acute stroke should accurately address the presence and size of an irreversible ischemic core. Further studies are required to confirm whether another measure or adjustment in CTA-SI values can be more reliable for evaluating the infarct core.


A Toll receptor from Chinese shrimp Fenneropenaeus chinensis is responsive to Vibrio anguillarum infection.
Toll-like receptors (TLRs) are an evolutionarily ancient family of pattern recognition receptors (PRRs), playing a crucial role in innate immune responses. Here we present a Toll homolog from Chinese shrimp Fenneropenaeus chinensis, designated FcToll. The full-length cDNA of FcToll is 4115 bp including a poly A-tail of 16 bp, encoding a putative protein of 931 amino acids. The predicted protein consists of an extracellular domain with a potential signal peptide, 16 leucine-rich repeats (LRR), two LRR-C-terminal (LRR-CT) motifs, and two LRR-N-terminal (LRR-NT) motifs, followed by a transmembrane segment of 23 amino acids, and a cytoplasmic Toll/Interleukin-1R (TIR) domain of 139 residues. Genomic structure of FcToll gene contains five exons and four introns. Phylogenetic analysis revealed that it belongs to insect-type invertebrate Toll family. Transcripts of FcToll gene were constitutively expressed in various tissues, with predominant level in lymphoid organ. Real-time PCR assays demonstrated that expression patterns of FcToll were distinctly modulated after bacterial or viral stimulation, with significant enhancement after 5h post-Vibrio anguillarum challenge but markedly reduced levels immediately after white spot syndrome virus (WSSV) exposure. These results suggest that FcToll might be involved in innate host defense, especially against the pathogen V. anguillarum.


Locally collective hydrogen bonding isolates lead octahedra for white emission improvement.
As one of next-generation semiconductors, hybrid halide perovskites with tailorable optoelectronic properties are promising for photovoltaics, lighting, and displaying. This tunability lies on variable crystal structures, wherein the spatial arrangement of halide octahedra is essential to determine the assembly behavior and materials properties. Herein, we report to manipulate their assembling behavior and crystal dimensionality by locally collective hydrogen bonding effects. Specifically, a unique urea-amide cation is employed to form corrugated 1D crystals by interacting with bromide atoms in lead octahedra via multiple hydrogen bonds. Further tuning the stoichiometry, cations are bonded with water molecules to create a larger spacer that isolates individual lead bromide octahedra. It leads to zero-dimension (0D) single crystals, which exhibit broadband 'warm' white emission with photoluminescence quantum efficiency 5 times higher than 1D counterpart. This work suggests a feasible strategy to modulate the connectivity of octahedra and consequent crystal dimensionality for the enhancement of their optoelectronic properties.


Effects of norepinephrine on lung fluid flow rate in the chronically catheterized fetal lamb.
The influence of norepinephrine on lung fluid flow rate was studied in seven chronically catheterized fetal lambs. Lung fluid was collected through a catheter inserted into the fetal trachea. In six experiments, continuous saline solution infusion for 1 hour followed by equivolumnar norepinephrine (3.0 micrograms/min) for 1 hour via the fetal jugular vein was carried out. In three additional experiments (two fetuses), a 3.0 mg intravenous bolus of propranolol was administered before norepinephrine infusion. Saline solution infusion did not influence the lung fluid flow rate or fetal biophysical and biochemical parameters. Norepinephrine increased fetal blood pressure by 22% and decreased lung fluid flow by 45% from control values. Lung fluid flow rate recovered within 2 hours after the end of the norepinephrine infusion. Pretreatment with propranolol did not alter the results. In addition to previous reports that demonstrated beta-sympathomimetic agonist-enhanced reabsorption of lung fluid from fetal alveolar epithelial cells, our present results suggest that a reduction in fetal lung fluid secretion may be implemented as well through stimulation of alpha-sympathomimetic receptor sites in the pulmonary vasculature.


