Vitamin E analogues and immune response in cancer treatment.
Chemotherapeutic drugs induce both proliferation arrest and apoptosis; however, some cancer cells escape drug toxicity and become resistant. The suppression of the immune system by chemotherapeutic agents and radiation promotes the development and propagation of various malignancies via "mimicry-induced" autoimmunity, and maintain a cytokine milieu that favors proliferation by inhibiting apoptosis. A novel, efficient approach is based on a synergistic effect of different anticancer agents with different modes of action. Recently, a redox-silent analogue of vitamin E, alpha-tocopheryl succinate (alpha-TOS), has come into focus due to its anticancer properties. alpha-TOS behaves in a very different way than its redox-active counterpart, alpha-tocopherol, since it promotes cell death. It exerts pleiotrophic responses in malignant cells leading to cell cycle arrest, differentiation, and apoptosis. Apart from its role in killing cancer cells via apoptosis, alpha-TOS affects expression of genes involved in cell proliferation and cell death in a "subapoptotic" manner. For example, it modulates the cell cycle machinery, resulting in cell cycle arrest. The ability of alpha-TOS to induce a prolonged S phase contributes to sensitization of cancer cells to drugs destabilizing DNA during replication. A cooperative antitumor effect was observed also when alpha-TOS was combined with immunological agents. alpha-TOS and TRAIL synergize to kill cancer cells either by upregulating TRAIL death receptors or by amplifying the mitochondrial apoptotic pathway without being toxic to normal cells. alpha-TOS and TRAIL in combination with dendritic cells induce INF-gamma production by CD4+ and CD8+ T lymphocytes, resulting in a significant tumor growth inhibition or in complete tumor regression. These findings are indicative of a novel strategy for cancer treatment that involves enhanced immune system surveillance.


Motility allows S. Typhimurium to benefit from the mucosal defence.
The mammalian intestine is colonized by a dense bacterial community, called microbiota. The microbiota shields from intestinal infection (colonization resistance). Recently, we have shown that enteropathogenic Salmonella spp. can exploit inflammation to compete with the intestinal microbiota. The mechanisms explaining the enhanced pathogen growth in the inflamed intestine are elusive. Here, we analysed the function of bacterial flagella in the inflamed intestine using a mouse model for acute Salmonella Typhimurium enterocolitis. Mutations affecting flagellar assembly (Fla(-)) and chemotaxis (Che(-)) impaired the pathogen's fitness in the inflamed intestine, but not in the normal gut. This was attributable to a localized source of high-energy nutrients (e.g. galactose-containing glyco-conjugates, mucin) released as an element of the mucosal defence. Motility allows Salmonella Typhimurium to benefit from these nutrients and utilize them for enhanced growth. Thus, nutrient availability contributes to enhanced pathogen growth in the inflamed intestine. Strategies interfering with bacterial motility or nutrient availability might offer starting points for therapeutic approaches.


Susceptibility of plasma low- and high-density lipoproteins to oxidation in patients with severe hyperhomocysteinemia.
A moderate increase in plasma homocysteine is increasingly considered an important risk factor of atherosclerosis and thrombosis. However, the mechanisms by which hyperhomocysteinemia induces vascular disease are not well defined. In vitro studies suggest that cysteine and homocysteine can induce oxidative modification of low-density lipoproteins (LDL). This suggestion is relevant because lipoprotein oxidation is thought to play a key role in the development of atherosclerosis and in the triggering of thrombotic events. An attractive model to study this topic is provided by patients with classical homocystinuria, an inherited disease characterized by severe hyperhomocysteinemia and a high incidence of thromboembolisms. We investigated the existence of oxidized LDL and the susceptibility to oxidation of the plasma cholesterol-rich lipoproteins in six patients with severe hyperhomocysteinemia, most likely due to classical homocystinuria, and compared the results with matched controls. The proportion of electronegative LDL and the concentration of thiobarbituric acid reactive substances in native LDL and high-density lipoproteins (HDL) did not differ between patients and controls, suggesting that the proportion of modified lipoproteins is not increased in patients with severe hyperhomocysteinemia. The susceptibility to oxidative modification of plasma LDL and HDL was also similar in the two groups, although the patients had homocysteine levels 18.3-fold higher than controls. Thus, increased oxidative modification is not likely to be a relevant mechanism in explaining their high incidence of vascular disease. A possible explanation for the lack of increased susceptibility to oxidation, as would be expected for the metabolic blockade that cause classical homocystinuria, is the 4.1-fold decrease in the concentration of cysteine in the plasma of patients. As a result the total concentration of homocysteine plus cysteine was slightly lower in patients than in controls. This interpretation implies that more studies are needed on lipoprotein susceptibility to oxidation in patients in which both plasma homocysteine and cysteine concentrations are increased. This metabolic situation may be frequent in the population with moderate hyperhomocysteinemia and vascular disease.


Decolorization of salt-alkaline effluent with industrial reactive dyes by laccase-producing Basidiomycetes strains.
The discharge of highly coloured synthetic dye effluents into rivers and lakes is harmful to the water bodies, and therefore, intensive researches have been focussed on the decolorization of wastewater by biological, physical or chemical treatments. In the present study, 12 basidiomycetes strains from the genus Pleurotus, Trametes, Lentinus, Peniophora, Pycnoporus, Rigidoporus, Hygrocybe and Psilocybe were evaluated for decolorization of the reactive dyes Cibacron Brilliant Blue H-GR and Cibacron Red FN-2BL, both in solid and liquid media. Among the evaluated fungi, seven showed great ability to decolorize the synthetic textile effluent, both in vivo (74-77%) or in vitro (60-74%), and laccase was the main ligninolytic enzyme involved on dyes decolorization. Pleurotus ostreatus, Trametes villosa and Peniophora cinerea reduced near to 60% of the effluent colour after only 1 h of treatment. The decolorization results were still improved by establishing the nitrogen source and amount to be used during the fungal strains cultivation in synthetic medium previous their action on the textile effluent, with yeast extract being a better nitrogen source than ammonium tartarate. These results contribute for the development of an effective microbiological process for decolorization of dye effluents with reduced time of treatment.


Critical depth for the survival of coral islands: effects on the hawaiian archipelago.
Coral islands drown when sea level rise exceeds the maximum potential of coral reefs to grow upward (about 10 millimeters per year). During the Holocene transgression (18,000 years ago to present) sea levels rose at rates of up to 10 to 20 millimeters per year, and most coral island reefs situated deeper than a critical depth of30 to 40 meters below present day sea level drowned. Coral islands that did not drown during the Holocene transgression apparently all developed on antecedent foundations shallower than critical depth. During low stands in sea level during the Pleistocene, these islands were elevated and subject to subaerial erosion. Today, in the Hawaiian Archipelago, the depth of drowned banks is inversely related to summit area; smaller banks are progressively deeper, evidently because of erosional truncation during low sea level stands. Bank summit area may therefore be an important factor determining the failure or success of coral islands.


Host recovery and reduced virus level in the upper leaves after Potato virus Y infection occur in tobacco and tomato but not in potato plants.
In this study, the recovery phenomenon following infection with Potato virus Y (PVY) was investigated in tobacco (Nicotiana tobaccum), tomato (Solanum lycopersicum) and potato (Solanum tuberosum) plants. In tobacco plants, infection of severe strains of PVY (PVYN or PVYN:O) induced conspicuous vein clearing and leaf deformation in the first three leaves above the inoculated leaves, but much milder symptoms in the upper leaves. The recovery phenotype was not obvious in tobacco plants infected with PVY strain that induce mild symptoms (PVYO). However, regardless of the virus strains, reduction in PVY RNA levels was similarly observed in the upper leaves of these plants. Removal of the first three leaves above the inoculated leaves interfered with the occurrence of recovery, suggesting that the signal(s) mediating the recovery is likely generated in these leaves. In PVYN or PVYN:O but not in PVYO-infected tobacco plants, the expression of PR-1a transcripts were correlated with the accumulation level of PVY RNA. Reduced level of PVY RNA in the upper leaves was also observed in infected tomato plants, whereas such phenomenon was not observed in potato plants. PVY-derived small RNAs were detected in both tobacco and potato plants and their accumulation levels were correlated with PVY RNA levels. Our results demonstrate that the recovery phenotype following PVY infection is host-specific and not necessarily associated with the expression of PR-1a and generation of PVY small RNAs.


