Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy.
Impaired autophagy is a pathogenic mechanism in the synucleinopathies. Sirolimus, a potent mTOR inhibitor and autophagy activator, had no beneficial effects in a randomized placebo-controlled trial in patients with multiple system atrophy (MSA). Whether sirolimus effectively inhibited brain mTOR activity was unknown. We aimed to evaluate if patients with MSA treated with sirolimus had evidence of inhibited brain mTOR pathways by measuring neuron-derived serum extracellular vesicles (NEVs). Serum samples were collected from participants of the sirolimus-MSA trial, which randomized patients to sirolimus (2-6 mg/day) or placebo for 48 weeks. NEVs were immunoprecipitated with three antibodies-against neurons. Brain mTOR engagement was quantified as the change in the NEV phosphorylated mTOR (p-mTOR) to total-mTOR (tot-mTOR) ratio after 48 weeks of sirolimus. Samples from 27 patients [mean (±SD) age, 59.2±7 years, 15 (55.5%) men] were analyzed (19 sirolimus, 8 placebo). Treated- and placebo-patients had similar p-mTOR:tot-mTOR ratio at 24 (placebo: 0.248 ± 0.03, sirolimus: 0.289 ± 0.02; P = 0.305) and 48 weeks (placebo: 0.299 ± 0.05, sirolimus: 0.261 ± 0.03; P = 0.544). The tot-mTOR, p-mTOR, or their ratio levels were not associated with Unified MSA Rating Scale (UMSARS) worsening. These results are consistent with no brain mTOR engagement by oral sirolimus up to 6 mg/day. NEV-based biomarkers are a rational approach to investigating target engagement in clinical trials of brain-targeted therapeutics.


Trinuclear Cobalt(II) Triple Helicate with a Multidentate Bithiazolebis(oxamate) Ligand as a Supramolecular Nanomagnet.
The cobalt(II)-mediated self-assembly of the potentially tris(chelating) N,N'-2,2'-(4,4'-bithiazole)bis(oxamate) (dabtzox) ligand gives a new metal-organic supramolecular nanomagnet of formula K6Co3(dabtzox)3·8H2O·MeOH (1) featuring a unique linear triple-stranded trinuclear structure of the helicate type.


Biochemical studies of immune complexes. I. Isolation of circulating immune complexes using a bifunctional exclusion chromatography matrix.
A simple and rapid method of isolating immune complexes from serum is described. The method utilizes the binding properties of a bifunctional chromatography matrix consisting of diethylaminoethyl and Cibacron blue F3GA functional groups linked to agarose beads. This column matrix binds all normal serum proteins except IgG and transferrin, excluding these proteins, and permitting them to be collected in the wash-through, void volume. Immune complexes prepared in vitro with human serum albumin were rapidly isolated from starting serum by this method. This method may have general application for the purification of immune complexes from serum in pathological conditions and should foster subsequent biochemical and immunological studies, including identification and characterization of immune complex antigens.


Percutaneous snare retrieval of a partially embedded Wallstent.
Although removal of a stent is a well described method for treating an acutely dislodged or embolized device, removal of a previously deployed stent is unusual. We describe a case where a partially dislodged wallstent in a saphenous vein graft was removed using a snare to permit deployment of a balloon mounted stent across a proximal vein graft stenosis.


Perfluorooctanoate suppresses spheroid attachment on endometrial epithelial cells through peroxisome proliferator-activated receptor alpha and down-regulation of Wnt signaling.
Exposure of animals to perfluorooctanoic acid (PFOA), a surfactant used in emulsion polymerization processes causes early pregnancy loss, delayed growth and development of fetuses. The mechanisms of action are largely unknown. We studied the effect of PFOA on implantation using an in vitro spheroid-endometrial cell co-culture model. PFOA (10-100μM) significantly reduced Jeg-3 spheroid attachment on RL95-2 endometrial cells. PFOA also suppressed β-catenin expression in Jeg-3 cells. The Wnt agonist Wnt3a stimulated β-catenin expression in Jeg-3 cells and reversed the PFOA suppression of the spheroid attachment. The putative PFOA receptors (PPARα, β, γ) present in both cell lines were not affected by PFOA (0.01-100μM). The PPARα antagonist MK886 restored the β-catenin and E-cadherin expression levels in Jeg-3 cells and reversed the suppression of the spheroid attachment caused by PFOA. Taken together, PFOA suppresses spheroid attachment through PPARα and Wnt signaling pathways via down-regulation of β-catenin and E-cadherin expression.


Wise use of perioperative antibiotics.
NOSOCOMIAL SURGICAL SITE INFECTIONS (SSIs), especially those caused by antibiotic-resistant organisms, are a major concern for perioperative nurses. Administering the correct antibiotic at its effective dose within the optimal time frame can help prevent SSIs. THE SIGNIFICANT RELATIONSHIP between microbial resistance and overuse of antibiotics justifies an examination of practices and a move away from widespread antibiotic administration. NEW ANTIBIOTIC GUIDELINES and research support recommendations for antibiotic administration for specific cardiac, colorectal, gynecologic, ophthalmologic, orthopedic, and urinary surgical procedures. Perioperative nurses can help protect their patients from nosocomial SSIs by using this clinical evidence.


Autoimmune vestibular dysfunction: preliminary report.
Since 1981, 28 patients have been diagnosed with autoimmune inner ear disease. This preliminary, retrospective study reviews clinical and laboratory manifestations of autoimmune vestibular dysfunction. Sixteen of 28 patients presented with dizziness (7 vertigo, 8 lightheadedness, 1 ataxia). Twelve of these patients presented with Meniere's syndrome. Seven of 16 dizzy patients underwent formal vestibular testing. Five had reduced vestibular response in the involved ear(s); one patient had positional nystagmus only; and one had normal results. Of 17 patients with adequate follow-up, 11 presented with dizziness. Hearing improved and dizziness resolved in two patients following treatment. Hearing stabilized and dizziness resolved in two. Hearing stabilized but lightheadedness (without vertigo) persisted in five. Hearing was lost and oscillopsia resulted in two patients. Preliminary conclusions are vestibular dysfunction in autoimmune inner ear disease is nonspecific; bilateral vestibular dysfunction is more common; Meniere's syndrome is relatively common; medical management usually is helpful; surgery at this time does not seem appropriate; vestibular treatment results tend to parallel auditory treatment results.


Versatility of the perforator radial artery flap in the reconstruction of the upper limbs and comparison of the outcomes with the "classic" radial flap, a retrospective study.
Radial forearm flap, first described in the early eighties in China, is a well-known and handy flap to cover soft tissue defects of the distal upper limb. It has, though, some inconveniences, such as the sacrifice of the radial artery and non-neglectable esthetic sequelae in the donor site. In the following years, a similar flap based on the perforators of the radial artery has been described as achieving similar results, allowing to spare a main vessel. The authors reviewed retrospectively the patients that underwent surgery with one of those two flaps in their center to compare outcomes. Patients operated between January 2016 and January 2022 have been reviewed. Ten had a classic radial artery flap, and ten had a radial artery perforator flap. Twelve weeks after surgery, Vancouver Scar Scale was used to assess the results at the donor site and over the flap. Reintervention and failure rate within one year and patient satisfaction -using a visual analog scale ranging from 0 to ten-at 12 months were also assessed. All classic radial artery flap group patients had "successful" surgery, and none needed secondary surgery. On the other side, three patients required a second surgery in the perforator flap group, and nine out of ten ended up with "successful" flaps. Mean Vancouver Scar Scale results regarding the flap are comparable, whereas those at the donor site are significantly better in the patients with the perforator flap. Patients' satisfaction results are similar in both groups. The radial artery perforator flap is an important flap to be held in mind by all surgeons approaching reconstruction of the elbow, the forearm, and the hand, and should be preferred, when possible, to the classic radial forearm flap.


Foetal brain development in the sheep.
The pattern of normal foetal brain development has been described for the Merino sheep. Controlled flock matings were used and foetuses removed by hysterotomy at 40, 54, 67, 81, 90, 95, 109, 121 and 150 days of gestation. Lambs at 7 days after birth and adults were also studied. The CNS was dissected, separated and weighed as four segments--cerebral hemispheres, brain stem, cerebellum and spinal cord. Determinations of DNA, RNA, protein, cholesterol and water content were subsequently carried out on each segment. Brain weight increased from 0.264 g (40 days) to 52.74 g at 150 days. The ratio to body weight decreased from 6.7% (40 days) to 1.5% (150 days). DNA increased more rapidly from 40 to 90 days in the cerebral hemispheres and brain stem than in the cerebellum and spinal cord and this increase preceded the main increase in weight. Increases in cholesterol and decreases in water content were also more marked in the cerebral hemispheres and brain stem. Increase in brain weight occurred in two phases, one up to 90 days followed by a more rapid and larger increase after 90 days which continued to birth. These two phases appear to reflect an increase in neuroblast multiplication followed by neuroglial multiplication and myelination respectively. At birth, brain weight had reached 50% of adult size, the cerebral hemispheres 52% of adult size, the cerebellum 40% and spinal cord 40%. The relative maturity of the brain at birth justifies the classification of the sheep as a prenatal brain developer.


[Effect of atherogenic risk factors on the state of complex intima-media of common carotid artery].
To elucidate relationship between presence of atherogenic risk factors (dyslipidemia, hypertension, smoking, etc.) and common carotid artery intima-media thickness. Color duplex carotid artery scanning and determination of blood lipids, lipo- and apolipoproteins were carried out in 160 patients aged 34-73 (mean 57.4+/-8.2) years. Dyslipidemia, hypertension (diastolic blood pressure > or = 95 mm Hg), smoking and intima-media thickness > 1 mm were present in 57, 49, 54 and 65% of patients, respectively. Intima-media thickness increased with age and in the presence of hypercholesterolemia, hypertension and smoking. Significant (p<0.05) correlations existed between intima-media thickness and levels of total cholesterol (r=0.512), triglycerides (r=0.411), apolipoprotein B (r=0.497), high density lipoprotein cholesterol (r=-0.404), apolipoprotein-A1 (r=-0.386), duration of hypertension (r=0.488). Ultrasound study of intima-media thickness allowed to assess harmful effect of various atherogenic risk factors (mechanical - hypertension, biochemical - dyslipidemia, toxic - smoking) on the state of arterial wall.