Role of Stat3 in suppressing anti-tumor immunity.
Recent evidence suggests that what sustains a tumor's survival and proliferation can also subvert the immune system from its defense role. As a point of convergence for numerous oncogenic signaling pathways, Stat3 is constitutively activated in diverse human cancer cells. Activated Stat3 not only upregulates genes crucial for survival, proliferation, angiogenesis, and metastasis but also promotes expression of immune suppressive factors while inhibiting Th1 immunostimulatory molecules. By virtue of its ability to promote expression of many factors that activate Stat3 in diverse cells, Stat3 allows malignant and immune cells resonate, forming close partnership for tumor immune evasion, tumor progression, and resistance to therapies.


Reconstitution of primary, severe, combined immunodeficiency in man and horse.
Severe combined immunodeficiency disease (SCID) in foals is the only known animal model for the autosomal recessive form of primary SCID in man. A major requirement in the treatment of SCID is the maintenance of the patient in a disease free state until definitive therapy can be undertaken. This paper reviews the current status of prophylactic and definitive therapy in man and the horse. Particular emphasis is placed on the methods of reconstitution available, involving foetal tissues and bone marrow.


The Effectiveness of Pharmacist Interventions on Cardiovascular Risk in Adult Patients with Type 2 Diabetes: The Multicentre Randomized Controlled RxEACH Trial.
Cardiovascular disease (CVD) is the leading cause of death among patients with diabetes. Management and control of CV risk factors in those with diabetes are generally poor. Pharmacists are frontline primary healthcare providers who see patients with chronic diseases frequently. As such, they are in a prime position to systematically identify patients with diabetes, assess their CV risk and assist in their disease management and preventive measures. to evaluate the effect of pharmacist case finding and intervention program on estimated CV risk in patients with diabetes. Sub-group analysis of a randomized controlled trial (RxEACH). Patients were randomized to receive intervention or usual care for 3 months. Those who were randomized to the intervention group received a Medication Therapy Management consultation which included patient assessment, laboratory assessment, individualized CV risk assessment. Treatment regimen adjustment, as needed, in order to meet treatment targets. Estimated CV risk was reduced from 26.9 +/- 21% to 26.5 +/- 21.3% in the control group and from 25.8 +/- 19.4% to 20.1 +/- 17.2% in the intervention group over the 3-month follow up period (an absolute reduction of 5.38; 95% confidence interval (CI) 4.24 to 6.52; p <0.001). Community pharmacy-based case finding and intervention program reduced the risk for major CV events by 21% when compared to usual practice. This represents a promising approach to help tackle the major public health problem of diabetes in Canada.


A comparison of young children's spatiotemporal measures of walking and running in three common types of footwear compared to bare feet.
Clinicians and footwear manufacturers often advise young children to wear soft-soled footwear when they are first learning to walk. There is limited evidence as to why this advice is given, and if soft-soled shoes are as close to barefoot as thought. What are the differences in spatiotemporal measures of gait during walking and running in three common types of children's footwear with a soft-soled compared to barefoot in young children? The study used a quasi-experimental design, with the condition order randomised using a Latin square sequence. Forty-seven children were recruited (2 - 4 years). Participants walked or ran the length of a GAITrite mat in a randomized order for barefoot and soft-soled sneaker, boot and sandal conditions. Linear regression analyses were used to investigate the main effect of each soft-soled footwear compared to bare feet in the different gait parameters. For walking and running trials, cadence decreased whereas step time and stride length increased in all footwear types compared to the barefoot condition. While wearing sneakers and sandals increased the stance percentage for walking and running trials, compared to barefoot, this difference was only apparent during the running trial for the boots. Likewise, although double support time increased for both the boots and sneakers in walking and running, compared to barefoot, this difference was only observed in the sandals during walking. This research found that various types of soft-soled footwear impacted gait compared to the barefoot condition, with some differences seen between walking and running trials. These findings challenge the assumption that soft-soled footwear facilitate a similar gait to barefoot walking and running, although the clinical significance of these differences is unknown.