The importance of accurate adiabatic interaction potentials for the correct description of electronically nonadiabatic vibrational energy transfer: a combined experimental and theoretical study of NO(v = 3) collisions with a Au(111) surface.
We present a combined experimental and theoretical study of NO(v = 3 → 3, 2, 1) scattering from a Au(111) surface at incidence translational energies ranging from 0.1 to 1.2 eV. Experimentally, molecular beam-surface scattering is combined with vibrational overtone pumping and quantum-state selective detection of the recoiling molecules. Theoretically, we employ a recently developed first-principles approach, which employs an Independent Electron Surface Hopping (IESH) algorithm to model the nonadiabatic dynamics on a Newns-Anderson Hamiltonian derived from density functional theory. This approach has been successful when compared to previously reported NO/Au scattering data. The experiments presented here show that vibrational relaxation probabilities increase with incidence energy of translation. The theoretical simulations incorrectly predict high relaxation probabilities at low incidence translational energy. We show that this behavior originates from trajectories exhibiting multiple bounces at the surface, associated with deeper penetration and favored (N-down) molecular orientation, resulting in a higher average number of electronic hops and thus stronger vibrational relaxation. The experimentally observed narrow angular distributions suggest that mainly single-bounce collisions are important. Restricting the simulations by selecting only single-bounce trajectories improves agreement with experiment. The multiple bounce artifacts discovered in this work are also present in simulations employing electronic friction and even for electronically adiabatic simulations, meaning they are not a direct result of the IESH algorithm. This work demonstrates how even subtle errors in the adiabatic interaction potential, especially those that influence the interaction time of the molecule with the surface, can lead to an incorrect description of electronically nonadiabatic vibrational energy transfer in molecule-surface collisions.


Hyperconnectivity is a fundamental response to neurological disruption.
In the cognitive and clinical neurosciences, the past decade has been marked by dramatic growth in a literature examining brain "connectivity" using noninvasive methods. We offer a critical review of the blood oxygen level dependent functional MRI (BOLD fMRI) literature examining neural connectivity changes in neurological disorders with focus on brain injury and dementia. The goal is to demonstrate that there are identifiable shifts in local and large-scale network connectivity that can be predicted by the degree of pathology. We anticipate that the most common network response to neurological insult is hyperconnectivity but that this response depends upon demand and resource availability. To examine this hypothesis, we initially reviewed the results from 1,426 studies examining functional brain connectivity in individuals diagnosed with multiple sclerosis, traumatic brain injury, mild cognitive impairment, and Alzheimer's disease. Based upon inclusionary criteria, 126 studies were included for detailed analysis. RESULTS from 126 studies examining local and whole brain connectivity demonstrated increased connectivity in traumatic brain injury and multiple sclerosis. This finding is juxtaposed with findings in mild cognitive impairment and Alzheimer's disease where there is a shift to diminished connectivity as degeneration progresses. This summary of the functional imaging literature using fMRI methods reveals that hyperconnectivity is a common response to neurological disruption and that it may be differentially observable across brain regions. We discuss the factors contributing to both hyper- and hypoconnectivity results after neurological disruption and the implications these findings have for network plasticity.


A replication-competent foot-and-mouth disease virus expressing a luciferase reporter.
Bioluminescence is a powerful tool in the study of viral infection both in vivo and in vitro. Foot-and-mouth disease virus (FMDV) has a small RNA genome with a limited tolerance to foreign RNA entities. There has been no success in making a reporter FMDV expressing a luciferase in infected cell culture supernatants. We report here for the first time a replication-competent FMDV encoding Nanoluciferase, named as Nano-FMDV. Nano-FMDV is genetically stable during serial passages in cells and exhibits growth kinetics and plaque morphology similar to its parental virus. There are applications for the use of Nano-FMDV such as real-time monitoring of FMDV replication in vitro and in vivo.


Acute lesion of rat myocardium by a single injection of cobalt dichloride.
The formation of infarctoid areas in rat myocardium following intraperitoneal injection of cobalt dichloride (30 mg/kg) is connected with metabolic (toxic) and ischaemic lesions of myocardial cells. The ischaemic lesions are sequelae of thrombosis taking place after 3-8 hours in consequence of thrombocytic aggregation in the capillary lumen. With the aid of polarization and electron microscopy, the myocardial-cell changes in the affected zones were classed into four morphological types, as follows: contracture type, intracellular myocytolysis, primary clumpy disintegration of myofibrils, and intravital autolysis of ischaemized cells.


Bistable light-driven π phase switching using a twisted nematic liquid crystal film.
A light-activated optical phase switch was developed, exploiting the conversion between left-handed and right-handed twisted nematic liquid crystals. Theoretical and experimental analyses revealed that the handedness inversion of the twisted nematic film altered the optical phase of the output waves by π. Herein, the competition between the helical twisting powers of the two reverse-handed chiral dopants determines the handedness of the twisted nematic film. The photo-responsibility and the bistability are attributed to the azobenzene chromophores in one of the chiral additives.


Stubbed finger osteomyelitis.
Forceful hyperextension of the distal phalanx may result in a Salter II fracture. Due to the anatomic relationship of bone and nail, a 'stubbed finger' injury may result in an inapparent compound fracture. When nail bedding is associated with a distal phalangeal fracture, antibiotics should be instituted.


Petroleum: its composition, analysis and processing.
The task of the occupational physician can be greatly assisted by a knowledge of the manufacturing processes in which workers are engaged, the nature of the products that these processes produce, and the raw materials upon which they depend. Because this is particularly true of the petroleum industry, this chapter is devoted to a challenging overview of petroleum composition, analysis and refining technology.


Bolaamphiphiles promote phospholipid translocation across vesicle membranes.
A series of membrane-spanning bolaamphiphiles (molecules with two hydrophilic end groups connected by a hydrophobic linker) were prepared by a modular synthetic method and evaluated for their abilities to affect the dynamics of a surrounding bilayer membrane. The goal was to determine if the bolaamphiphiles promote the translocation of phospholipids across vesicle membranes. The bolaamphiphiles were incorporated at low levels (up to 5 mol %) in vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Inward translocation assays were performed using fluorescent, NBD-labeled phospholipid probes with phosphocholine (PC) or phosphoglycerol (PG) headgroups. The membrane-spanning bolaamphiphiles promote the translocation of both phospholipid probes in the order PG > PC, whereas shorter bolaamphiphiles (structures that must adopt a U-shape and keep both end groups in the same leaflet of the membrane), and regular amphiphiles with one hydrophilic end group, are inactive. These results are an exception to the rule-of-thumb that membrane-spanning bolaamphiphiles are inherently membrane-stabilizing molecules that inhibit all types of membrane transport.


[Vertical retraction syndrome].
The authors describe a three-year-old girl with congenital unilateral restriction of elevation, associated with retraction of the globe and narrowing of the palpebral fissure. The pathogenetic possibilities are discussed; the presence of a vertical innervation anomaly, similar to Duane's syndrome, is postulated.


The tissue profile of metabolically active coenzyme forms of vitamin B12 differs in vitamin B12-depleted rats treated with hydroxo-B12 or cyano-B12.
Recent rat studies show different tissue distributions of vitamin B12 (B12), administered orally as hydroxo-B12 (HO-B12) (predominant in food) and cyano-B12 (CN-B12) (common in supplements). Here we examine male Wistar rats kept on a low-B12 diet for 4 weeks followed by a 2-week period on diets with HO-B12 (n 9) or CN-B12 (n 9), or maintained on a low-B12 diet (n 9). Plasma B12 was analysed before, during and after the study. The content of B12 and its variants (HO-B12, glutathionyl-B12, CN-B12, 5'-deoxyadenosyl-B12 (ADO-B12), and methyl-B12 (CH3-B12)) were assessed in the tissues at the end of the study. A period of 4 weeks on the low-B12 diet reduced plasma B12 by 58 % (from median 1323 (range 602-1791) to 562 (range 267-865) pmol/l, n 27). After 2 weeks on a high-B12 diet (week 6 v. week 4), plasma B12 increased by 68 % (HO-B12) and 131 % (CN-B12). Total B12 in the tissues accumulated differently: HO-B12>CN-B12 (liver, spleen), HO-B12<CN-B12 (kidneys), and HO-B12≈CN-B12 (brain, heart). Notably, more than half of the administered CN-B12 remained in this form in the kidneys, whereas HO-B12 was largely converted to the bioactive ADO-B12. Only <10 % of the other cofactor, CH3-B12, were found in the tissues. In conclusion, dietary CN-B12 caused a higher increase in plasma and total kidney B12 but provided less than half of the active coenzymes in comparison to dietary HO-B12. These data argue that HO-B12 may provide a better tissue supply of B12 than CN-B12, thereby underscoring the lack of a direct relation between plasma B12 and tissue B12.