The nickel phosphate rods derived from Ni-MOF with enhanced electrochemical activity for non-enzymatic glucose sensing.
In this work, spherical Ni-based metal-organic frameworks (Ni-MOFs) were used as precursors for preparing nanorod-like nickel phosphate (r-NiPO) with enhanced electro-catalytic properties in detection of glucose. It was found that the addition of nickel ion has a profound effect on construction of nickel phosphate with flower-like, rod-like, and ribbon-like structure in presence of H2PO2-. The r-NiPO consisted of multiple phases of nickel phosphate showed porous, interconnected structure and abundant active Ni(II)/Ni(III) pairs, which was beneficial to facilitate glucose oxidation. In comparison with Ni-MOF, r-NiPO exhibited the superior electrocatalytic property on oxidation of glucose because of the exposing more active Ni sites in r-NiPO than that of Ni-MOF precursor. r-NiPO modified glassy carbon electrode (r-NiPO/GCE) showed a good linear response to glucose from 1.0 μM to 3.0 mM with a high sensitivity of 3169 μA mM-1 cm-2. In addition, r-NiPO/GCE can be used to detect glucose in human serum with satisfactory recoveries (90-97%).


Searching the literature for proteins facilitates the identification of biological processes, if advanced methods of analysis are linked: a case study on microgravity-caused changes in cells.
More than one hundred reports were published about the characterization of cells from malignant and healthy tissues, as well as of endothelial cells and stem cells exposed to microgravity conditions. We retrieved publications about microgravity related studies on each type of cells, extracted the proteins mentioned therein and analyzed them aiming to identify biological processes affected by microgravity culture conditions. The analysis revealed 66 different biological processes, 19 of them were always detected when papers about the four types of cells were analyzed. Since a response to the removal of gravity is common to the different cell types, some of the 19 biological processes could play a role in cellular adaption to microgravity. Applying computer programs, to extract and analyze proteins and genes mentioned in publications becomes essential for scientists interested to get an overview of the rapidly growing fields of gravitational biology and space medicine.


End-to-Trunk Masseteric to Facial Nerve Transfer With Selective Neurectomy for Facial Reanimation.
To examine functional outcomes following end-to-trunk masseteric to facial nerve transfer in patients with chronic flaccid facial paralysis. Retrospective chart review. Tertiary-care private practice setting. Patients with complete unilateral facial paralysis of less than 24 months duration. Direct end-to-trunk masseteric to facial nerve anastomosis. Outcome measures included time to first movement, development of synkinesis, and an objective assessment of the resting tone and dynamic movement that was achieved. Patient age at the time of transfer ranged from 6 to 61. Follow-up ranged from 12 to 24 months. No patients had any perioperative complications. No patient experienced significant mass movement or synkinetic facial movement with chewing. No patient had worsened chewing or swallowing. Patients have not yet recovered significant resting tone. All patients achieved smile activity when biting down with a median (interquartile range) oral commissure excursion of 7.57 mm (5.19-9.94 mm), starting 3 to 5 months after transfer. End-to-trunk masseteric to facial nerve transfer is a safe and effective procedure. Patients had rapid reinnervation with good excursion and achieved a natural appearing smile. The rehabilitated smile appears better than that achieved with hypoglossal-facial nerve transfer. The procedure can be performed coincident with cross-facial nerve grafting, and in some cases may produce dynamic facial movement that obviates the need for free muscle transfer.


Are patients with cancer receiving adequate treatment for thrombosis? Results from FRONTLINE.
The current practice of clinicians worldwide in the treatment of venous thromboembolism was assessed via responses to the FRONTLINE survey. Significant regional differences in practice were noted. Use of low-molecular-weight heparin was reported as the most common initial treatment for venous thromboembolism, although, in North America, unfractionated heparin was widely used to treat surgical cancer patients after a thrombotic episode. Oral anticoagulants were favoured for long-term treatment of venous thromboembolism, particularly in Western Europe and North America. Case study reports from the survey revealed that a substantial proportion of patients with cancer had been perceived to be at low risk of thrombosis, had consequently not received thromboprophylaxis and developed VTE.


Statistical power and false positive rates for interdependent outcomes are strongly influenced by test type: Implications for behavioral neuroscience.
Statistical errors in preclinical science are a barrier to reproducibility and translation. For instance, linear models (e.g., ANOVA, linear regression) may be misapplied to data that violate assumptions. In behavioral neuroscience and psychopharmacology, linear models are frequently applied to interdependent or compositional data, which includes behavioral assessments where animals concurrently choose between chambers, objects, outcomes, or types of behavior (e.g., forced swim, novel object, place/social preference). The current study simulated behavioral data for a task with four interdependent choices (i.e., increased choice of a given outcome decreases others) using Monte Carlo methods. 16,000 datasets were simulated (1000 each of 4 effect sizes by 4 sample sizes) and statistical approaches evaluated for accuracy. Linear regression and linear mixed effects regression (LMER) with a single random intercept resulted in high false positives (>60%). Elevated false positives were attenuated in an LMER with random effects for all choice-levels and a binomial logistic mixed effects regression. However, these models were underpowered to reliably detect effects at common preclinical sample sizes. A Bayesian method using prior knowledge for control subjects increased power by up to 30%. These results were confirmed in a second simulation (8000 datasets). These data suggest that statistical analyses may often be misapplied in preclinical paradigms, with common linear methods increasing false positives, but potential alternatives lacking power. Ultimately, using informed priors may balance statistical requirements with ethical imperatives to minimize the number of animals used. These findings highlight the importance of considering statistical assumptions and limitations when designing research studies.


Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation.
A virus that reproduces in a host without killing cells can easily establish a successful infection. Previously, we showed that dengue-2, a virus that threatens 40% of the world, induces autophagy, enabling dengue to reproduce in cells without triggering cell death. Autophagy further protects the virus-laden cells from further insults. In this study, we evaluate how it does so; we show that dengue upregulates host pathways that increase autophagy, namely endoplasmic reticulum (ER) stress and ataxia telangiectasia mutated (ATM) signaling followed by production of reactive oxygen species (ROS). Inhibition of ER stress or ATM signaling abrogates the dengue-conferred protection against other cell stressors. Direct inhibition of ER stress response in infected cells decreases autophagosome turnover, reduces ROS production and limits reproduction of dengue virus. Blocking ATM activation, which is an early response to infection, decreases transcription of ER stress response proteins, but ATM has limited impact on production of ROS and virus titers. Production of ROS determines only late-onset autophagy in infected cells and is not necessary for dengue-induced protection from stressors. Collectively, these results demonstrate that among the multiple autophagy-inducing pathways during infection, ER stress signaling is more important to viral replication and protection of cells than either ATM or ROS-mediated signaling. To limit virus production and survival of dengue-infected cells, one must address the earliest phase of autophagy, induced by ER stress.


Primary membranous nephropathy in two siblings with one combined with anti-glomerular basement membrane disease: a case report.
The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear. We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA typing showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01. We describe a familial case of PLA2R-related MN supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in the Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01.


"Une plus brillante moisson de citoyens sains et robustes": Eugenic Discourses in French Canada (1902-10).
The Association des médecins de langue française d'Amérique du Nord (AMLFAN) was founded in Québec at the turn of the twentieth century. The physicians who convened at the Association between 1902 and 1910 shared a concern for the degeneration of the French-Canadian "race" under the effects of alcoholism, tuberculosis, and syphilis. For hygienists such as Arthur Rousseau and Charles-Narcisse Valin, this state of degeneration called for hygienic measures that would help regenerate and improve the French-Canadian race. While their suggestion that marriages be matched scientifically in order to prevent the transmission of hereditary and acquired defects from parent to offspring may be reminiscent of eugenics, French-Canadian physicians seemed to have no knowledge of Sir Francis Galton - eugenics' "founding father" - and his work on the topic. This article compares French-Canadian eugenic discourses with Galtonian eugenics in order to shed light on the particularities of the French-Canadian case.


Risk Factors and Outcomes of Preterm Premature Rupture of Membranes in a Cohort of 6968 Pregnant Women Prospectively Recruited.
We revisited risk factors and outcomes related to the preterm premature rupture of membranes (PPROM). A total of 7866 pregnant women were recruited during 5 years at their first prenatal visit to the perinatal clinic of the institution. We compared three groups (women without prematurity, women with spontaneous preterm labor with intact membranes (sPL with IM), women with PPROM) regarding 60 criteria about characteristics, lifestyle, medical, gynecological, obstetrical history of mothers, medication during pregnancy, events at delivery, and complications in neonates. Logistic regression analyses adjusting for potential confounding factors were used. Of the 6968 women selected, 189 (2.8%) presented a PPROM, and 225 (3.2%) an sPL with IM. The specific risk factors for PPROM were body mass index (BMI) <18.5 kg/m2 (adjusted odds ratio, aOR: 2.00 (1.09-3.67)), history of PPROM (aOR: 2.75 (1.19-6.36)), nulliparity (aOR: 2.52 (1.77-3.60)), gestational diabetes (aOR: 1.87 (1.16-2.99)), and low level of education (aOR: 2.39 (1.20-4.78)). The complications associated with PPROM were abruption placentae, cesarean, APGAR 5' <4, birth weight <2500 g, stillbirth, neonatal jaundice, and hospitalization of mother and neonates. All these complications were also associated with sPL with IM. Our study confirms some of the risk factors of PPROM and highlights a new one: gestational diabetes. Outcomes of PPROM are related to prematurity.


Effect of substance P on non-cholinergic fast and slow post-stimulus depolarization in the guinea-pig ileum.
Membrane potentials were recorded with intracellular electrodes from the circular muscle cells of the guinea-pig ileum, in vitro, in the presence of atropine (1.4 X 10(-6) M) at 30 degrees C. Under such conditions, the preparations did not show any spontaneous activity. Exposure of the tissue to substance P (10(-7)-10(-6)M) for a short period of time (less than 5 min) caused depolarization and action potentials. At this time the membrane resistance appeared to be decreased and after transmural nerve stimulation the fast post-stimulus depolarization, which followed the inhibitory junction potential (IJP), triggered action potentials. After prolonged exposure of the tissue to substance P (greater than 10 min), the contractile activity of the preparation subsided, the membrane potential was decreased by 6.4 +/- 1.1 mV and the membrane resistance was increased; following transmural nerve stimulation, the amplitude of the IJP was increased, the fast post-stimulus depolarization was abolished and the later slow post-stimulus depolarization was enhanced and in some preparations reached threshold for action potential generation. In the latter preparations in the absence of transmural nerve stimulation, the membrane potential occasionally showed regular oscillations of approximately 10 mV in amplitude every 5-8 s. When the tissue was hyperpolarized by anodal current, after prolonged exposure to substance P, the fast post-stimulus depolarization did not return indicating that its abolition was not a secondary effect due to the depolarization of the tissue by substance P.