A model of ovum transport.
A theoretical fluid dynamical model of ovum transport in the oviduct incorporating transport mechanisms due to ciliary activity, muscular activity and an applied pressure drop across the oviduct is developed. Theory suggests that the cilia provide the steady component of ovum transport whereas muscular activity results in highly oscillatory motion. If muscular activity is to provide transport in a pro-uterine direction, a coordinated sequence of muscular activity with a strong pro-uterine bias is needed. Changes in pressure are highest in the narrowest sections. The highly convoluted rugae may allow "leakback" around the ovum so relieving the pressure drop across the ovum in narrower sections of the oviduct.


Effect of cyclic AMP, disodium cromoglycate and other anti-allergic drugs on histamine secretion from rat mast cells stimulated with the calcium ionophore ionomycin.
Cyclic AMP analogues and the anti-allergic drugs disodium cromoglycate, quercetin, doxantrazole and theophylline inhibited histamine secretion from rat peritoneal mast cells stimulated with the calcium ionophore ionomycin. The potency of the compounds varied inversely with the concentration of ionophore and with the period of incubation. The drugs were active in both the presence and absence of extracellular calcium. These results cannot be explained in terms of the postulated effect of the compounds on the receptor-mediated activation of calcium-channels. Alternative mechanisms for their action are thus considered.


Olivocochlear neuron central anatomy is normal in alpha 9 knockout mice.
Olivocochlear (OC) neurons were studied in a transgenic mouse with deletion of the alpha 9 nicotinic acetylcholine receptor subunit. In this alpha 9 knockout mouse, the peripheral effects of OC stimulation are lacking and the peripheral terminals of OC neurons under outer hair cells have abnormal morphology. To account for this mouse's apparently normal hearing, it has been proposed to have central compensation via collateral branches to the cochlear nucleus. We tested this idea by staining OC neurons for acetylcholinesterase and examining their morphology in knockout mice, wild-type mice of the same background strain, and CBA/CaJ mice. Knockout mice had normal OC systems in terms of numbers of OC neurons, dendritic patterns, and numbers of branches to the cochlear nucleus. The branch terminations were mainly to edge regions and to a lesser extent the core of the cochlear nucleus, and were similar among the strains in terms of the distribution and staining density. These data demonstrate that there are no obvious changes in the central morphology of the OC neurons in alpha 9 knockout mice and make less attractive the idea that there is central compensation for deletion of the peripheral receptor in these mice.


Allogeneic astrocytoma in immune competent dogs.
We have induced in canines long-term immune tolerance to an allogeneic cell line derived from a spontaneous canine astrocytoma. Allogeneic astrocytoma cells were implanted endoscopically into the subcutaneous space of fetal dogs before the onset of immune competency (< 40th gestational day). At adulthood, dogs rendered tolerant successfully serve as recipients of intracranial transplants of their growing allogeneic, subcutaneous tumor. Transplanted dogs subsequently develop a solid brain tumor with histological features similar to the original astrocytoma. This model may allow rapid development and evaluation of new therapies for brain tumors, as well as afford tumor biology studies that are untenable in smaller, immune incompetent, or inbred animals harboring less representative tumors.


MicroRNA profiling in denatured dermis of deep burn patients.
Denatured dermis is a part of the dermis in deep burn wound and has the ability to restore normal morphology and function. Skin grafting with the preservation of denatured dermis is a new kind of surgical procedure and has reported satisfactory clinical effects, such as lessened scar contracture and a better restoration of the appearance and function. However, the underlying mechanism of the recovery of denatured dermal function remains unclear. MicroRNAs (miRNAs) are a new class of regulatory noncoding single-stranded RNAs, which play a key role in normal development and physiology, as well as in disease development. This study analysed the profile of miRNAs in denatured dermis from patients and further investigated the possible roles of miRNAs played in the functional recovery of denatured dermis by prediction of the potential target genes of differentially expressed miRNAs. The denatured dermis and paired normal skin were collected and analysed by miRNA array. The miRNA profiling results were validated by real-time reverse transcriptase polymerase chain reaction (RT-PCR), and bioinformatics' analysis was employed to further predict the miRNA targets. A total of 66 miRNAs were differentially expressed in denatured dermis compared with those in normal skin, among which 34 were down-regulated while 32 are up-regulated. The most significantly up-regulated miRNA was miR-663, and the most significantly down-regulated one was miR-203. Differentially expressed miRNAs were predicted to be related with several signalling pathways in wound healing. The differential miRNA expression identified in this study supplies experimental basis for further understanding the mechanisms of functional recovery of the denatured dermis.