Survival After Surgical Aortic Valve Replacement in Low-Risk Patients: A Contemporary Trial Benchmark.
The use of transcatheter aortic valve replacement for severe aortic stenosis in low-risk patients necessitates an evaluation of contemporary long-term, real-world outcomes of similar patients undergoing surgical aortic valve replacement (SAVR) in a national cohort. All patients undergoing primary, isolated SAVR in The Society of Thoracic Surgeons (STS) database between 2011 and 2019 were examined. The study population of 42,586 adhered to the inclusion/exclusion criteria of the Placement of Aortic Transcatheter Valves (PARTNER) 3 and Evolut Low Risk randomized trials. Patients were further stratified by STS predicted risk of mortality (PROM), age, and left ventricular ejection fraction. The primary end-point was all-cause National Death Index mortality. Unadjusted survival to 8 years was estimated using the Kaplan-Meier method. Mean age was 74.3 ± 5.7 years and mean STS PROM was 1.9% ± 0.8%. The overall Kaplan-Meier time to event analysis for all-cause mortality at 1, 3, 5, and 8 years was 2.6%, 4.5%, 7.1%, and 12.4%, respectively. In subset analyses, survival was significantly better for (1) lower STS PROM (P < .001), (2) younger vs older age (P < .001), and (3) higher vs lower left ventricular ejection fraction (P < .001). When STS PROM was below 1% or the patient age was below age 75 years, the 8-year survival after SAVR was 95%. The results of this national study confirm that long-term survival after SAVR remains excellent, at 92.9% at 5 years. These contemporary longitudinal data serve to aid in the balanced interpretation of current and future trials comparing SAVR and transcatheter aortic valve replacement and may assist in the clinical decision-making process for patients of lower surgical risk.


High-Affinity Host-Guest Recognition for Efficient Assembly and Enzymatic Responsiveness of DNA Nanostructures.
The combination of multiple orthogonal interactions enables hierarchical complexity in self-assembled nanoscale materials. Here, efficient supramolecular polymerization of DNA origami nanostructures is demonstrated using a multivalent display of small molecule host-guest interactions. Modification of DNA strands with cucurbit[7]uril (CB[7]) and its adamantane guest, yielding a supramolecular complex with an affinity of order 1010 m-1 , directs hierarchical assembly of origami monomers into 1D nanofibers. This affinity regime enables efficient polymerization; a lower-affinity β-cyclodextrin-adamantane complex does not promote extended structures at a similar valency. Finally, the utility of the high-affinity CB[7]-adamantane interactions is exploited to enable responsive enzymatic actuation of origami nanofibers assembled using peptide linkers. This work demonstrates the power of high-affinity CB[7]-guest recognition as an orthogonal axis to drive self-assembly in DNA nanotechnology.


Sowing Methods Influence Soil Bacterial Diversity and Community Composition in a Winter Wheat-Summer Maize Rotation System on the Loess Plateau.
Soil bacterial diversity and community composition are crucial for soil health and plant growth, and their dynamics in response to agronomic practices are poorly understood. The aim of this study was to investigate the response of soil bacterial community structure to the changes of sowing methods, soil depth and distance to roots in a winter wheat-summer maize crop rotation system on the Loess Plateau in china (35°17'38''N, 111°40'24''E). The experiment was laid out as completely randomized block design with three replications. Sowing methods trialed were: traditional sowing (TS), film-mulched ridge and furrow sowing (FMR&F), wide ridge and narrow furrow sowing (WR&NF) and unplanted control (CK). The result showed that the WR&NF sowing method treatment significantly decreased soil bacterial diversity (Chao 1 and Shannon indices) compared to the TS and FMR&F treatment, but increased abundance of beneficial bacteria such as genera Bacillus and Pseudomonas compared to the TS treatment. These genera showed a stronger correlation with soil properties and contributed to the soil nutrient cycling and crop productivity. Bacillus, Pseudomonas, Nevskia, and Lactococcus were the keystone genera in this winter wheat-summer maize rotation system on the Loess Plateau. Strong correlations between changes in soil properties and soil bacterial diversity and abundance were identified. In summary, we suggest that the WR&NF treatment, as a no-mulching film and no-deep tillage sowing method, would be the most suitable sowing technique in the winter wheat-summer maize rotation on Loess soil.


Identifying Patients Eligible for a Short Hospital Stay After Stoma Closure.
The implementation of enhanced recovery programmes after elective colorectal surgery has dramatically reduced the length of stay. The objective of this study was to assess the selection of good candidates for short post-operative stay (GCSS) in the context of stoma closure. Between January 2011 and December 2014, 222 patients were included in the present retrospective, single-center study. The primary endpoint was the proportion of GCSS. We also identified factors associated with GCSS status and built a predictive score. The study population was predominantly male (n = 122, 55%). 60% of the patients had undergone ileostomy and 85% had undergone hand-sewn anastomosis. The postoperative ileus rate was 5% and the readmission rate was 3.5%. 41% (n = 92) of the study population were considered to be GCSS. In a multivariate analysis, age under 50 (odds ratio (OR) [95% confidence interval (CI)] = 2.8 [1.2-5.6], p = 0.008), the absence of vascular comorbidities (OR [95%CI] = 3.2 [1.3-12.3]; p = 0.006) and stapled anastomosis (OR: 4.2, 95%CI: 1.1-17.3, p = 0.03) were associated with GCSS status. Predictive scores of 0, 1, 2, and 3 were associated with GCSS rates of 20%, 18%, 44%, and 62%, respectively (p < 0.001). In the context of stoma closure, 41% of patients were GCSS.


Research Advances in the Intervention of Inflammation and Cancer by Active Ingredients of Traditional Chinese Medicine.
A large body of evidence has shown that inflammation and cancer are strongly related. Thus anti-inflammatory agents have been investigated for cancer prevention and treatment in preclinical and clinical studies, including the nonsteroidal anti-inflammatory drugs (NSAIDs) and traditional Chinese medicine (TCM). In TCM, there exist a wide range of biologically active substances, such as saponins, flavonoids, alkaloids, polysaccharides, polyphenols, phenylpropanoids, and quinones. Many of these active ingredients have been reported to inhibit inflammation, activate inflammatory immune response, and/or inhibit cancer cell proliferation and tumor growth. Given the potential role of inflammation in cancer initiation and progression, the inflammatory tumor microenvironment, the cross-talks between inflammatory and cancer cells, and multitargeting activities of some TCM compounds, we summarize the current knowledge on the anti-inflammatory and anti-cancer properties of ingredients of TCM together with their underlying mechanisms in an integrated way. We hope to provide a reliable basis and useful information for the development of new treatment strategies of inflammation and cancer comprehensively using TCM and their active ingredients.


Isolation of psychrophilic bacteriophage-host systems from refrigerated food products.
Thirty-eight bacteriophage-host systems were isolated from 22 of 45 refrigerated food products examined under psychrophilic conditions. Isolates were obtained from ground beef, pork sausage, chicken, raw skim milk, and oysters, whereas no isolations were made from liquid egg whites and processed meat products. Thirty of the 38 psychrophilic bacterial hosts were gram-negative rods, and 27 of these were classified within the genus Pseudomonas; three were members of the family Enterobacteriaceae. The remaining eight were gram-positive cocci, which were tentatively classified as Leuconostoc. Plate counts of psychrophilic bacteria were greater than 2.2 x 10(5)/ml (g) in all but one sample which contained phage, whereas phage titers ranged from less than 100 to 6.3 x 10(6) plaque-forming units/ml (g). Phage isolates showed limited host ranges usually attacking only those hosts upon which they were isolated. Of eight phages tested against 13 cultures of known identity, one showed lytic action, and this was against strains of P. fragi.


Dynamic interactions between heart rate and atrioventricular conduction.
We examined the beat-by-beat alterations in atrioventricular (AV) conduction time that accompany both linear and abrupt changes in heart rate (HR). We used alpha-chloralose-anesthetized and autonomically decentralized dogs (n = 10) and recorded electrocardiogram (ECG), arterial pressure, and electrograms from sinus node, right ventricle, and His bundle. Abrupt or linear HR changes of known slope were generated by computer and displayed graphically with AV interval as a function of time. HR was increased linearly from 10 to 110 beats/min above control over 15, 30, and 60 s and then decreased in a linear fashion. AV interval was dependent on direction of HR change with marked asymmetry between increases and decreases in HR. Similar data were apparent irrespective of whether the decrease followed the increase or vice versa. To study determinants of 1:1 conduction, HR was increased linearly by 200 beats/min above control over 15, 30, and 60 s. As rate of change of HR increased, 1:1 conduction continued to a higher HR; however, the last conducted AV interval was negatively correlated with rate of change of HR. Abrupt sustained increases in HR of 25, 50, 75, and 100% above control resulted in marked accommodation of AV interval only at higher levels of HR. Thus in the absence of autonomic neural tone, 1) cardiac cycle length is not associated with a fixed AV interval but is dependent on magnitude and direction of HR change; and 2) the HR at which 1:1 AV conduction fails is significantly altered by the rate of change of HR.