Automated Time-Lapse Imaging and Manipulation of Cell Divisions in Arabidopsis Roots by Vertical-Stage Confocal Microscopy.
The analysis of dynamic cellular processes such as plant cytokinesis stands and falls with live-cell time-lapse confocal imaging. Conventional approaches to time-lapse imaging of cell division in Arabidopsis root tips are tedious and have low throughput. Here, we describe a protocol for long-term time-lapse simultaneous imaging of multiple root tips on a vertical-stage confocal microscope with automated root tracking. We also provide modifications of the basic protocol to implement this imaging method in the analysis of genetic, pharmacological or laser ablation wounding-mediated experimental manipulations. Our method dramatically improves the efficiency of cell division time-lapse imaging by increasing the throughput, while reducing the person-hour requirements of such experiments.


Screening for familial intracranial aneurysms: decision and cost-effectiveness analysis.
To evaluate the potential benefits, harms, and cost-effectiveness of screening for asymptomatic, unruptured intracranial aneurysms in family members of patients with aneurysmal subarachnoid hemorrhage (SAH). Using a Markov model, we performed a decision and cost-effectiveness analysis comparing magnetic resonance (MR) angiography screening for asymptomatic, unruptured intracranial aneurysms to no screening in family members of patients with aneurysmal SAH. Treatment of unruptured intracranial aneurysms was determined according to patient age and aneurysm size and location. Cohort age was taken as 40 years. In family members with two or more affected first-degree relatives, screening compared with no screening had an incremental cost-effectiveness ratio (ICER) of $37,400 per quality-adjusted life-year (QALY). With screening, life expectancy increased from 39.44 years to 39.55 years. The ICER of screening was >$50,000 per QALY if age at screening was > or =50 years. In family members with one affected first-degree relative, screening compared with no screening had an ICER of $56,500 per QALY. The results suggest that MR angiography screening for asymptomatic, unruptured intracranial aneurysms in family members with two or more affected first-degree relatives is cost-effective. The benefit and cost-effectiveness are dependent on age at screening.


DNA damage and repair in cells of lead exposed people.
One of the main sources of occupational exposure to lead in Colombia is in workers of battery industries and lead smelters. Genotoxic studies in human populations exposed to this metal have had conflicting results; this type of study has not been reported in Colombia. Genotoxic effects of lead were studied in blood cell samples from workers of electric battery factories exposed to lead compounds. Single strand breaks and interference with DNA repair processes after an in vitro exposure of x-rays (300 cGy) were analyzed using the Comet Assay. The battery workers (n = 43) and 13 people not occupationally exposed to lead compounds who were selected as a control group, were classified into four categories according to their blood lead level. A significant difference was observed in DNA damage before the x-rays exposure (basal) between the lowest and highest categories of lead (mean DNA migration 55.6 micro and 85.9 micro, respectively). Additionally, a significant difference in DNA migration was also found immediately after irradiation between the lowest and highest lead categories (mean DNA migration: 199.8 micro and 317.8 micro respectively). The DNA migrations at different times after irradiation did not show a significant difference among the different lead levels. We concluded that although the single strand breaks following irradiation were not affected by blood lead concentration, the metal seems to sensitize the cells to damage induced by other genotoxicants.


Suppressed Layered-to-Spinel Phase Transition in δ-MnO2 via van der Waals Interaction for Highly Stable Zn/MnO2 Batteries.
Although birnessite-type manganese dioxide (δ-MnO2 ) with a large interlayer spacing (≈7 Å) is a promising cathode candidate for aqueous Zn/MnO2 batteries, the poor structural stability associated with Zn2+ intercalation/deintercalation limits its further practical application. Herein, δ-MnO2 ultrathin nanosheets are coupled with reduced graphene oxide (rGO) via van der Waals (vdW) self-assembly in a vacuum freeze-drying process. It is interesting to find that the presence of vdW interaction between δ-MnO2 and rGO can effectively suppress the layered-to-spinel phase transition in δ-MnO2 during cycling. As a result, the coupled δ-MnO2 /rGO hybrid cathode with a sandwich-like heterostructure exhibits remarkable cycle performance with 80.1% capacity retained after 3000 cycles at 2.0 A g-1 . The first principle calculations demonstrate that the strong interfacial interaction between δ-MnO2 and rGO results in improved electron transfer and strengthened layered structure for δ-MnO2 . This work establishes a viable strategy to mitigate the adverse layered-to-spinel phase transition in layered manganese oxide in aqueous energy storage systems.


Mid-trimester serum relaxin concentrations and post-partum pelvic floor dysfunction.
To compare mid-trimester serum relaxin concentration (SRC) in primiparous women with or without pelvic floor dysfunction (PFD--stress urinary incontinence (SUI), genital prolapse). Nested observational cohort study. Urogynecology clinic of affiliated University hospital. Primiparous women one to four years post-partum, who had, at time of index pregnancy, participated in a prospective observational study looking at mid-trimester serum relaxin and preterm delivery. Relaxin had been obtained during the index pregnancy at 24 and 28 weeks. Primiparous women who had not given birth to a subsequent child were contacted and asked to return for a single visit assessing pelvic floor function. Pelvic Organ Prolapse Quantification system (POPQ) and Urogenital Distress Inventory (UDI-6). Fifty women participated, of whom 40 delivered vaginally. Seventeen (34%) women had prolapse and 23 (46%) had stress incontinence. Relaxin was slightly higher (not significantly) in women with PFD than in those without. Relaxin concentration declined significantly more rapidly from 24 to 28 weeks in incontinent women, after adjusting for baseline and obstetrical factors. In contrast to previous reports, mid-gestation relaxin tended to be higher and fall significantly faster in women with PFD. Acknowledging relaxin's effects on collagen turnover, our findings explore the association between childbirth and PFD.


Activation of a Si=Si Bond by eta1-coordination to a transition metal.
Reaction of the disilenide 1 with Cp2ZrCl2 yields 2, the first transition metal complex with an eta1-sigma-bonded disilene moiety. The compound 2 exhibits a strongly red-shifted UV-vis absorption, resulting in an intensely green color. The Si=Si bond in 2 is considerably activated as shown by the rearrangement to a silyl-substituted zirconocene 3. X-ray diffraction studies on 2 reveal that the Si=Si bond is significantly longer than that in the precursor 1. Conversely, the Zr-Si distance is considerably smaller than the corresponding distance in 3, suggesting a certain degree of electron donation toward the 16e- zirconium center.


CT imaging determinants of persistent hypoxemia in acute intermediate-risk pulmonary embolism.
The factors associated with persistent hypoxemia after pulmonary embolus (PE) are not well understood. Predicting the need for oxygen post discharge at the time of diagnosis using available CT imaging will enable better discharge planning. To examine the relationship between CT derived imaging markers (automated computation of arterial small vessel fraction, pulmonary artery diameter to aortic diameter ratio (PA:A), right to left ventricular diameter ratio (RV:LV) and new oxygen requirement at the time of discharge in patients diagnosed with acute intermediate-risk PE. CT measurements were obtained in a retrospective cohort of patients with acute-intermediate risk PE admitted to Brigham and Women's Hospital between 2009 and 2017. Twenty one patients without a history of lung disease requiring home oxygen and 682 patients without discharge oxygen requirements were identified. There was an increased median PA:A ratio (0.98 vs. 0.92, p = 0.02) and arterial small vessel fraction (0.32 vs. 0.39, p = 0.001) in the oxygen-requiring group], but no difference in the median RV:LV ratio (1.20 vs. 1.20, p = 0.74). Being in the upper quantile for the arterial small vessel fraction was associated with decreased odds of oxygen requirement (OR 0.30 [0.10-0.78], p = 0.02). Loss of arterial small vessel volume as measured by arterial small vessel fraction and an increase in the PA:A ratio at the time of diagnosis were associated with the presence of persistent hypoxemia on discharge in acute intermediate-risk PE.


Comparison between OPCABG and CABG Surgical Revascularization Using Transit Time Flow Measurement (TTFM).
To compare the intraoperative quality of coronary anastomoses performed with or without cardiopulmonary bypass using transit time flow measurement (TTFM) parameters. We collected data from 588 consecutive patients who underwent surgical revascularization. We retrospectively reviewed data from two groups: 411 with cardiopulmonary bypass (CABG group) and 177 off-pump (OPCABG group). Transit time flow measurement parameters: mean graft flow (MGF), pulsatile index (PI), and diastolic filing (DF) were measured for each graft and patient. Patients in the OPCABG group had higher EuroSCORE compared with the CABG group (3.53 ± 2.32 versus 2.84 ± 2.15, P = .002). Overall comparison of TTFM parameters showed no statistical difference between the two surgical techniques except for PI in circumflex artery territory, which was higher in the OPCABG group for all types of grafts 3.0 ± 4.9 versus 2.4 ± 2.0 in, P = .026. The comparison between OPCABG and CABG in this study showed comparable results with both surgical techniques. PI was higher in the OPCABG group in harder-to-reach vessel territories. Measurement of transit time may improve the quality, safety, and efficacy of coronary artery bypass grafting and should be considered as a routine procedure.