A Twitter Education: Why Psychiatrists Should Tweet.
Social media tools such as blogs, microblogs, social networking sites, podcasts, and video-sharing sites are now ubiquitous. These tools enable instantaneous interactions with a global community of individuals, including medical professionals, learners, and patients. An understanding of social media tools and how they can be used by psychiatrists is increasingly important. This review defines some relevant social media terms and addresses challenges specific to the use of social media in psychiatry. Focused primarily on Twitter, one of the most commonly used social media tools, the review describes how Twitter is being used in non-psychiatric medical fields and highlights four current and/or potential uses of Twitter in psychiatry: (1) patient care and advocacy, (2) lifelong learning, (3) research data collection and collaboration, and (4) scholarly recognition and impact.


Population pharmacodynamics of midazolam administered by target controlled infusion in SICU patients after CABG surgery.
Midazolam is used commonly for sedation in the surgical intensive care unit. A suboptimal dosing regimen may lead to relative overdosing, which could result in delayed extubation and increased cost. This multicenter trial characterized midazolam pharmacodynamics in patients recovering from coronary artery bypass grafting. Three centers enrolled 90 patients undergoing coronary artery bypass grafting. All patients received sufentanil and midazolam via target-controlled infusion. After surgery, midazolam was titrated to a Ramsay sedation score of 5 for 2 h and then decreased to maintain a sedation score of 3 or 4 for at least another 4 h. Pharmacodynamic parameters were derived using NONMEM. The model was cross-validated to test performance. The probability of a given level of sedation was related to the midazolam concentration by this equation: P(Sedation > or = ss) = Cn/(Cn + C(50,ss)n), where ss is the sedation score, C is the sum of the midazolam concentration and a term reflecting the dissipating effect of anesthesia: C = [midazolam] + theta x e(-Kt), where theta = 256 ng/ml and K = 0.19 h(-1). C(50,ss) values for Ramsay scores of 2 to 6 were 5.7, 71, 171, 260, and 659 ng/ml, respectively. The model predicted 57% of the data points correctly and 88% within one sedation score. Despite previous reports of high interindividual variability in midazolam pharmacodynamics in patients in the surgical intensive care unit, these cross-validation results suggest that, when midazolam is administered using a target-controlled infusion device, the level of sedation can be predicted within 1 sedation score in 88% of patients based on the target midazolam concentration and the time since the conclusion of the anesthetic.


Thymectomy by thoracoscopic approach in myasthenia gravis.
A series of 25 thoracoscopic thymectomies performed in the Department of General Surgery and Liver Transplantation of the Fundeni Clinical Institute between April 1999 and April 2000 is analyzed. Thoroscopic thymectomies were performed on 4 male patients (16%) and 21 female patients (84%), aged between 8 and 60 years. The mean operative time was 90 (+/-15) min. There were no conversions to open thymectomy. Mortality was nil, and morbidity consisted of one minor postoperative right pneumothorax probably related to a injury to right mediastinal pleura that was not observed intraoperatively. Hospital stay ranged from 2 to 4 days, with a mean of 2.28 days. The patients were transferred to the neurological department and they were usually discharged after 1 more day. Postoperatively, all patients had clinical improvement of their disease both in symptoms and medication requirements, but a longer follow-up is necessary. The results are edifying regarding the very low morbidity, the lack of mortality, the acceptance of the patients, and the short hospitalization.


Brown-Mclean syndrome associated with corneal endotheliitis in a pseudophakic eye.
A healthy 65-year-old woman had uncomplicated unilateral extracapsular cataract extraction followed by iridocapsular intraocular lens (IOL) implantation. Three and one half years after surgery, the inferior cornea developed marked edema with moderate retrocorneal precipitates, a phenomenon that recurred three more times during her eight-year postoperative course. Values obtained by laser flare cell meter coincided with each recurrence of corneal edema. Each occurrence was managed well by steroid therapy. Corneal endothelial cell density of the affected eye changed from a presurgical value of 3,260 cells/mm2 (central) to 553 (upper), 519 (central), and 363 (inferior). The intraocular lens was not touching the cornea, and there were no signs of general and local herpetic infections. The recurrent corneal edema responded well to steroid therapy, suggesting concurrent corneal endotheliitis and Brown-Mclean syndrome.