Application areas of 3D bioprinting.
Three dimensional (3D) bioprinting has been a powerful tool in patterning and precisely placing biologics, including living cells, nucleic acids, drug particles, proteins and growth factors, to recapitulate tissue anatomy, biology and physiology. Since the first time of cytoscribing cells demonstrated in 1986, bioprinting has made a substantial leap forward, particularly in the past 10 years, and it has been widely used in fabrication of living tissues for various application areas. The technology has been recently commercialized by several emerging businesses, and bioprinters and bioprinted tissues have gained significant interest in medicine and pharmaceutics. This Keynote review presents the bioprinting technology and covers a first-time comprehensive overview of its application areas from tissue engineering and regenerative medicine to pharmaceutics and cancer research.


Nigrostriatal dopamine neurons express low levels of GTP cyclohydrolase I protein.
A previous study using the in situ hybridization technique showed that serotonin neurons contain substantially more GTP cyclohydrolase I mRNA than do either dopamine or norepinephrine neurons. The objective of the current study was to determine whether these differences in mRNA abundance are predictive of the amount of GTP cyclohydrolase I protein available for tetrahydrobiopterin biosynthesis. The double-label immunofluorescence technique was used to localize GTP cyclohydrolase I protein to the tyrosine hydroxylase-positive A9 dopamine neurons of the substantia nigra and the A6 norepinephrine neurons of the locus ceruleus or the tryptophan hydroxylase-positive B6/B7 serotonin neurons of the dorsal raphe nucleus. Although GTP cyclohydrolase I immunofluorescence within serotonin and norepinephrine neurons was relatively intense, the fluorescence signal within dopamine neurons was faint to nondetectable. An immunoautoradiographic technique was developed to quantify these apparent differences in GTP cyclohydrolase I protein expression at the cellular level. Significant differences between all three neurochemical subdivisions were found and comparisons showed that on average serotonin neurons contain between 2.3- and 7.3-fold more GTP cyclohydrolase I protein than do either norepinephrine or dopamine neurons, respectively. Nigrostriatal dopamine neurons thus appear to synthesize and maintain tetrahydrobiopterin at low levels. Because dopamine and norepinephrine neurons express essentially equal amounts of GTP cyclohydrolase I mRNA, posttranscriptional events may serve to maintain low levels of GTP cyclohydrolase I protein within dopamine neurons. Phenotypic differences in GTP cyclohydrolase I protein expression across populations of monoamine neurons may be an important control point in neurotransmitter biosynthesis.


The RFX protein RfxA is an essential regulator of growth and morphogenesis in Penicillium marneffei.
Fungi are small eukaryotes capable of undergoing multiple complex developmental programs. The opportunistic human pathogen Penicillium marneffei is a dimorphic fungus, displaying vegetative (proliferative) multicellular hyphal growth at 25 degrees C and unicellular yeast growth at 37 degrees C. P. marneffei also undergoes asexual development into differentiated multicellular conidiophores bearing uninucleate spores. These morphogenetic processes require regulated changes in cell polarity establishment, cell cycle dynamics, and nuclear migration. The RFX (regulatory factor X) proteins are a family of transcriptional regulators in eukaryotes. We sought to determine how the sole P. marneffei RFX protein, RfxA, contributes to the regulation of morphogenesis. Attempts to generate a haploid rfxA deletion strain were unsuccessful, but we did isolate an rfxA(+)/rfxADelta heterozygous diploid strain. The role of RfxA was assessed using conditional overexpression, RNA interference (RNAi), and the production of dominant interfering alleles. Reduced RfxA function resulted in defective mitoses during growth at 25 degrees C and 37 degrees C. This was also observed for the heterozygous diploid strain during growth at 37 degrees C. In contrast, overexpression of rfxA caused growth arrest during conidial germination. The data show that rfxA must be precisely regulated for appropriate nuclear division and to maintain genome integrity. Perturbations in rfxA expression also caused defects in cellular proliferation and differentiation. The data suggest a role for RfxA in linking cellular division with morphogenesis, particularly during conidiation and yeast growth, where the uninucleate state of these cell types necessitates coupling of nuclear and cellular division tighter than that observed during multinucleate hyphal growth.


Influence of external peer reviewer scores for funding applications on funding board decisions: a retrospective analysis of 1561 reviews.
To evaluate the influence of external peer reviewer scores on the National Institute for Health Research (NIHR) research funding board decisions by the number of reviewers and type of reviewer expertise. Retrospective analysis of external peer review scores for shortlisted full applications for funding (280 funding applications, 1236 individual reviewers, 1561 review scores). Four applied health research funding programmes of NIHR, UK. Board decision to fund or not fund research applications. The mean score of reviewers predicted funding decisions better than individual reviewer scores (area under the receiver operating characteristic (ROC) curve 0.75, 95% CI 0.69 to 0.81 compared with 0.62, CI 0.59 to 0.65). There was no substantial improvement in how accurately mean reviewer scores predicted funding decisions when the number of reviewers increased above 4 (area under ROC curve 0.75, CI 0.59 to 0.91 for four reviewers; 0.80, CI 0.67 to 0.92 for seven or more). Reviewers with differing expertise influenced the board's decision equally, including public and patient reviewers (area under ROC curves from 0.57, CI 0.47 to 0.66 for health economists to 0.64, CI 0.57 to 0.70 for subject-matter experts). The areas under the ROC curves were quite low when using reviewers' scores, confirming that boards do not rely solely on those scores alone to make their funding decisions, which are best predicted by the mean board score. Boards value scores that originate from a diverse pool of reviewers. On the basis of independent reviewer score alone, there is no detectable benefit of using more than four reviewer scores in terms of their influence on board decisions, so to improve efficiency, it may be possible to avoid using larger numbers of reviewers. The funding decision is best predicted by the board score.


Petrologic implications of plate tectonics.
Petrologists can make significant contributions to the plate tectonic concept. Fixing the stability fields of the principal rock types involved will provide the limits of pressure and temperature of the various environments. Experimental determination of the partition coefficients of the trace elements will be helpful. Studies of the partial melting behavior of possible parental materials in the absence and presence of water, especially the undersaturated region, will contribute to the understanding of magma production. Experimental observations on the rheological properties of the peridotites below and just above the solidus will lead to a better evaluation of the convective mechanism. Measurement of the fundamental properties of rocks, such as the density of solids and liquids at high pressures and temperatures, would contribute to understanding the concepts of diapiric rise, magma segregation, and the low-velocity zone. Broader rock sampling of the oceanic areas of all environments will do much to define the petrologic provinces. The field petrologist specializing in the Paleozoic regions and Precambrian shields can contribute by examining those regions for old plate boundaries and devising new criteria for their recognition.


Principles for Managing Patients with Spinal Ailments in the Coronavirus Disease 2019 Era: What Do We Know So Far? An Evidence-Based, Narrative Review.
The coronavirus disease 2019 (COVID-19) pandemic has significantly affected all specialty practices in medicine, including the field of spinal surgery. Spinal surgery is unique in that the procedures include not only fully elective and fully emergent interventions, but also involve a separate group of semi-emergent surgeries, where delayed intervention may lead to permanent neurological deficits. Here, we present an evidence-based review on the impact of the COVID-19 pandemic on spinal surgery and our current knowledge about this issue. We conducted a thorough search of the PubMed, Medline, and Google Scholar databases using the keywords, "COVID-19," "COVID-19 impact on spine surgery," "coronavirus impact on spine surgery," "COVID-19 impact on neurosurgery," "coronavirus impact on neurosurgery," "COVID-19 impact on spine surgeons," and "coronavirus impact on spine surgeons" on May 6, 2020. A total of 8,322 articles were identified in the initial search. Articles that were duplicated, those that did not pertain to COVID-19 or spine surgeries, those with details not pertaining to the current topic of interest, and those published in languages other than English were excluded from our analyses. After complete screening, six articles were included in this review. During the previous few weeks, the COVID pandemic has significantly influenced all major aspects of spine surgery across the world. Outpatient care has been gradually shifted from physical visits to tele-health and online consultations. General recommendations have favored the conservative approach over surgeries, although no patient should be deprived of standard care owing to concerns about COVID. The general principles followed by spine surgeons should include early detection of COVID symptomatology; triaging of patients based on underlying spinal pathology; prescription of appropriate investigations to confirm the COVID status; isolation, as needed; selection of optimal management method as per the guidelines; adherence to best intraoperative practices; and ensuring protective measures for non-infected patients, family members, fellow heath care providers, and themselves against the disease.