Drug enrichment and discovery from schizophrenia genome-wide association results: an analysis and visualisation approach.
Using successful genome-wide association results in psychiatry for drug repurposing is an ongoing challenge. Databases collecting drug targets and gene annotations are growing and can be harnessed to shed a new light on psychiatric disorders. We used genome-wide association study (GWAS) summary statistics from the Psychiatric Genetics Consortium (PGC) Schizophrenia working group to build a drug repositioning model for schizophrenia. As sample size increases, schizophrenia GWAS results show increasing enrichment for known antipsychotic drugs, selective calcium channel blockers, and antiepileptics. Each of these therapeutical classes targets different gene subnetworks. We identify 123 Bonferroni-significant druggable genes outside the MHC, and 128 FDR-significant biological pathways related to neurons, synapses, genic intolerance, membrane transport, epilepsy, and mental disorders. These results suggest that, in schizophrenia, current well-powered GWAS results can reliably detect known schizophrenia drugs and thus may hold considerable potential for the identification of new therapeutic leads. Moreover, antiepileptics and calcium channel blockers may provide repurposing opportunities. This study also reveals significant pathways in schizophrenia that were not identified previously, and provides a workflow for pathway analysis and drug repurposing using GWAS results.


Comparison of the effectiveness of trauma-focused cognitive behavioral therapy and paroxetine treatment in PTSD patients: design of a randomized controlled trial.
The two most common interventions for Posttraumatic Stress Disorder (PTSD) are pharmacological treatment with SSRIs such as paroxetine and psychological treatment such as Trauma-Focused Cognitive Behavioral Therapy (TF-CBT). International guidelines recommend trauma-focused psychological interventions for all PTSD patients as first-line treatment (NICE). However, no clear-cut evidence is available to support this recommendation. In order to compare pharmacological treatment (paroxetine) and psychological treatment (TF-CBT) in (cost-) effectiveness on the short and the long term, we will randomize 90 patients with chronic PTSD to either paroxetine (24 weeks) or TF-CBT (10-12 weeks). We will assess symptom severity and costs before and after the intervention with the Clinician Administered PTSD Scale (CAPS), the Clinical Global Impression Scale (CGI) and the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TiC-P). This study is unique for its direct comparison of the most commonly used psychological intervention (TF-CBT) and pharmacological intervention (paroxetine) on (cost-) effectiveness on the short and the long term. The anticipated results will provide relevant evidence concerning long-term effects and relapse rates and will be beneficial in reducing societal costs. It may also provide information on who may benefit most from which type of intervention. Some methodological issues will be discussed. Dutch Trial registration: NTR2235.


A Dosimetric Correlation Between Radiation Dose to Bone and Reduction of Hemoglobin Levels After Radiation Therapy for Prostate Cancer.
The aim of this work was to investigate the correlation between dose to pelvic bone marrow and anemia when treating prostate cancer (PC) with definitive radiation. Patients were selected from a prospective institutional database of patients with PC treated between 2008 and 2021. Pelvic bone (L3/L4 interface through ischial tuberosities) was contoured, and the dose to this structure was calculated. Doses were converted to 2-Gy equivalent doses using an α/β of 10. Exploratory analysis suggested dichotomizing into low-volume exposures of ≤1000 cc (LVE) and high-volume exposures of >1000 cc (HVE). Nonparametric kernel regressions were performed evaluating the effects of time, dose, and androgen deprivation therapy use on hemoglobin (Hgb) values. Reoptimization of plans was performed to evaluate the feasibility of adjusting significant dose levels. A total of 203 patients were included in the final analysis. Median baseline Hgb was 14.9 g/dL (interquartile range, 14.1-15.6). Patients with bone marrow HVE ≥15 Gy were found to have significantly lower predicted Hgb levels compared with those with LVE at day 90: 12.8 g/dL (95% CI, 12.4-13.3) versus 14.5 g/dL (95% CI, 14.0-14.9), respectively (P < .05). When normalizing starting Hgb levels, HVE patients still had significantly lower predicted Hgb levels than LVE at day 90: 86.1% (95% CI, 83.2%-89.7%) versus 96.2% (95% CI, 92.4%-100%), respectively. Reoptimizing 20 plans with high volume of bone marrow receiving 15 Gy resulted in a mean reduction from 1422 cc to 997 cc without compromise of other organs at risk or target coverage. Patients with >1000 cc of bone marrow receiving ≥15 Gy had significantly lower predicted Hgb levels than those with ≤1000 cc. Reoptimization of plans demonstrated that this dose constraint is achievable without impairing plan quality. This dose constraint can be considered to limit acute marrow toxicity in patients with PC.


Microbial diversity composition of apple tree roots and resistance of apple Valsa canker with different grafting rootstock types.
The composition and diversity of root microbial community are affected by plant genotypes and soil environment, which in turn affect plant growth and development. Grafting rootstock types of the apple tree can affect phenotypes in cultivation practice, but it is not clear whether grafting rootstock types can affect the composition and diversity of root microbial community and the resistance of apple tree to apple Valsa canker. To explore root microbial differences and the correlation, 16S rRNA and ITS genes were sequenced using Novaseq technology. The results showed that the influence of grafting rootstock types on the composition of the root fungal community was greater than that of bacteria. And the bacterial community richness was higher in the healthy (OTUs: 1693) and dwarfing rootstock (OTUs: 1526) than in the disease (OTUs: 1181) and standard rootstock (OTUs: 1412), while the fungal community richness was the opposite. Moreover, the bacterial abundance of root zone, rhizosphere, and root endophytic microorganisms with the same grafting rootstock type exhibited a decreasing trend. Results of Nested PCR assay on soil and root tissue of Valsa mali showed that the content of V. mali in dwarfing rootstocks are lower than standard rootstocks. These results suggest that apple trees grafting with dwarfing rootstocks are more resistant to V. mali than standard rootstocks. Under different grafting types, the effect on the composition of fungal community in apple tree root was greater than that of bacteria. The bacterial community in dwarfing rootstocks is more abundant and diverse, including more beneficial microorganisms. Therefore, dwarfing rootstock is more conducive to the resistance to apple Valsa canker from biological control.


Artificial Neural Networks for Predicting the Diameter of Electrospun Nanofibers Synthesized from Solutions/Emulsions of Biopolymers and Oils.
In the present work, different configurations of nt iartificial neural networks (ANNs) were analyzed in order to predict the experimental diameter of nanofibers produced by means of the electrospinning process and employing polyvinyl alcohol (PVA), PVA/chitosan (CS) and PVA/aloe vera (Av) solutions. In addition, gelatin type A (GT)/alpha-tocopherol (α-TOC), PVA/olive oil (OO), PVA/orange essential oil (OEO), and PVA/anise oil (AO) emulsions were used. The experimental diameters of the nanofibers electrospun from the different tested systems were obtained using scanning electron microscopy (SEM) and ranged from 93.52 nm to 352.1 nm. Of the three studied ANNs, the one that displayed the best prediction results was the one with three hidden layers with the flow rate, voltage, viscosity, and conductivity variables. The calculation error between the experimental and calculated diameters was 3.79%. Additionally, the correlation coefficient (R2) was identified as a function of the ANN configuration, obtaining values of 0.96, 0.98, and 0.98 for one, two, and three hidden layer(s), respectively. It was found that an ANN configuration having more than three hidden layers did not improve the prediction of the experimental diameter of synthesized nanofibers.


Immunostaining of human brain capillaries by antibodies to very late antigens.
Normal and neurologically diseased brain tissue was stained with antibodies directed against very late antigens (VLAs) 1, 2, 3, 5, 6, their common beta 1-subunit, and three extracellular proteins: collagen type IV, laminin and fibronectin. Strong staining of capillaries was obtained in both normal and pathological tissue with antibodies to collagen type IV and its putative receptor VLA-1; laminin and its putative receptor VLA-6; and the common VLA beta 1-subunit. Only residual plasma in vessels was stained with the antibody to fibronectin. Negative staining was obtained with antibodies to the fibronectin receptor VLA-5 and VLA-3. Trace staining was obtained with the antibody to VLA-2.


2'-benzyloxychalcone derivatives stimulate glucose uptake in 3T3-L1 adipocytes.
By a cell-based glucose uptake screening assay, a chalcone derivative, 3-nitro-2'-benzyloxychalcone (compound 1) was identified. Compound 1 stimulated glucose uptake and potentiated insulin-stimulated glucose uptake in a concentration-dependent manner in 3T3-L1 adipocytes. When cells were treated with various concentrations of insulin in the presence of compound 1, marked enhancement of insulin-stimulated glucose uptake was observed at each concentration, suggesting that the compound might function as an insulin sensitizer. Preliminary study on the structure-activity relationships revealed that two aromatic benzene rings tolerated several substituents, but substitution by acidic or highly polar groups abolished the activity. Among several chalcone derivatives, 4-chloro-2'-benzyloxychalcone (compound 8) showed the highest level of activity. Compound 8-stimulated glucose uptake was almost completely inhibited by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). These results suggest that the action of chalcone derivatives is mediated via a pathway involving PI3K.


Influence of temperature on the mixed micelles of Pluronic F127 and P103 with dimethylene-bis-(dodecyldimethylammonium bromide).
The steady state fluorescence measurements have been performed on Pluronic F127 and P103 with dimethylene-bis-(dodecyldimethylammonium bromide) (12-2-12) mixtures at 21-40 degrees C. From the pyrene fluorescence, the critical micelle concentration (cmc), micelle mole fraction (x), micropolarity, and aggregation number have been computed for both mixtures over the whole mixing range at different temperatures. These micelle parameters indicate that the mixed micelle formation between the unlike components of both mixtures takes place due to the synergistic interactions and which increase with an increase in temperature.


Recent patents in allergy and immunology: A quantitative real-time polymerase chain reaction method for diagnosing asthma and asthma exacerbation.
Asthma is diagnosed based on a history of the characteristic symptoms and evidence of expiratory airflow limitation. However, asthma diagnosis using the existing tests is associated with a risk of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 spread. In this study, we developed a quantitative real-time polymerase chain reaction (qRT-PCR)-based asthma diagnosis tool. We detected nectin-4 in the plasma of patients with asthma using qRT-PCR, explored the relationship of clinical variables. quantitative real-time polymerase chain reaction revealed that plasma nectin-4 mRNA levels were higher in asthmatics than controls. These results correlated with lung function. Those results suggest that qRT-PCR for nectin-4 may aid asthma diagnosis and monitoring.