[Removability of tooth deposits by cleaning with toothbrushes and toothpaste].
The abrasion strength of the exogenous pellicle (EP) was investigated in in vitro experiments on extracted human teeth. The aim of the study was to elucidate the effect of daily brushing on the EP. EP-coated tooth specimens were cleansed under in vivo-like conditions. Five toothpastes with different degrees of abrasiveness were variously diluted with artificial saliva. The evaluation was done on the transmission electron microscope. The individual toothpastes differed significantly with respect to their abrasive effect on EP, which extended from only a slight effect on EP, which extended from only a slight effect to extensive removal of the pellicle. EP abrasion was considerably reduced by increasing dilution of the pastes with artificial saliva. No changes of the EP could be observed after brushing with only the toothbrush and saliva.


mRNA adenosine methylase (MTA) deposits m6A on pri-miRNAs to modulate miRNA biogenesis in Arabidopsis thaliana.
In Arabidopsis thaliana, the METTL3 homolog, mRNA adenosine methylase (MTA) introduces N6-methyladenosine (m6A) into various coding and noncoding RNAs of the plant transcriptome. Here, we show that an MTA-deficient mutant (mta) has decreased levels of microRNAs (miRNAs) but accumulates primary miRNA transcripts (pri-miRNAs). Moreover, pri-miRNAs are methylated by MTA, and RNA structure probing analysis reveals a decrease in secondary structure within stem-loop regions of these transcripts in mta mutant plants. We demonstrate interaction between MTA and both RNA Polymerase II and TOUGH (TGH), a plant protein needed for early steps of miRNA biogenesis. Both MTA and TGH are necessary for efficient colocalization of the Microprocessor components Dicer-like 1 (DCL1) and Hyponastic Leaves 1 (HYL1) with RNA Polymerase II. We propose that secondary structure of miRNA precursors induced by their MTA-dependent m6A methylation status, together with direct interactions between MTA and TGH, influence the recruitment of Microprocessor to plant pri-miRNAs. Therefore, the lack of MTA in mta mutant plants disturbs pri-miRNA processing and leads to the decrease in miRNA accumulation. Furthermore, our findings reveal that reduced miR393b levels likely contributes to the impaired auxin response phenotypes of mta mutant plants.


Migraine patients with and without neck pain: Differences in clinical characteristics, sensitization, musculoskeletal impairments, and psychological burden.
This study aims to assess differences in clinical characteristics across healthy controls and migraine patients with (MNP) and without (MwoNP) neck pain. This study assessed: headache frequency; headache disability index (HDI); central sensitization inventory (CSI); Hospital Anxiety (HADS-A) and Depression (HADS-D) scale; active range of motion (AROM); flexion rotation test (FRT); activation pressure score (APS); number of active/latent myofascial trigger points (MTrPs) in head/neck muscles; number of positive cervical vertebral segments (C1/C2) who reproduce migraine pain; wind-up ratio (WUR); mechanical pain threshold (MPT) and static pressure pain threshold (sPPT) over the trigeminal area; sPPT and dynamic PPT (dPPT) over the cervical area; sPPTs and MPT over the hand. Compared to controls, MNP had: worse CSI, HADS-A, and HADS-D (all, p < 0.002); reduced AROM (flexion, extension, left lateral-flexion, and right-rotation), FRT, APS, and a higher number of MTrPs and positive cervical vertebral segments (all, p < 0.020); reduced trigeminal MPT and sPPT, cervical sPPT and dPPT, hand MPT and sPPT (all, p < 0.006). Compared to controls, MwoNP had: worse CSI, and HADS-A (all, p < 0.002); reduced AROM (flexion, and left lateral-flexion), FRT, APS, and a higher number of MTrPs and positive cervical vertebral segments (all, p < 0.017); reduced trigeminal MPT and cervical dPPT (all, p < 0.007). Compared to MwoNP, MNP had higher headache frequency, worse HDI and CSI (all, p < 0.006); reduced AROM (flexion, and right rotation) (all, p < 0.037); reduced cervical dPPT (all, p < 0.002). MNP had worse headache characteristics, more pronounced cervical musculoskeletal impairments, enhanced signs and symptoms related to sensitization, and worse psychological burden compared to MwoNP.