PREDICTION OF IRON DEFICIENCY IN CHILDREN USING EASY LABORATORY TOOLS.
Iron deficiency anemia is a common condition in children that can impair growth and development. This study aimed to evaluate the utility of easy, routinely available laboratory tests in predicting iron deficiency anemia. Medical records of 55 children (mean age 4.9±3.2 years) with laboratory evaluation of anemia were analyzed retrospectively. Parameters included complete blood count, serum iron, total iron binding capacity (TIBC), serum ferritin and transferrin saturation. Based on reference ranges, hemoglobin, hematocrit, serum ferritin and transferrin saturation were reduced below normal, indicating clear iron deficiency. Although within normal limits, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin and serum iron were close to lower limits, suggesting subtle deficiency. In contrast, red cell distribution width, platelet count, white blood cell count, TIBC and unsaturated iron binding capacity were unaffected. In conclusion, hemoglobin, and hematocrit from complete blood count, along with subtle changes in some of the red cell indices, can strongly suggest, iron deficiency anemia in children, Taking into consideration the increased body demand of iron in this age group with follow-up to ensure a desirable response, with less need for more advanced iron studies. These widely available, inexpensive tests may facilitate early detection and treatment of this common pediatric condition.


Augmented venoarteriolar response with ageing is associated with morning blood pressure surge.
What is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied. What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age-related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning. The venoarteriolar response (VAR) is a non-adrenergic, non-baroreflex-mediated mechanism of vasoconstriction, which has been proposed to contribute ∼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35-40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults (r = -0.4, P = 0.02) but not in the young adults (r = -0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans.


Determinants of cerebral perfusion pressure during carotid endarterectomy.
To define cerebral perfusion pressure during carotid clamping, carotid back and jugular venous pressures were measured in 100 consecutive carotid endarterectomies in 92 patients. The mean +/- 1 SD was 40.5 +/- 16.0 mm Hg for carotid back pressure, 11.8 +/- 4.8 mm Hg for jugular venous pressure, and 28.7 15.4 mm Hg for cerebral perfusion pressure. A number of variables affect jugular venous pressure, including jugular vein compression, patient position, and the anesthetic type. The lower the carotid back pressure, the more likely that back pressure alone is poor determinant of cerebral perfusion pressure and, hence, of the adequacy of collateral cerebral blood flow. To accurately use the carotid back or stump pressure method. The jugular venous pressure must also be measured, and the cerebral perfusion pressure must be calculated. Based on established safe levels of cerebral blood flow, it is probable that patients who undergo a carotid endarterectomy with a cerebral perfusion pressure of less than 18 mm Hg have cerebral ischemia and may require a shunt. Selective shunting, based on the cerebral perfusion pressure, gave a 1% mortality and 2% permanent neurologic deficit in this series.


A pre-anesthetic bolus of ketamine versus dexmedetomidine for prevention of postoperative delirium in elderly patients undergoing emergency surgery: a randomized, double-blinded, placebo-controlled study.
We aimed to evaluate whether a single dose of ketamine or dexmedetomidine before induction of general anesthesia could reduce the incidence of postoperative delirium (primary outcome) or cognitive dysfunction (secondary outcome) in elderly patients undergoing emergency surgery. This randomized, double-blinded, placebo-controlled trial included 60 elderly patients who were scheduled for emergency surgery. The patients were randomly assigned into one of three groups (n = 20): group I received 0.9% normal saline, group II received 1 µg/kg dexmedetomidine, and group III received 1 mg/kg ketamine right before anesthesia induction. Patients were observed for three days after surgery and tested for postoperative delirium and cognitive dysfunction using the delirium observation screening scale and the mini-mental state examination score, respectively. The dexmedetomidine group had the lowest incidence of delirium (p = 0.001) and cognitive dysfunction (p = 0.006) compared to the ketamine and placebo groups. The multivariate logistic regression model revealed that dexmedetomidine reduced the incidence of postoperative delirium by 32% compared to placebo (reference) (OR = 0.684, 95% CI: 0.240-0.971, p = 0.025), whereas ketamine increased the risk by threefold (OR = 3.012, 95% CI: 1.185-9.681, p = 0.013). Furthermore, dexmedetomidine reduced the incidence of postoperative cognitive dysfunction by 62% (OR = 0.375, 95% CI: 0.091-0.543, p = 0.012), whereas ketamine increased the risk by 4.5 times (OR = 4.501, 95% CI: 1.161-8.817, p = 0.006). A single pre-anesthetic bolus of dexmedetomidine is a practical choice for preventing postoperative delirium in elderly patients undergoing emergency surgery. This study was approved by the Ethics Committee of Aswan University Hospital (approval number: aswu/548/7/2021; registration date: 06/07/2021) and registered on ClinicalTrials.gov (NCT05341154) (22/04/2022).


Penetration of trovafloxacin into cerebrospinal fluid in humans following intravenous infusion of alatrofloxacin.
A single-dose study was conducted to determine concentrations of trovafloxacin (CP-99,219) achieved in the cerebrospinal fluid (CSF) relative to those in the serum of healthy subjects after intravenous infusion of alatrofloxacin (CP-116,517), the alanyl-alanyl prodrug of trovafloxacin. Twelve healthy subjects were administered single doses of alatrofloxacin at a trovafloxacin equivalent of 300 mg as an intravenous infusion over 1.0 h. CSF samples were taken by lumbar puncture at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 24 h after the start of the infusion; each subject was sampled at only one time point. Serum samples were taken from each subject at the time of CSF collection. A mean concentration of 5.8 microg of trovafloxacin per ml was present in serum 1.0 h after the start of the infusion. CSF/serum ratios ranged from 0.14 to 0.33 in the postdistribution phase (5 to 24 h postinfusion), with a mean ratio of 0.25. The most common adverse events were dizziness, nausea, and rash and were mild or moderate in intensity. The potency of trovafloxacin against susceptible organisms, coupled with its rapid penetration of CSF following the intravenous administration of alatrofloxacin, suggests that it may be useful in the treatment of bacterial meningitis in humans.


Isolation by environment.
The interactions between organisms and their environments can shape distributions of spatial genetic variation, resulting in patterns of isolation by environment (IBE) in which genetic and environmental distances are positively correlated, independent of geographic distance. IBE represents one of the most important patterns that results from the ways in which landscape heterogeneity influences gene flow and population connectivity, but it has only recently been examined in studies of ecological and landscape genetics. Nevertheless, the study of IBE presents valuable opportunities to investigate how spatial heterogeneity in ecological processes, agents of selection and environmental variables contributes to genetic divergence in nature. New and increasingly sophisticated studies of IBE in natural systems are poised to make significant contributions to our understanding of the role of ecology in genetic divergence and of modes of differentiation both within and between species. Here, we describe the underlying ecological processes that can generate patterns of IBE, examine its implications for a wide variety of disciplines and outline several areas of future research that can answer pressing questions about the ecological basis of genetic diversity.


Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI.
We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC.


The role of resuscitative endovascular balloon occlusion of the aorta (REBOA) as an adjunct to ACLS in non-traumatic cardiac arrest.
Non-traumatic cardiac arrest is a major public health problem that carries an extremely high mortality rate. If we hope to increase the survivability of this condition, it is imperative that alternative methods of treatment are given due consideration. Balloon occlusion of the aorta can be used as a method of circulatory support in the critically ill patient. Intra-aortic balloon pumps have been used to temporize patients in cardiogenic shock for decades. More recently, resuscitative endovascular balloon occlusion of the aorta (REBOA) has been utilized in the patient in hemorrhagic shock or cardiac arrest secondary to trauma. Aortic occlusion in non-traumatic cardiac arrest has the effect of reducing the vascular volume that the generated cardiac output is distributed across. This augments myocardial and cerebral perfusion, increasing the probability of a return to a good quality of life for the patient. This phenomenon has been the subject of numerous animal studies dating back to the early 1980s; however, the human evidence is limited to several small case series. Animal research has demonstrated improvements in cerebral and coronary perfusion pressure during ACLS that lead to statistically significant differences in mortality. Several case series in humans have replicated these findings, suggesting the efficacy of this procedure. The objectives of this review are to: 1) introduce the reader to REBOA 2) review the physiology of NTCA and examine the current limitations of traditional ACLS 3) summarize the literature regarding the efficacy and feasibility of aortic balloon occlusion to support traditional ACLS.