Disagreement between tissue Doppler imaging and conventional pulsed wave Doppler in the measurement of myocardial performance index.
Myocardial performance index (MPI) is usually measured with pulsed wave Doppler (PWD). Our aim was to assess the degree of agreement between PWD and a method based on tissue Doppler imaging (TDI). Seventy-five patients with prior myocardial infarction and 20 healthy subjects underwent measurement of time intervals and MPI with PWD and pulsed TDI at septal and lateral sides of mitral annulus. MPI and TDI-MPI at septal side showed the best intraclass correlation coefficient (ICC=0.54; p<0.0005). Ninety-five percent interval of agreement ranged from -0.27 to 0.22. These differences were attributed to discrepancies in isovolumic contraction and relaxation times. In the healthy group the results were similar (ICC=0.44), although the 95% interval of agreement was lower (from -0.13 to 0.12). The agreement between PWD and TDI in the measurement of MPI is only moderate. This should be taken into account in the interpretation of studies in which TDI is used for this measurement.


Decision support to general practice in choice of chest imaging for patients with pulmonary symptoms.
The choice of chest imaging for patients with respiratory problems is based on risk profile and symptoms. In 2018-2020, GPs in the catchment area of Silkeborg Regional Hospital, Denmark, were offered direct referral for either X-ray or low-dose computed tomography (LDCT) of the chest for patients with respiratory symptoms who did not meet the criteria for a contrast-enhanced CT (CECT) of the chest and upper abdomen as part of the lung cancer referral pathway. The aim of this study was 1) to estimate the percentage of patients referred for LDCT or chest X-ray who met CECT criteria based on the clinical information in the referral letters, and 2) to assess the GPs' response to standard questions regarding the active feedback provided. The study was conducted from April to October 2019. Radiographers initially assessed all referrals for X-ray or LDCT, and contacted the GPs if they assessed that symptoms and clinical characteristics justified CECT. In the study period, 1,112 referrals for chest imaging from GPs were received; in 97 cases (9%), the referral information warranted CECT as part of a lung cancer referral package. In 71% (69/97) of these cases, the GP accepted the conversion to CECT; 55 of 73 LDCTs and 14 of 24 X-rays. In 15 cases, the GP adhered to the requested imaging owing to clinical assessment or their agreement with the patient, and in the remaining 13 cases no specific reason was given. The feedback provided was well received by GPs and the approach adopted may be a step towards structured decision support to facilitate the choice of chest imaging. None. Not relevant.


Immunomodulatory and immunosuppressive drug protocols in the treatment of canine primary immune thrombocytopenia, a scoping review.
Primary immune thrombocytopenia (ITP) is a cause of severe thrombocytopenia in dogs. Immunosuppressive corticosteroid drugs are frequently used in the management of ITP, but treatment failure may occur. Immunomodulatory and non-corticosteroid immunosuppressive drugs might improve outcomes from therapy either alone or in combination with corticosteroids. The objectives of this scoping review were (1) to evaluate the current evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP, and (2) to answer the clinical question, whether or not therapy with immunomodulatory or non-corticosteroid immunosuppressive drugs alone or in combination with corticosteroids could improve outcome, compared to therapy with corticosteroids alone. A literature search was performed in the electronic databases of Agricola, CAB Abstracts, Embase, Medline and Web of Science for publications in November 2019 and again February 1, 2021. Selection criteria were relatively strict and included peer-reviewed research papers reporting outcome measures from immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP with a pre-therapeutic mean or median platelet count < 50,000/µL as a strict criterion for inclusion. Studies were evaluated if they had an appropriate diagnostic work up to exclude underlying conditions. Outcome measures and adverse events were compared between drug protocols both within studies and between studies. The search identified 456 studies, with six studies being eligible for inclusion. The studies were mostly case series while two were randomized controlled trials. Level of evidence varied with an overall uncertain subject enrollment, small groups, inadequate description and variable use of drug protocols or outcome measures. For outcomes such as platelet recovery time and duration of hospitalization, an improvement was observed using adjunctive therapy (human intravenous immunoglobulin) compared to therapy with corticosteroids alone. For outcomes of complete platelet recovery time, survival (6-month), mortality and relapse, no improvement was observed using adjunctive drugs compared to corticosteroids alone. Specifically, therapy with mycophenolate mofetil alone and adjunctive azathioprine were associated with more severe adverse events compared to other drug protocols. Evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP was of variable quality. Future larger case-controlled trials are required for determination of optimal treatment protocols in canine ITP.


In situ growth of 0D silica nanospheres on 2D molybdenum disulfide nanosheets: Towards reducing fire hazards of epoxy resin.
This report described a facile process for the preparation of 2D/0D MoS2-SiO2 hybrids using a simple in situ growth method, with the purpose of promoting the dispersion of MoS2 in polymer matrices and improving the properties of polymer materials. FTIR, XPS, TGA and TEM measurements were performed to characterize the structure and morphology of the synthesized hybrids which were then introduced into epoxy to reduce flammability. The hybrids dispersed well in the epoxy matrix. No obvious agglomerations were observed. In comparison with those of neat epoxy, the incorporation of a low loading of MoS2-SiO2 hybrids resulted in significant decrements in heat release rate, total heat release and volume of toxic effluents released during combustion, which indicated that the fire hazards of epoxy composites were strongly reduced. The good dispersion, labyrinth barrier effect and the catalytic effect of MoS2-SiO2 hybrids on char formation may contribute to the observed decrease in the flammability of epoxy resin.


The expression of the thyroid-stimulating hormone (TSH) receptor and the cAMP-dependent protein kinase RII beta regulatory subunit confers TSH-cAMP-dependent growth to mouse fibroblasts.
TSH activates its specific receptor in thyroid cells and induces cAMP, a robust stimulator of thyroid cell proliferation. Conversely, cAMP is a potent inhibitor of growth in mouse fibroblasts. To dissect the signals mediating cAMP-dependent growth, we have expressed in mouse fibroblasts the human thyrotropin receptor (TSHR) or a constitutively active mutant, under the control of the tetracyclin promoter. Both TSHR and cAMP levels were modulated by tetracyclin. In the presence of serum, activation of TSHR by TSH induced growth arrest. In the absence of serum, cells expressing TSHR stimulated with TSH, replicated their DNA, but underwent apoptosis. Co-expression of cAMP-dependent protein kinase (PKA) regulatory subunit type II (RIIbeta) inhibited apoptosis and stimulated the growth of cells only in the presence of TSH. Expression of RIIbeta-PKA, in the absence of TSHR, induced apoptosis, which was reversed by cAMP. Growth, stimulated by TSHR-RIIbeta-PKA in mouse fibroblasts, was also dependent on Rap1 activity, indicating cAMP-dependent growth in thyroid cells. As for the molecular mechanism underlying these effects, we found that in normal fibroblasts, TSH induced AKT and ERK1/2 only in cells expressing TSHR and RII. Similarly, activation of TSHR increased cAMP levels greatly, but was unable to stimulate CREB phosphorylation and transcription of cAMP-induced genes in the absence of RII. These data provide a simple explanation for the anti-proliferative and proliferative effects of cAMP in different cell types and indicate that RII-PKAII complements TSHR action by stably propagating robust cAMP signals in cell compartments.


QSAR of the testosterone binding globulin affinity by means of correlation weighting of local invariants of the graph of atomic orbitals.
Numerical values of the testosterone binding globulin affinity have been modeled as a mathematical function of molecular structure in two versions of molecular structure elucidation: first, by hydrogen-filled molecular graphs (HFG); second, by the so-called graphs of atomic orbitals (GAO). Increased orders of Morgan extended connectivity in the HFG and GAO have been examined as local invariants. Using optimisation of the correlation weights of the above-mentioned invariants, quantitative structure-activity relationships (QSAR) have been obtained. Best statistical characteristics of these QSARs are derived in the case of the Morgan extended connectivity of first order in the GAO. They are as follows: n = 11, r2 = 0.6540, s = 0.824, F = 17 (training set); n = 9, r2 = 0.8791, s = 0.388, F = 51 (test set).


Contribution of wood smoke to in vivo formation of N-nitrosothiazolidine-4-carboxylic acid: initial studies.
The effect of administering liquid smoke or smoked food products to rats on in vivo formation of N-nitrosamino acids was investigated. Rats treated by gavage with either cysteine, formaldehyde or nitrite excreted urine containing no detectable levels of N-nitrosothiazolidine-4-carboxylic acid (NTCA). All three precursor compounds were required for NTCA formation. Two liquid smokes, when administered to rats in combination with cysteine and nitrite also produced measurable quantities of NTCA. Ascorbate inhibited in vivo formation of NTCA by approximately 90% when given to rats simultaneously with cysteine, formaldehyde, and nitrite. alpha-Tocopherol was much less effective than ascorbate in blocking NTCA formation. When smoked bacon, smoked Swiss cheese, and chicken barbecued with a sauce containing smoke flavouring were fed to rats along with nitrate, NTCA was again detected in the urine.


Same total normal forms sperm counts of males from Lhasa and Shanghai, China.
Male infertility may be caused by genetic and/or environmental factors that impair spermatogenesis and sperm maturation. High-altitude (HA) hypoxic environments represent one of the most serious challenges faced by humans that reside in these areas. To assess the influence of the plateau environment on semen parameters, 2,798 males, including 1,111 native Tibetans and 1,687 Han Chinese individuals living in the plains (HCILP) who underwent pre-pregnancy checkups, were enrolled in this study. The semen samples of males were evaluated to determine conventional sperm parameters, sperm morphology, and sperm movement. Reproductive endocrine hormones (REHs) were detected in 474 males, including 221 Tibetans and 253 HCILP. Due to recurrent abortions in partners, the DNA fragmentation index (DFI) of 133 native Tibetans and 393 HCILP individuals was further compared. Luteinizing hormone (LH) (4.94 ± 2.12 vs. 3.29 ± 1.43 U/L), prolactin (11.34 ± 3.87 vs. 8.97 ± 3.48 nmol/L), E2/T (0.22 ± 0.11 vs 0.11 ± 0.05), median total sperm motility (61.20% vs. 51.56%), and DFI (23.11% vs. 7.22%) were higher in males from plateau areas while median progressive motility (PR) (35.60% vs. 41.12%), total number of PR sperms (51.61 vs. 59.63 mil/ejaculate), percentage of normal form sperms (3.70% vs. 6.00%), curvilinear velocity (36.10 vs. 48.97 μm/s), straight-line (rectilinear) velocity (14.70 vs. 31.52 μm/s), estradiol (103.82 ± 45.92 vs. 146.01 ± 39.73 pmol/L), progesterone (0.29 ± 0.27 vs. 2.22 ± 0.84 nmol/L), testosterone (4.90 ± 1.96 vs. 14.36 ± 5.24 nmol/L), and testosterone secretion index (ratio of testosterone to LH) (33.45 ± 22.86 vs 145.78 ± 73.41) were lower than those in males from the plains. There was no difference in median total sperm number (157.76 vs. 151.65 mil/mL), sperm concentration (52.40 vs. 51.79 mil/mL), volume (3.10 vs. 3.10 mL), total normal form sperms (5.91 vs. 6.58 mil/ejaculate, p50), and follicle-stimulating hormone (FSH) levels (4.13 ± 2.55 U/L vs 3.82 ± 2.35 U/L) between the two groups of males. The REH and sperm parameters of males from HA hypoxic environments were adaptively altered. Although the total number of PR sperm decreased and DFI increased, the Tibetan population that lives at HAs has been found to grown continuously and rapidly. These results supplement prior findings regarding the impact of HA on male reproductive function.