T cell-mediated cytotoxicity via Fas/Fas ligand signaling in Helicobacter pylori-infected gastric corpus.
Helicobacter pylori infection induces T helper-1 immune responses in inflamed mucosa. However, the role of T cell-mediated cytotoxicity in the induction of epithelial apoptosis is still unclear. The aim of this study was to investigate the involvement of the Fas/Fas ligand (Fas/Fas-L) system in the H. pylori-infected gastric corpus. Gastric fundic biopsy specimens were taken from patients with and without H. pylori infection. The expression of Fas and Fas-L was examined by immunohistochemistry and RT-PCR. Subsets of gastric infiltrating T cells in the biopsy specimens were studied by immunohistochemistry and flow cytometry. In histological sections, apoptosis was detected by the TUNEL method. We studied the in vitro expression of Fas-L in peripheral T cells after stimulation with H. pylori antigen and interferon-gamma (IFN-gamma). The Fas-mediated in vitro cytotoxicity of activated T cells was assessed by flow cytometry. The numbers of CD4+ and CD8+ T cells were greater in H. pylori-infected subjects. Fas expression was abundantly increased on fundic gland epithelium, and Fas-L was detected on lamina propria mononuclear cells in H. pylori-infected mucosa. TUNEL-positive epithelial cells were also increased in H. pylori-infected subjects. H. pylori antigen and IFN-gamma induced Fas-L mRNA expression in both CD4+ and CD8+ T cells. In cytotoxic assay, activated T cells induced apoptosis in AGS cells, which could be significantly inhibited by neutralizing Fas-L antibody. T cell-mediated cytotoxicity via Fas/Fas-L signaling may contribute to the induction of apoptosis in gastric epithelial cells during H. pylori infection.


The ontogeny of Mullerian inhibiting substance in the gonads of the chicken.
Mullerian inhibiting substance (MIS) was studied in the testis, ovary, and ovotestis of the domestic fowl, from early embryonic development to adulthood by a graded organ-culture method using the urogenital ridge of a 14.5 day fetal rat. The chick testis had high levels of MIS from 8 days of embryonic development (4-5+) until sexual maturity, when activity declined (2+) but persisted throughout adulthood. The right gonad (ovotestis) of the hen showed moderate levels of MIS activity from 8 to 12 days of embryonic life (1-3+) before its normal involution by the time of hatching (21 days). The left gonad (ovary) of the hen also produced MIS at levels similar to that seen in the testis. Activity was high during embryonic development (4+) and after hatching, and persisted in the adult hen at diminished levels (2+). MIS production by the female gonads explains regression of the right Mullerian duct, but the mechanisms that allow preservation of the left duct remain unexplained. Evidence suggests that ovarian estrogens may interact with MIS at the receptor level to protect the left Mullerian duct. MIS persists in the sexually mature gonads of both the hen and cockeral, long after the Mullerian duct has regressed, suggesting a wider role for this substance in reproductive physiology.