Sensitive immunohistochemical detection of WT1 protein in tumors with anti-WT1 antibody against WT1 235 peptide.
The Wilms' tumor 1 (WT1) gene is overexpressed in leukemia and various types of solid tumor, such as lung and colorectal cancer, and plays an oncogenic role in their tumorigenesis. Recent studies have demonstrated the potential of WT1-targeting cancer immunotherapy in clinical settings. As expression of WT1 protein in tumor cells is a prerequisite for WT1-targeting immunotherapy, immunohistochemical methods to detect WT1 protein with high sensitivity and specificity are required. In the present study, we developed a rabbit polyclonal antibody (WT1-R) against the 9-mer WT1 235 peptide, which is used for vaccination. The specificity of WT1-R was confirmed by immunoprecipitation, western blotting analysis, and competitive enzyme-linked immunosorbent assay. Immunocytochemistry showed the same reactivity against five cell lines (K562, Daudi, HT-180, SW480, and PC-14), whereas levels of WT1 mRNA expression determined by real-time qPCR (RT-PCR) analysis were not equivalent. Next, we examined the reactivity of WT1-R in tissue samples compared with a previously developed anti-WT1 antibody, 6F-H2. WT1-R showed greater sensitivity for detecting WT1 protein expression in samples from four different breast cancer patients than 6F-H2 antibody. The discrepancy in WT1 expression between these methods suggested that immunohistochemical detection of WT1 peptide may be advantageous for predicting the efficacy of WT1 vaccine compared to RT-PCR, and the highly sensitive WT1 antibody, WT1-R, may be useful to detect WT1 protein in tumors.


The E3 ubiquitin ligase SCFTIR1/AFB and membrane sterols play key roles in auxin regulation of endocytosis, recycling, and plasma membrane accumulation of the auxin efflux transporter PIN2 in Arabidopsis thaliana.
The PIN family of auxin efflux transporters exhibit polar plasma membrane (PM) localization and play a key role in auxin gradient-mediated developmental processes. Auxin inhibits PIN2 endocytosis and promotes its PM localization. However, the underlying mechanisms remain elusive. Here, we show that the inhibitory effect of auxin on PIN2 endocytosis was impaired in SCF(TIR1/AFB) auxin signaling mutants. Similarly, reducing membrane sterols impaired auxin inhibition of PIN2 endocytosis. Gas chromatography-mass spectrometry analyses indicate that membrane sterols were significantly reduced in SCF(TIR1/AFB) mutants, supporting a link between membrane sterols and auxin signaling in regulating PIN2 endocytosis. We show that auxin promoted PIN2 recycling from endosomes to the PM and increased PIN2 steady state levels in the PM fraction. Furthermore, we show that the positive effect of auxin on PIN2 levels in the PM was impaired by inhibiting membrane sterols or auxin signaling. Consistent with this, the sterol biosynthetic mutant fk-J79 exhibited pronounced defects in primary root elongation and gravitropic response. Our data collectively indicate that, although there are distinct processes involved in endocytic regulation of specific PM-resident proteins, the SCF(TIR1/AFB)-dependent processes are required for auxin regulation of endocytosis, recycling, and PM accumulation of the auxin efflux transporter PIN2 in Arabidopsis thaliana.


Preanaesthetic use of atropine in small animals.
Although it is unwise to recommend any preanaesthetic drug or regimen to be used routinely without consideration for the individual patient, the procedure being undertaken or the other drugs that will be used during the anaesthetic, of all anaesthetic-related drugs that might be under review, atropine is probably one of the least 'toxic' and least likely to cause life-threatening complications when used correctly. In most small veterinary practices there isn't the luxury of a dedicated anaesthetist available to monitor and manage each anaesthetised patient and the best form of cardiac monitor available may be an audible rate monitor. In this situation the advantages combined with the usual indications probably far outweigh the disadvantages of using atropine prophylactically. If a choice must be made, a sinus tachycardia under anaesthesia is probably preferable to a profound bradyarrhythmia. Absolute contraindications for using atropine are rare; the drug, when used alone, has low incidence of toxicity at clinically recommended doses in dogs and cats. Further, the new inhalation agents available to veterinarians (enflurane and isoflurane) do not sensitise the heart to the effect of catecholamines, so that the predominance of sympathetic tone produced when atropine is used is unlikely to precipitate dysarrthythmias during gaseous anaesthesia. Rhythm disturbances that occur under halothane anaesthesia when atropine is used, suggest there is some other cause, or agent, that is arrhythmogenic, such as an alpha 2 agonist, excessively deep level of anaesthesia, hypercapnia or hypoxaemia. Notwithstanding the above arguments, my preference, as a specialist anaesthetist, is that a drug is given only as required (not before) and that when, for example, any unusual heart rhythm occurs, all possible reasons for the occurrence (such as excessively deep anaesthesia or hypoventilation) are eliminated before other drugs like atropine or antiarrhythmics are administered.


Detection of Minimal Hepatic Encephalopathy in Iranian Patients with Cirrhosis.
BACKGROUND Minimal hepatic encephalopathy (MHE) is the mildest type of hepatic encephalopathy in patients with cirrhosis. Patients with MHE have normal clinical and physical examination but they show some neurocognitive dysfunctions that affect their quality of life negatively. The aim of the current study is to diagnose MHE in patients with cirrhosis and its associated factors. METHODS This is a cross-sectional study on 120 known cases of cirrhosis referred to hospitals affiliated to Isfahan University of Medical Sciences during 2014-17. The patients' cirrhosis severity was evaluated using laboratory tests and physical examinations based on MELD (Model for End-stage Liver Disease) and Child-Pugh criteria. The patients' demographics were filled in a checklist. All included patients with cirrhosis were asked to respond to the questions of Psychometric Hepatic Encephalopathy Score (PHES) test. RESULTS Mean age of the patients was 51.2 ± 9.7 years. 62 (51.7%) patients were men and 58 (48.3%) patients were women. The mean score of the patients based on MELD criteria was 14.03 ± 6.09. 26.7% of the patients presented MHE. Mean age of the patients with MHE was statistically less than the patients without MHE (p value < 0.001). Mean score of MELD criteria among the patients with diagnosis of MHE was significantly higher than the other group (p value < 0.001). The patients' Child class was statistically associated with MHE (p value < 0.001). Men were significantly more affected than women (p value = 0.03). CONCLUSION MHE was associated with MELD score and Child class of the patients with cirrhosis. The noticeable point was reversible association of age with MHE. Further studies are recommended.


An animal model for screening topical and systemic drugs for potential use in the treatment of psoriasis.
A new hairless mouse model using ultraviolet light to stimulate increased epidermal cell turnover and hyperplasia and thus simulate psoriasis has been designed so that drugs may be tested both topically and systemically for possible therapeutic value in this disease. Two methods of determining drug antimitotic activity have been used, the mitotic index and the extraction of epidermal DNA and the determination of the radioactivity of the sample. Results show that 2% 5-fluorouracil in propylene glycol and 2% nitrogen mustard in water topically and cyclophosphamide systemically, which are drugs known to be effective in psoriasis, significantly reduce the mitotic index. DNA synthesis is similarly decreased by the latter two drugs. The effect of the topical agents is shown to be local and not systemic. Cyclophosphamide, which is ineffective topically in psoriasis, is ineffective in the model.


Hypocapnia-induced contraction of porcine airway smooth muscle.
Hypocapnia constricts peripheral airways in vivo. This study investigated the role of airway smooth muscle in this phenomenon and the mechanism of hypocapnia-induced contraction in vitro. Isometric tension, intracellular pH (pHi) and intracellular free calcium concentration ([Ca2+]i) were measured in porcine airway smooth muscles suspended in organ baths in the presence of 5% or 0% CO2. In tracheal strips precontracted with carbachol, hypocapnic challenge (0% CO2) produced increases in tension, pHi, and [Ca2+]i. In bronchial rings or tracheal strips precontracted with carbachol, nifedipine administered between consecutive contractions attenuated responses to hypocapnia (75+/-11% above carbachol-precontracted tension before nifedipine versus 39+/-9% after nifedipine, n=7 bronchial rings, p<0.05). Neither indomethacin (5 microM), nordihydroguaiaretic acid (10 microM) nor phenidone (10 microM) significantly altered responses. These data suggest that enhanced Ca2+ influx through voltage-dependent Ca2+ channels of airway smooth muscle cells is important in airway responses to hypocapnia.