Mental health interventions for immigrant-refugee children and youth living in Canada: a scoping review and way forward.
Traumatic life events experienced by immigrant-refugee children and youth may deteriorate their mental health and well-being. It is a public health priority to develop appropriate mental health interventions for this population. To understand the psychosocial needs of immigrant-refugee children and youth resettled in Canada in the context of their school and community and to identify the characteristics of school-/community-based mental health programs for this group. Arksey and O'Malley's methodology for scoping reviews was used to select the studies based on criteria, extract data in a table, and synthesize main findings. Fifteen peer-reviewed articles and five grey literature were identified. Key findings show that collaboration between schools, communities, and families play a crucial role in developing and implementing comprehensive mental health interventions for immigrant-refugee children/youth. Involving cultural brokers/interpreters and racially diverse school teachers/staff, is important to establish a trustful relationship between school authorities and marginalized population. Further research is needed to examine the impact of collaborative mental healthcare among multiracial and newcomer families in Canada. Furthermore, there is a need to study the impact of adopting creative expression programs at schools/communities to improve emotional/behavioural problems and enhance school performance of these groups.


Biochemical findings in sudden unexpected death in epilepsy: Hospital based case-control study.
A review study on the biochemistry of epilepsy showed that in epileptic patients, serum glucose and cholesterol concentrations are low, sodium is unaffected, potassium increases, glucose is high and mild hypocalcemia. We have conducted a biochemical study on sudden unexpected death in epilepsy (SUDEP) cases in an attempt to establish the characteristic biochemical values to diagnose these deaths. This was a hospital based case-control study done at All India Institute of Medical Sciences, New Delhi for one year. Twenty SUDEP cases and 20 age- and sex-matched controls were included in the study. Femoral blood, cerebrospinal fluid, vitreous humor, and pericardial fluid were biochemically analyzed for sodium, potassium, calcium, glucose, N-acetyl- cysteine activated creatine kinase (CK-NAC) and isoenzyme CK-MB. Serum sodium, CK-MB and CK-NAC level was found significantly increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. Likewise, in CSF, sodium and CK-NAC was found increased and potassium level was found decreased in SUDEP cases. In vitreous humor, sodium and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. In pericardial fluid, sodium, CK-NAC and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. It concludes that high sodium level and low potassium level could be associated with SUDEP. However, this is a small size study, a larger study is needed to verify the findings. Furthermore, it is difficult to conclude whether these findings are exclusive to SUDEP.


Advances in BPA-induced Oxidative Stress and Related Effects and Mechanisms in Liver, 1991-2017.
Bisphenol A (BPA) is a widely spreading environmental endocrine disruptor . Its characteristics, including small doses and frequent contact, make it easy to enter human body through drinking water, food, air and other pathways, leading to tumors, infertility, and liver damage. The present review summarizes the underlying mechanism of oxidative stress and its related effects induced by BPA in the liver. The progress of the mechanism for oxidative stress induced by BPA is summarized, including mitochondrial dysfunction, lipid peroxidation and inflammation reaction, liver dyslipidemia, apoptosis, and cell death mechanism. In the future, it is necessary to elucidate the molecular mechanisms and timing of oxidative stress to clarify the effects on different exposures to different genders and growth stages. Besides, studying the toxic effects on BPA surrogates, BPA metabolites and BPA combined with other pollutants in the environment is beneficial to clarify the environmental and human health effects of BPA and provide technical reference for the development of practical control measures.


The twisted structure of the fetal calcaneal tendon is already visible in the second trimester.
The progress in morphological science results from the greater possibilities of intra-pubic diagnosis and treatment of congenital disabilities, including the motor system. However, the structure and macroscopic development of the calcaneal tendon have not been investigated in detail. Studies on the adult calcaneal tendon showed that the calcaneal tendon is composed of twisted subtendons. This study aimed to investigate the internal structure of the fetal calcaneal tendon in the second trimester. Thirty-six fetuses fixed in 10% formaldehyde were dissected using the layer-by-layer method and a surgical microscope. The twisted structure of the calcaneal tendon was revealed in all specimens. The posterior layer of the calcaneal tendon is formed by the subtendon from the medial head of the gastrocnemius muscle. In contrast, the anterior layer is formed by the subtendon from the lateral head of the gastrocnemius muscle. The subtendon from the soleus muscle constitutes the anteromedial outline of the calcaneal tendon. The lateral outline of the calcaneal tendon is formed by the subtendon originating from the medial head of the gastrocnemius muscle. In contrast, the medial outline is formed by the subtendon from the soleus muscle. In most of the examined limbs, the plantaris tendon attached to the tuber calcanei was not directly connected to the calcaneal tendon. The twisted structure of the subtendons of the fetal calcaneal tendon is already visible in the second trimester and is similar to that seen in adults.


A genome-wide genetic screen uncovers determinants of human pigmentation.
Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.


Persistently elevated IgA antibodies to Mycoplasma pneumoniae in patients with internal carotid artery stenosis.
It has been suggested that Mycoplasma pneumoniae may play a role in the development of atherosclerosis, but to date this association is still a matter of debate due to conflicting findings. We have investigated the levels of specific IgA antibodies to M. pneumoniae in 91 patients with internal carotid artery (ICA) stenosis using a commercial kit (SeroMP™ IgA; Savyon Diagnostics, Israel; cut-off value: 20 binding units; BU). All patients underwent surgery for ICA stenosis. From each patient, the first serum sample (S1) was taken before surgery, and the second after an interval of 6 month (S2). The S1 seroprevalence was 18.7% (17/91). Thirteen of the 17 patients with positive S1 levels also remained positive after six month, whereby no decrease of IgA level was seen (median S1 level: 34 BU, range: 22-65 BU; median S2 level: 37 BU, range: 22-58 BU). Specifically, six of the patients showed an increased level after 6 months, and six a decrease, with the level remaining constant in one patient. In contrast, only 3 of the 74 S1 negative patients became positive for anti-M. pneumoniae IgA between the taking of the first and the second serum specimen (p<0.01). None of the assessed demographic factors or risk factors for atherosclerosis was associated with IgA seropositivity, neither were the degree CAVK or the degree of stenosis. These findings cannot be explained throughout by the general seroprevalence, or by past respiratory tract infections with the pathogen, and therefore may suggest a role for M. pneumoniae in the development of atherosclerosis, since a chronic infection must be assumed.


2-Mercapto-1-(beta-4-pyridethyl) benzimidazole inhibition of basal and aldosterone-stimulated sodium transport but prolongation of the transient theophylline-induced stimulation in the toad bladder.
2-Mercapto-1-(beta-4-pyridethyl) benzimidazole (MPB) was originally introduced as a reversible inhibitor of RNA synthesis, but subsequent findings made this suggestion doubtful. We examined the effect of MPB on active sodium transport, measured as short-circuit current (scc), across the isolated urinary bladder of the toad (Bufo marinus). The drug caused a rapid, dose-dependent inhibition of baseline scc; 25 micrograms/ml MPB reduced it by 70%. Sensitivity to MPB was the same in the presence and absence of metabolizable substrate. The transport stimulation by aldosterone (7 X 10(-8)M) was abolished entirely when MPB was introduced 30 min before the hormone. In bladders incubated with MPB with or without aldosterone, removal of both agents resulted in a rise in scc, which was more rapid in the aldosterone-pretreated hemibladders; a significant difference was observed after 30 min. This suggests that MPB inhibited transport at a site distal to messenger RNA accumulation. The effect of 3 hr of pretreatment with MPB on the response of the bladders to antidiuretic hormone (ADH, 20 mU) and cyclic AMP (cAMP, 10 mM) was then examined. The absolute increment in scc due to these agents was the same as in the absence of MPB, though the baseline was much reduced by the drug. After challenging MPB-pretreated bladders with theophylline (22.5 mM), sodium transport rose continuously for 90 min, in contrast to the small, short-lived rise in the absence of MPB. It is proposed that, in the toad bladder, MPB may: (1) inhibit cAMP-dependent protein kinase, as found by us in other tissues; and (2) counteract the accumulation of a transport inhibitor, possibly calcium or cyclic GMP, in tissues treated with endogenous or exogenous cAMP.


Incorporating Measurement Error from Modeled Air Pollution Exposures into Epidemiological Analyses.
Outdoor air pollution exposures used in epidemiological studies are commonly predicted from spatiotemporal models incorporating limited measurements, temporal factors, geographic information system variables, and/or satellite data. Measurement error in these exposure estimates leads to imprecise estimation of health effects and their standard errors. We reviewed methods for measurement error correction that have been applied in epidemiological studies that use model-derived air pollution data. We identified seven cohort studies and one panel study that have employed measurement error correction methods. These methods included regression calibration, risk set regression calibration, regression calibration with instrumental variables, the simulation extrapolation approach (SIMEX), and methods under the non-parametric or parameter bootstrap. Corrections resulted in small increases in the absolute magnitude of the health effect estimate and its standard error under most scenarios. Limited application of measurement error correction methods in air pollution studies may be attributed to the absence of exposure validation data and the methodological complexity of the proposed methods. Future epidemiological studies should consider in their design phase the requirements for the measurement error correction method to be later applied, while methodological advances are needed under the multi-pollutants setting.