Tumor-infiltrating lymphocytes (TILs) in feline melanocytic tumors: A preliminary investigation.
The presence and the role of tumor-infiltrating lymphocytes (TILs) in different types of tumors, but particularly in melanoma, has become more and more investigated during the last decade, both in human and veterinary medicine. Melanocytic tumors are quite rare in cats, with diffuse iris melanoma being the most commonly diagnosed in this species. The aim of this study was to characterize the lymphocytic infiltration in feline melanocytic tumors and to analyze their association with the histological features of malignancy recognized in these tumors, as well as with the expression of the most commonly used immunohistochemical markers. Thirty-eight feline melanocytic tumors were retrospectively selected; histological and immunohistochemical characterization of the tumors (histologic criteria of malignancy; S100, Melan A, and PNL2 expression) and of TILs (presence/absence, density, distribution, and grade; CD3, CD20 expression) were performed and associations between them tested. Results showed that TILs grade increased with cellular pleomorphism (P < 0.05) and, within the group of cutaneous melanocytic tumors, also with the mitotic count (P < 0.05). On the other hand, TILs grade was inversely associated with the percentage of neoplastic cells positive for Melan A (P < 0.05) and PNL2 (P < 0.05). Both CD3+ and CD20+ lymphocytes increased significantly with TILs grade and in association with mitotic count, when stratified in low/high quantity. This preliminary study suggests that TILs in feline melanoma may be associated with histologic features of malignancy and loss of melanocytic-specific markers, such as Melan A and PNL2. Further studies, with a larger cohort and follow-up information, are recommended.


Group choice and individual choices: modeling human social behavior with the Ideal Free Distribution.
Group choice describes the behavioral phenomenon in which a group of individuals chooses between two behavioral alternatives over time and the Ideal Free Distribution (IFD) [Acta Biotheor. 19 (1970) 16] describes group choice analogous to individual choice and the matching law. Our experiments investigated the usefulness of IFD analyses of human group choice based on a procedure reported in Sokolowski et al. [Psych. Bull. Rev. 6 (1999) 157]. A group of humans distributed into two subgroups to receive points that could earn cash prizes. The participants aligned themselves into subgroups by choosing between two rows of chairs, two different colored cards, or two cyber-subgroups. Different methods of distributing points to participants showed that IFD matching was dependent on the method (i.e. sharing points evenly produced near IFD matching, but probabilistic point distribution produced more undermatching). In addition, the sensitivity measures of individual choices in the groups differed from the sensitivity of the groups' choices.


An outbreak of cryptosporidiosis in an urban swimming pool: why are such outbreaks difficult to detect?
To describe an outbreak of Cryptosporidium gastroenteritis in a swimming pool in Melbourne in early 1998 that was not detected through routine surveillance, and discuss difficulties in identifying such outbreaks. The Water Quality Study (WQS) was a large community-based study of gastroenteritis. Following suspicion of an outbreak of cryptosporidiosis within the study group, due to pool "X", a nested case control study was performed. Each case of Cryptosporidium gastroenteritis was matched with six controls and data from weekly Health Diaries from the WQS were reviewed. The Department of Human Services also instigated active surveillance among patrons at pool "X" using a systematic sample of 50 people from the pool's swim-school enrollment list. There were seven cases of Cryptosporidium gastroenteritis in the case control study. Five cases and eight controls swam at pool "X" during the outbreak period. The adjusted odds of developing cryptosporidial diarrhoea if an individual swam at pool "X" was 34.5 (CI 2.3-2548). DHS identified another 11 laboratory confirmed cases associated with pool "X" as well as cases not linked to pool "X". 125 cases were identified throughout Melbourne with the suspected involvement of seven swimming pools. Despite a high odds ratio of developing cryptosporidiosis this outbreak was not detected by routine surveillance methods. Current outbreak detection methods lack sensitivity, specificity or timeliness. Improved surveillance systems are required if outbreaks of gastroenteritis are to be detected early so an intervention can be instigated to reduce the amount of subsequent illness.


Characterization of electrode dissolution products on the high-voltage electron microscope.
Deposits left by electrodes and biocompatibility test specimens implanted in brain or peripheral nerve were characterized by X-ray microprobe analysis, electron diffraction and stereoscopic imaging using a high-voltage electron microscope. Examination of thick (1-micron) sections of neural tissue confirmed that the electron-dense bodies found adjacent to electrode positions consist of elements originating in the implant material (with the exceptions of the S and Se found in association with Ag). These elements have no long-range order, suggesting they are complexed with biological molecules. In some cases the deposits appear to be caused by pulsing the electrode with current, while in other cases the deposits are corroded or abraded from the electrode or are otherwise not associated with the neuroprosthetic functioning of the implant.