A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure.
Lethal respiratory failure is primarily caused by a deficiency of pulmonary surfactant, and is the main cause of neonatal death among preterm infants. Pulmonary surfactant metabolism dysfunction caused by variants in the ABCA3 gene is a rare disease with very poor prognosis. Currently, the mechanisms associated with some ABCA3 variants have been determined, including protein mistrafficking and impaired phospholipid transport. However, some novel variants and their underlying pathogenesis has not been fully elucidated yet. In this study we aimed to identify the genetic features in a family with lethal respiratory failure. We studied members of two generations of a Chinese family, including a female proband, her parents, her monozygotic twin sister, and her older sister. Trio whole exome sequencing (WES) were used on the proband and her parents to identify the ABCA3 variants. Sanger sequencing and real-time quantitative polymerase chain reaction (PCR) were used on the monozygotic twin sister of proband to validate the ABCA3 synonymous variant and exon deletion, respectively. The potential pathogenicity of the identified synonymous variant was predicted using the splice site algorithms dbscSNV11_AdaBoost, dbscSNV11_RandomForest, and Human Splicing Finder (HSF). All patients showed severe respiratory distress, which could not be relieved by mechanical ventilation, supplementation of surfactant, or steroid therapy, and died at an early age. WES analysis revealed that the proband had compound heterozygous ABCA3 variants, including a novel synonymous variant c.G873A (p.Lys291Lys) in exon 8 inherited from the mother, and a heterozygous deletion of exons 4-7 inherited from the father. The synonymous variant was consistently predicted to be a cryptic splice donor site that may lead to aberrant splicing of the pre-mRNA by three different splice site algorithms. The deletion of exons 4-7 of the ABCA3 gene was determined to be a likely pathogenic variant. The variants were confirmed in the monozygotic twin sister of proband by Sanger sequencing and qPCR respectively. The older sister of proband was not available to determine if she also carried both ABCA3 variants, but it is highly likely based on her clinical course. We identified a novel synonymous variant and a deletion in the ABCA3 gene that may be responsible for the pathogenesis in patients in this family. These results add to the known mutational spectrum of the ABCA3 gene. The study of ABCA3 variants may be helpful for the implementation of patient-specific therapies.


Perceptions of African American Women and Health Care Professionals Related to Pre-Exposure Prophylaxis to Prevent HIV.
To describe the perceptions of African American women and health care professionals (HCPs) about factors that likely influence the use of pre-exposure prophylaxis (PrEP) to prevent HIV among African American women. Prospective mixed methods. Chicago, IL. Fifty-eight participants included HCPs (n = 10) and African American women (n = 48). Following the six steps of concept mapping, participants identified and rated factors they perceived to influence decisions to use PrEP among African American women. African American women generated a list of statements, and we grouped the statements into eight clusters: access, financial, best benefits, protection, medication, setbacks, network, and fear. HCPs ranked having an HIV-positive partner as the most influential factor that affected African American women's decisions to use PrEP (network cluster). African American women ranked ability to prevent HIV when condom use cannot be negotiated as their top reason (best benefits cluster) for using PrEP. African American women wanted to know how they could protect themselves and were open to using PrEP. For African American women considering the use of PrEP, the most influential factors were related to the benefits and accessibility of PrEP. HCPs should know that African American women are not afraid to discuss HIV risk and testing.


The treatment of monostotic fibrous dysplasia of the first metatarsal with free vascularized fibular bone graft.
Historically, patients suffering from fibrous dysplasia of the metatarsals faced amputation or resection as the treatments of choice. Although the lesion itself is not malignant, pain, swelling, and disability dictated the treatment. With recent refinements in microvascular surgery, vascularized bone grafting has offered a viable alternative for this and similar conditions that offers the potential for a functional, pain-free foot.


The effect of intracerebroventricular application of the caspase-3 inhibitor zDEVD-FMK on neurological outcome and neuronal cell death after global cerebral ischaemia due to cardiac arrest in rats.
Global cerebral ischaemia after cardiac arrest (CA) leads to programmed cell death (PCD) with characteristic signs of apoptosis in selectively vulnerable areas of the brain. The activation of caspase-3, an executioner caspase, plays a key role in the apoptotic cascade. We, therefore, studied the effects of the application of the specific caspase-3 inhibitor zDEVD-FMK on neurological outcome and neuronal cell death after experimental CA in rats. A 6-min CA was induced in anaesthetised and mechanically ventilated male Wistar rats. After cardiopulmonary resuscitation (CPR) and restoration of spontaneous circulation (ROSC) the animals were randomised to two groups to receive a continuous intracerebroventricular (i.c.v.) infusion for 7 days of zDEVD-FMK or placebo (artificial cerebrospinal fluid, CSF). At 24h, 3 and 7 days after ROSC, animals were tested according to a neurological deficit score (NDS). Seven days after ROSC, coronal sections of the brain were taken at the dorsal hippocampal level and analysed with cresyl-violet staining, the TUNEL technique and a caspase activity assay. Viable and TUNEL-positive neurons were counted in the hippocampal CA-1 sector. The NDS demonstrated severe deficits 1 and 3 days after ROSC, which resolved by 7 days with no difference between the two groups. At 7 days after ROSC neuronal death could be detected using cresyl-violet and TUNEL staining with no difference between the groups. We conclude that zDEVD-FMK administration has no effect on neurological outcome and PCD after global cerebral ischaemia following CA in rats. Other mechanisms or pathways must be identified in the pathophysiology of PCD after CA.


SARS-CoV-2 infection risk is higher in vaccinated patients with inflammatory autoimmune diseases or liver transplantation treated with mycophenolate due to an impaired antiviral immune response: results of the extended follow up of the RIVALSA prospective cohort.
A relevant proportion of immunocompromised patients did not reach a detectable seroconversion after a full primary vaccination cycle against SARS-CoV-2. The effect of different immunosuppressants and the potential risks for SARS-CoV-2 infection in these subjects is largely unknown. Patients from the Rivalsa prospective, observational cohort study with planned anti SARS-CoV-2 third dose mRNA vaccination between October and December 2021 were asked to participate to this follow-up study. Patients were asked about eventual confirmed positivity to SARS-CoV-2 infection within 6 months from the third dose and to undergo a blood draw to evaluate seroconversion status after the additional vaccine shot. 19 out of 114 patients taking part in the survey developed a confirmed SARS-CoV-2 infection; we identified mycophenolate treatment as an independent predictor of an increased risk of infection even after the third vaccine dose (OR: 5.20, 95% CI: 1.70-20.00, p=0.0053). This result is in agreement with the in vitro evidence that MMF impairs both B and T lymphocytes driven immune responses (reduction both in memory B cells producing anti-spike antibodies and in proliferating CD4+ and CD8+ T cells). Immunocompromised patients need an additional vaccine administration to reach a detectable seroconversion, thus fostering a more personalized approach to their clinical management. Moreover, patients undergoing mycophenolate treatment show a specific increased infection risk, with respect to other immunosuppressants thus supporting a closer monitoring of their health status.


Inherent versatility of P-450 oxygenase. Conferring dehydroepiandrosterone hydroxylase activity to P-450 2a-4 by a single amino acid mutation at position 117.
Mouse steroid 15 alpha-hydroxylase P-450 2a-4 is restricted in its substrate specificity to the delta 4, 3-ketone steroids such as androstenedione. As a result, the P-450 exhibits little hydroxylase activity toward delta 5, 3-hydroxysteroids including dehydroepiandrosterone (DHEA). A single amino acid mutation of Ala at position 117 to Val, however, is enough to confer a high DHEA hydroxylase activity to P-450 2a-4 with 7 alpha-OH DHEA as one of the two major hydroxylated metabolites. Mouse coumarin 7-hydroxylase P-450 2a-5 contains Val at position 117, but it exhibits very low DHEA hydroxylase activity. P-450 2a-5 acquires high DHEA hydroxylase activity, however, by a mutation of Phe-209 to Asn. Moreover, the mutant P-450 2a-5 loses its activity when Val is replaced by Ala at position 117. The residue at position 117, therefore, plays the principal role in the determination of the DHEA hydroxylase activity of the P-450s. Conversely, mutations at residue 117 have little effect on the androstenedione hydroxylase activities of the P-450s. Further modeling of the DHEA binding orientation in the substrate-heme pocket of bacterial P-450cam (Iwasaki, M., Darden, T., Pedersen, L., Davis, D. G., Juvonen, R. O., Sueyoshi, T., and Negishi, M. (1993) J. Biol. Chem. 268, 759-762) provides support for the hypothesis that the type of residue at position 117 determines the steroid-substrate specificity of the P-450 depending on the substituent at the C3 position of steroid molecule.


Arthrogryposis multiplex congenita as part of an inherited symptom complex: two case reports and a review of the literature.
Two first cousins appear to have an autosomal recessive disorder consisting of arthrogryposis multiplex congenita (AMC), pterygium coli, congenital cervical spine fusions, and some features of the Eagle-Barrett syndrome. A review of the literature is summarized including the broad concepts of AMC as well as some syndromes in which AMC is but one manifestation.


Increased relative growth rate of normal rat cells in vitro with crocetin.
The carotenoid crocetin (earlier found to increase relative growth of Walker 256 tumor cells and their radiosensitivity), is shown to increase the relative growth of normal Sprague-Dawley rat muscle derived cells in vitro, presumably by increasing oxygen transport.


Spread of clonal T-cell expansions in rheumatoid arthritis patients.
Despite a large number of studies identifying expanded T-cell clones among infiltrating lymphocytes, little is known about their distribution in patients suffering from rheumatoid arthritis. To evaluate the clonality of alpha/beta T-cell populations in arthritic locations and PBL, we determined the CDR3 size lengths of TCR beta-chain transcripts using BV (Vbeta), BC (Cbeta), BJ (Jbeta), and clonotype-specific primers. Transcripts from PBL of healthy donors show gaussian profiles of approximately eight CDR3 size peaks in most BV subfamilies. Dominant peaks standing out above the normal background identify expansions of one or several T-cell clones within a given BV subfamily. The analysis of six patients suffering from rheumatoid arthritis showed clonal expansions in all samples including PBL. Synovial tissue infiltrates revealed less complex repertoires with a greater number of expanded clones than PBL. Expanded clones varied from one patient to another; no recurrences were observed. Most interestingly, identical clones were identified bilaterally in arthritic knee joints and PBL from the same patient. Our data show that given T-cell clones are not only locally expanded but can also be found in the periphery, and strongly suggest that many similar clones spread throughout the bodies of patients.


Bioinformatic approach to identify chaperone pathway relationship from large-scale interaction networks.
We describe a computational protocol to identify functional modules and pathway relationship of chaperones based on physical interaction data derived from high-throughput proteomic experiments. The protocol first identifies interacting proteins shared by the different chaperone systems to organize the chaperones into functional modules. The chaperone functional modules represent groups of chaperones that are involved in mediating the folding of the shared interacting proteins. Either the chaperones in a module can function along a single folding pathway of a given substrate protein or the substrate protein might have two or more different folding pathways that the chaperones act on independently. As described in our computational protocol, probabilities of these pathway relationships between two chaperones in a two-component chaperone module can be determined using whole-genome expression and cellular pathways as reference. This protocol is potentially useful for identifying functional modules and pathway relationships in other biological systems that involve multiple proteins with many identified interactions.


A comparison of alcohol, tobacco and drug use as determined from household and school surveys.
Comparisons of results from different types of surveys are necessary to establish the best and cheapest methods of assessing drug use. This paper reports results from a school survey and a household survey conducted in Ontario. Both surveys were done in 1983 and used unbiased samples of the population in the same age groups. There are some methodological differences between the two studies. Younger students were more likely to report the use of tobacco, alcohol and cannabis in the student survey than in the household survey. Similarly, older students (18 and 19) reported more alcohol use in the student survey. In general, the results indicate that respondents are more likely to give socially desirable answers to questions answered at home than at school. Also, alcohol and drug users may be more likely to be missed in household than in school studies as the former have a much higher non-response rate.


Rectal Cancer: Staging.
The imaging of rectal cancer has evolved noticeably over the past 2 decades, paralleling the advances in therapy. The methods for imaging rectal cancer are increasingly used in clinical practice with the purpose of helping to detect, characterize and stage rectal cancer. In this setting, MR imaging emerged as the most useful imaging method for primary staging of rectal cancer; the present review focuses on the role of MR imaging in this regard.


Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: a randomized clinical trial.
Respiratory support for patients recovering from cardiopulmonary bypass and cardiac surgery uses large tidal volumes and a minimal level of positive end-expiratory pressure. Recent data indicate that these ventilator settings might cause pulmonary and systemic inflammation in patients with acute lung injury. We examined the hypothesis that high tidal volumes and low levels of positive end-expiratory pressure might worsen the inflammatory response associated to cardiopulmonary bypass. Forty patients undergoing elective coronary artery bypass were randomized to be ventilated after cardiopulmonary bypass disconnection with high tidal volume/low positive end-expiratory pressure (10-12 mL/kg and 2-3 cm H2O, respectively) or low tidal volume/high positive end-expiratory pressure (8 mL/kg and 10 cm H2O, respectively). Interleukin 6 and interleukin 8 levels were measured in the bronchoalveolar lavage fluid and plasma. Samples were taken before sternotomy (time 0), immediately after cardiopulmonary bypass separation (time 1), and after 6 hours of mechanical ventilation (time 2). Interleukin 6 and interleukin 8 levels in the bronchoalveolar lavage fluid and plasma significantly increased at time 1 in both groups but further increased at time 2 only in patients ventilated with high tidal volume/low positive end-expiratory pressure. Interleukin 6 and interleukin 8 levels in the bronchoalveolar lavage fluid and in the plasma at time 2 were higher with high tidal volume/low positive end-expiratory pressure than with low tidal volume/high positive end-expiratory pressure. Mechanical ventilation might be a cofactor able to influence the inflammatory response after cardiac surgery.


Glutathione reductase activity and its relationship to pyridoxine phosphate activity in G6PD deficiency.
Per cent stimulation of GR activity by FAD in vitro and PNP oxidase activity were measured in G6PD deficiency, heterozygous beta-thalassaemia and controls. It is confirmed that, in contrast to the high stimulation of GR by FAD commonly found in in thalassaemia indicating red-cell deficiency of FAD, and shown here to be greater in the Italian subjects, GR is usually saturated with FAD in G6PD deficiency, leading to high in vitro activity. Unexpectedly, on the other hand, low FMN-dependent PNP oxidase activity due to red-cell deficiency of FMN, confirmed by response to oral riboflavin, was found in the majority of subjects with G6PD deficiency, similar to that found in heterozygous beta-thalassaemia. Whereas this is explained in thalassaemia by an inherited slow red-cell metabolism of riboflavin to FMN, it is suggested that in G6PD deficiency an increased rate of red-cell metabolism of FMN to FAD leads to the low FMN and high FAD. When G6PD deficiency occurs with heterozygous beta-thalassaemia, GR is usually saturated with FAD as in G6PD deficiency alone, unless there is an inherited, very slow red-cell metabolism of riboflavin to FMN. The part played by GR in haemolytic crises in G6PD deficiency is discussed.


Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment.
High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events. Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21 mg (9-24)) was 23 weeks (6-96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p<0.001). Median aspartate aminotransferase and alanine aminotransferase concentrations decreased from 34 U/l (20-59) and 64 U/l (15-175) to 23 U/l (18-40; p=0.003) and 20 U/l (14-48; p=0.019), respectively. Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients.


Expression of circadian Per1 and Per2 genes in the liver and breast tumor tissues of HER2/neu transgenic mice of different age.
The expression of Per1, Per2, and Cry1 circadian genes in the liver and breast tumors were studied by real-time PCR in FVB/N mice of different age transfected with HER-2/neu gene. The expression of Per1 and Per2 genes in breast tumor tissue decreased in comparison with their expression in the lever. The expression of these genes decreased with age in both the liver and tumor tissue.


The site of tumor development determines immunogenicity via temporal mobilization of antigen-laden dendritic cells in draining lymph nodes.
The elimination of solid tumors largely depends on effective T-cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC-rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i.d.), but not s.c. tumors are rapidly rejected in a T-cell-dependent manner and induce protective T-cell responses. The rejection of i.d. tumors correlates with rapid recruitment of dermal DCs presenting the tumor antigen to both CD4 and CD8 T cells in the draining lymph nodes (dLNs). The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Altogether, our results show that the anatomical site of tumor development influences tumor immunogenicity, notably by controlling the kinetics of DC mobilization in the draining LNs.


Be more specific! Laser-assisted microdissection of plant cells.
Laser-assisted microdissection (LAM) is a powerful tool for isolating specific tissues, cell types and even organelles from sectioned biological specimen in a manner conducive to the extraction of RNA, DNA or protein. LAM, which is an established technique in many areas of biology, has now been successfully adapted for use with plant tissues. Here, we provide an overview of the processes involved in conducting a successful LAM study in plants and review recent developments that have made this technique even more desirable. We also discuss how the technology might be exploited to answer some pertinent questions in plant biology.


The roles of Rhodobacter sphaeroides copper chaperones PCu(A)C and Sco (PrrC) in the assembly of the copper centers of the aa(3)-type and the cbb(3)-type cytochrome c oxidases.
The α proteobacter Rhodobacter sphaeroides accumulates two cytochrome c oxidases (CcO) in its cytoplasmic membrane during aerobic growth: a mitochondrial-like aa(3)-type CcO containing a di-copper Cu(A) center and mono-copper Cu(B), plus a cbb(3)-type CcO that contains Cu(B) but lacks Cu(A). Three copper chaperones are located in the periplasm of R. sphaeroides, PCu(A)C, PrrC (Sco) and Cox11. Cox11 is required to assemble Cu(B) of the aa(3)-type but not the cbb(3)-type CcO. PrrC is homologous to mitochondrial Sco1; Sco proteins are implicated in Cu(A) assembly in mitochondria and bacteria, and with Cu(B) assembly of the cbb(3)-type CcO. PCu(A)C is present in many bacteria, but not mitochondria. PCu(A)C of Thermus thermophilus metallates a Cu(A) center in vitro, but its in vivo function has not been explored. Here, the extent of copper center assembly in the aa(3)- and cbb(3)-type CcOs of R. sphaeroides has been examined in strains lacking PCu(A)C, PrrC, or both. The absence of either chaperone strongly lowers the accumulation of both CcOs in the cells grown in low concentrations of Cu(2+). The absence of PrrC has a greater effect than the absence of PCu(A)C and PCu(A)C appears to function upstream of PrrC. Analysis of purified aa(3)-type CcO shows that PrrC has a greater effect on the assembly of its Cu(A) than does PCu(A)C, and both chaperones have a lesser but significant effect on the assembly of its Cu(B) even though Cox11 is present. Scenarios for the cellular roles of PCu(A)C and PrrC are considered. The results are most consistent with a role for PrrC in the capture and delivery of copper to Cu(A) of the aa(3)-type CcO and to Cu(B) of the cbb(3)-type CcO, while the predominant role of PCu(A)C may be to capture and deliver copper to PrrC and Cox11. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes.


Measurement of azygos venous blood flow in the evaluation of portal hypertension in patients with cirrhosis. Clinical and haemodynamic correlations in 100 patients.
Blood flow in the azygos vein, an index of blood flow through gastro-oesophageal collaterals, was measured by continuous thermal dilution in 100 patients with cirrhosis. Azygos blood flow was directly related to portal pressure (r = 0.54, P less than 0.001). Patients with portal hypertension had very high azygos blood flow (692 +/- 32 ml/min) in comparison with controls (n = 11, 174 +/- 29 ml/min). Patients with previous oesophageal bleeding had similar azygos blood flow as those without, but azygos blood flow was significantly greater in patients with massive or recurrent bleeding than in those with less severe haemorrhage, suggesting that the magnitude of collateral flow may influence the course of variceal bleeding. Patients with grade III varices had higher azygos blood flow than those with grades II or I. In addition, both oesophageal tamponade and vasopressin infusion, procedures of known value in variceal bleeding, markedly reduced azygos blood flow (-40% and -25%, respectively). Measurement of azygos blood flow allows evaluation of haemodynamic changes in the oesophageal collaterals of patients with portal hypertension, and provides useful information on the effect of therapeutic procedures aimed at arresting or preventing variceal haemorrhage.