Working collaboratively to support medical education in developing countries: the case of the Friends of Moi University Faculty of Health Sciences.
Developing and sustaining medical schools in developing countries can be challenging. Some collaborations between medical schools in developing countries and one or more medical schools in developed countries have been helpful. However, medical schools in developing countries can be vulnerable to the sudden withdrawal of funds (particularly if they have only one partner). Also, uncoordinated support from multiple partners can lead to problems. We describe the 15-year experience of a unique "Friends" consortium, which was established between Moi University Faculty of Health Sciences ("Moi") in Kenya and four medical schools in developed countries. Information about the Friends' activities with Moi and their relationships with each other was collected from key members of each institution during the annual Friends meeting and through e-mail correspondence. Each school, under the leadership of a few individuals, has maintained a continuous collaboration with Moi. Most of the focus has been on education. Some institutions have been able to expand their activities. Others have maintained more limited but steady support. Coordination of activities of the partner institutions has been facilitated by annual joint meetings, leading to clarity about needs to be met as well as ways to avoid overlap. We believe that effectiveness of the individual efforts of each institution have been enhanced through working cooperatively. Ongoing problems include gaps in support at Moi, with uneven program development in some areas. We have learned that working together cooperatively has increased the effectiveness of individual efforts, and encourage others to consider adopting a "Friends" consortium model through actively contacting other partners. National or international health education organizations may be able to play a role in facilitation of these relationships.


¡Habla de VPH! An Educational Activity for College Students in Puerto Rico.
To evaluate human papillomavirus (HPV) infection knowledge, willingness to get vaccinated, and vaccination uptake, following a brief educational activity entitled ¡Habla de VPH! (Let's talk about HPV!) in a sample of college students at the University of Puerto Rico, Bayamón. Participants completed a self-administered questionnaire developed by the research team, which gathered information regarding sociodemographic characteristics, HPV vaccination status, and willingness to receive the vaccine. Once the participant completed the survey, the staff of the Outreach Program conducted an educational activity. Study participants completed a pre- and post-test, which included a scale with items related to knowledge about HPV infection, associated malignancies, and the vaccine. To compute the mean knowledge score for each test, the correct responses were summed; the total scores for each test ranged from 0 to 11. Follow-up interviews (3 and 6 months) explored knowledge changes and-in the previously unvaccinated students-vaccine uptake. A total of forty students answered the questionnaire. A significant difference between the average knowledge before (7.6 ± 2.1) and after the intervention (10.6 ±0.6) (P < .001) was observed. Of the non-vaccinated group, 59.3% reported being interested in receiving the vaccine. By the 3- and 6-month follow-ups, only 2 students had started the vaccine series. Knowledge about HPV and associated malignancies increased significantly. However, few students initiated the vaccine after either of the followups. Future efforts should line up the vaccine promotion and outreach activities with immunization services, making the vaccine available in the communities to be impacted.


Diagnostic Value of Magnetic Resonance Neurography in Cervical Radiculopathy: Plexus Patterns and Peripheral Nerve Lesions.
The aim of this study was to assess the imaging appearance and diagnostic value of plexus and peripheral nerve magnetic resonance neurography (MRN) in cervical radiculopathy. This prospective study was approved by our institutional ethics committee and written informed consent was obtained from all participants. A total of 24 patients were included with a diagnosis of cervical radiculopathy based on clinical examination, supporting electrophysiological examinations and spinal imaging consistent with the clinical syndrome. All patients then underwent a high-resolution MRN protocol including the brachial plexus from nerve roots to plexus cords using a 3-dimensional turbo spin echo with variable flip angle short tau inversion recovery and sagittal-oblique T2-weighted spectral adiabatic inversion recovery sequence, and ulnar, median, and radial nerves at the upper arm and elbow in T2-weighted fat saturated sequences. Two readers independently rated plexus elements regarding the presence of lesions at neuroforaminal levels, roots, trunks, and cord segments. Median, ulnar, and radial nerves were likewise rated. Findings were then compared to a referenced standard of cervical radiculopathy that was defined as the combined diagnosis of clinical syndrome including supporting electrophysiological exams and matching positive spinal imaging, and diagnostic performance parameters were calculated. Additional quantitative and qualitative analysis assessed peripheral nerve caliber and normalized T2-signal at arm level in cervical radiculopathy and compared them to 25 inflammatory neuropathy controls. Cervical radiculopathy resulted in distinct plexus lesion patterns for each level of neuroforaminal stenosis. Overall, brachial plexus MRN in cervical radiculopathy reached a sensitivity of 81%, a specificity of 96%, a positive predictive value of 87%, and overall diagnostic accuracy of 87%. Initial spinal magnetic resonance imaging showed multiple positive findings for clinically unaffected root levels and resulted in a specificity of 69%, a positive predictive value of 54%, and an overall diagnostic accuracy of 78%.T2-weighted peripheral nerve lesions were detected in 79% of cervical radiculopathy cases and imitated imaging appearance of inflammatory neuropathies both quantitatively and qualitatively. Complementing spine imaging in cervical radiculopathy with brachial plexus MRN can improve diagnostic accuracy by increasing specificity and positive predictive value. T2-weighted lesions of peripheral nerves can be caused by cervical radiculopathy, which must be considered a relevant diagnostic pitfall in MRN of peripheral neuropathies.


Electrical stimulation in the relief of pain: a pilot study.
A group of 26 patients who suffered from chronic pain resistant to other therapeutic measures, were given electrical stimulation in two forms. The first utilised penetrating acupuncture needles connected to a standard Chinese electrical impulse generator and the second method employed American transcutaneous stimulators with conducting skin electrodes. At long term follow-up 50 percent of patients treated exhibited sustained relief--20 percent when the device was used alone and a further 30 percent when it was combined with other forms of specific pain therapy. There was no difference in the response to needle acupuncture or transcutaneous stimulation. The best response was seen in patients with neuralgic disorders and painful musculo skeletal syndromes affecting the cervico thoracic region.


The affective beneficence of vigorous exercise revisited.
OBJECTIVES: High exercise intensity may be associated with reduced adherence to exercise programmes, possibly because it is perceived as aversive. However, several authors have suggested that an intensity as high as 60% or 70% of maximal aerobic capacity (VO(2max)) is necessary for exercise to elicit positive affective changes. To elucidate this discrepancy, the affective responses to increasing levels of exercise intensity were examined. DESIGN: In total, 30 volunteers rated their affect every minute as they ran on a treadmill while the speed and grade were progressively increased. METHOD: The methodology was unique in three respects: (1) affect was assessed in terms of the dimensions of the circumplex model instead of distinct affective states, (2) affect was assessed repeatedly before, during, and after exercise, not only before and after, and (3) exercise intensity was standardized across participants in terms of metabolically comparable phases (beginning, ventilatory threshold, VO(2max)) instead of percentages of maximal capacity. RESULTS: Pre-to-post-exercise comparisons indicated affective benefits in the form of increased energetic arousal and decreased tense arousal. During exercise, however, affective valence deteriorated beyond the ventilatory threshold and until VO(2max), a trend that reversed itself instantaneously during cool-down. CONCLUSIONS: Exercise intensity that requires a transition to anaerobic metabolism can have a transient but substantial negative impact on affect and this may, in turn, reduce adherence to exercise programmes.


Sickling rates of human AS red cells infected in vitro with Plasmodium falciparum malaria.
The kinetics of sickling of malaria-infected red cells from humans with sickle cell trait were studied in vitro in an attempt to obtain direct experimental evidence for a selective advantage of the hemoglobin S heterozygote in a malarious region. The sickling rates of cells infected with Plasmodium falciparum and of non-infected cells were studied both in the total absence of oxygen (by dithionite addition) and at several different concentrations of oxyhemoglobin which might obtain in vivo. In all cases, red cells containing small plasmodium parasite forms (ring forms) sickled approximately eight times as readily as uninfected cells. Cells containing large parasitic forms (trophozoites and schizonts) appeared to sickle less readily than uninfected cells, by light microscopy criteria, but electron micrographs demonstrated the presence of polymerized deoxyhemoglobin S with a high frequency. It is concluded that enhanced sickling of plasmodium-infected AS cells may be one mechanism whereby the hemoglobin S polymorphism is balanced in favor of the heterozygote.


Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America.
Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real-clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real-world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child-Pugh B at baseline and one patient died due to multi-organ failure. Follow up HCV-RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child-Pugh A cirrhosis in non-European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child-Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.


Arp2/3 nucleates F-actin coating of fusing insulin granules in pancreatic β cells to control insulin secretion.
F-actin dynamics are known to control insulin secretion, but the point of intersection with the stimulus-secretion cascade is unknown. Here, using multiphoton imaging of β cells isolated from Lifeact-GFP transgenic mice, we show that glucose stimulation does not cause global changes in subcortical F-actin. Instead, we observe spatially discrete and transient F-actin changes around each fusing granule. This F-actin remodelling is dependent on actin nucleation and is observed for granule fusion induced by either glucose or high potassium stimulation. Using GFP-labelled proteins, we identify local enrichment of Arp3, dynamin 2 and clathrin, all occurring after granule fusion, suggesting early recruitment of an endocytic complex to the fusing granules. Block of Arp2/3 activity with drugs or shRNA inhibits F-actin coating, traps granules at the cell membrane and reduces insulin secretion. Block of formin-mediated actin nucleation also blocks F-actin coating, but has no effect on insulin secretion. We conclude that local Arp2/3-dependent actin nucleation at the sites of granule fusion plays an important role in post-fusion granule dynamics and in the regulation of insulin secretion.


The Impact of COVID-19 Pandemic on Ophthalmology Residency Education.
The aim of this study is to investigate the theoretical, practical, and academic effects of the Coronavirus disease 2019 (COVID-19) pandemic on ophthalmology residents. The web-based survey consisting of 28 questions was sent through Email to 37 educators who provides resident training. We divided the pandemic period into three, according to the severity of the pandemic and the measures, compared with pre-pandemic period (PreP), separately. Between March 2020 and June 2020 was named as P1, June 2020-October 2020 was named as P2, and October 2020-March 2021 was named as P3. Responses received from 35 centers (17 university hospitals, 18 training and research state hospitals). There were totally 458 residents in the hospitals. Two hundred and forty-six of them (53.71%) worked on COVID-19 duties, with an average working time of 69.57 days. There were significant decreases in the number of patients examined by resident doctors and theoretical training time in the P1, P2, and P3 periods compared to PreP (p<0.05 for all). Furthermore, in terms of the total number of surgeries in clinics and surgeries performed by residents, there were significant decreases in P1 and P2 compared to PreP (p<0.001 for both), but there was no significant difference in P3 (p=0.109). In the examinations held in the clinic, in the 1st year of the pandemic, the grade average was lower than before the pandemic (p<0.05). Seventeen residents (3.74%) resigned or moved to another hospital. The COVID-19 pandemic has severely affected the theoretical, practical, and academic training of ophthalmology residents.


Development of a rapid automated influenza A, influenza B, and respiratory syncytial virus A/B multiplex real-time RT-PCR assay and its use during the 2009 H1N1 swine-origin influenza virus epidemic in Milwaukee, Wisconsin.
Rapid, semiautomated, and fully automated multiplex real-time RT-PCR assays were developed and validated for the detection of influenza (Flu) A, Flu B, and respiratory syncytial virus (RSV) from nasopharyngeal specimens. The assays can detect human H1N1, H3N2, and swine-origin (S-OIV) H1N1 Flu A viruses and were effectively used to distinguish Flu A infections (of all subtypes) from Flu B and RSV infections during the current S-OIV outbreak in Milwaukee, WI. The analytical limits of detection were 10(-2) to 10(1) TCID(50)/ml depending on the platform and analyte and showed only one minor cross-reaction among 23 common respiratory pathogens (intermittent cross-reaction to adenovirus at >10(7) TCID(50)/ml). A total of 100 clinical samples were tested by tissue culture, both automated assays, and the US Food and Drug Administration-approved ProFlu+ assay. Both the semiautomated and fully automated assays exhibited greater overall (Flu A, Flu B, and RSV combined) clinical sensitivities (93 and 96%, respectively) and individual Flu A sensitivities (100%) than the Food and Drug Administration-approved test (89% overall sensitivity and 93% Flu A sensitivity). All assays were 99% specific. During the S-OIV outbreak in Milwaukee, WI, the fully automated assay was used to test 1232 samples in 2 weeks. Flu A was detected in 134 clinical samples (126 H1N1 S-OIV, 5 H1N1 [human], and 1 untyped) with 100% positive agreement compared with other "in-house" validated molecular assays, with only 2 false-positive results. Such accurate testing using automated high-throughput molecule systems should allow clinicians and public health officials to react quickly and effectively during viral outbreaks.


[Macro-Baermann--a method for parasitological examination of herbage samples].
A Baermann technique for extraction of trichostrongylide larvae (L3) from herbage samples is described. The technique is a modification/simplification of a technique previously described by Persson (1974). On examination of 150-200 g samples 30-60% of larvae of Ostertagia ostertagi and Cooperia oncophora were recovered.


Electrocardiographic changes after alcohol septal ablation in hypertrophic obstructive cardiomyopathy.
To report acute and mid-term electrocardiographic changes in patients with hypertrophic obstructive cardiomyopathy (HOCM) after alcohol ablation of the first large septal branch of the left anterior descending coronary artery; and to relate electrocardiographic data with the left ventricular outflow tract pressure gradients. Nine consecutive symptomatic patients with HOCM (mean (SD) age 45 (12) years). Analysis of baseline and post-procedure ECGs and 24 hour ambulatory monitoring (up to six months). ECG data were related to left ventricular outflow tract pressure gradients. One patient developed complete atrioventricular block requiring permanent pacing. The PR interval was significantly prolonged up to third month after ablation. Immediately after the procedure all patients developed right bundle branch block. At the sixth month of follow up, right bundle branch block was present in four patients. New anterior ST elevation developed immediately after ablation in five of the nine patients, and new Q waves in four. The QRS duration was significantly prolonged immediately after ablation and during follow up. There was significant but transient prolongation of QT-mean and QTc-mean intervals. QT dispersion, QTc dispersion, and JTc-mean interval were not affected. JT and JTc dispersions were transiently prolonged. No serious ventricular arrhythmias were recorded during Holter monitoring, either before or after the procedure. There were no significant correlations between the left ventricular outflow tract pressure gradient and QTc, QT-d, QTc-d, JTc, JT-d, JTc-d, or QRS duration before and after ablation. Alcohol septal ablation for HOCM induces significant changes in the resting ECG in most patients, despite the occlusion of a relatively small artery. The changes include new Q waves, new bundle branch block, transient anterior ST segment elevation, atrioventricular block, and transient prolongation of QT interval.


Quality of life instruments in the evaluation of new drugs.
The importance of measuring changes in a patient's quality of life when evaluating the efficacy of new drugs is increasingly recognised. In this paper, we review the steps associated with this process--recognising the opportunity and the need to include quality of life instruments during the investigation, choosing the most suitable instrument(s) and interpreting the results. To be useful in clinical trials, quality of life measures must be both responsive (able to detect all important differences) and valid. Generic instruments are applicable to a wide variety of populations but may lack responsiveness. Disease-specific instruments are more likely to be responsive and are directly relevant to patients and clinicians. The approach to measurement in a specific clinical trial should be dictated by the goals of the investigators.


Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol.
Even though endothelin is recognized as an important vasoregulatory molecule, the roles of endothelin receptors in specific cell types are not yet fully understood. Mice with a null mutation in endothelin A receptor gene (ET(A)) or in the gene of its ligand (endothelin 1) die neonatally due to craniofacial and cardiac abnormalities. This early lethality has in the past hindered studies on the role of endothelin in cardiovascular physiology and pathophysiology. To overcome this obstacle, we utilized the cre/loxP technology to generate mice in which the ET(A) gene could be deleted specifically in cardiomyocytes. The cre recombinase transgene driven by the alpha-myosin heavy-chain promoter deleted the floxed ET(A) allele specifically in the hearts of these mice, resulting in a 78% reduction in cardiac ET(A) mRNA level compared to wild-type controls. Cardiomyocyte-specific ET(A) knockout animals are viable and exhibit normal growth, cardiac anatomy, and cardiac contractility, as assessed by echocardiography. In addition, these animals exhibit hypertrophic and contractile responses to 10-day infusion of angiotensin II or isoproterenol similar to those observed in control animals. These results indicate that in adult mice cardiac ET(A) receptors are not necessary for either baseline cardiac function or stress-induced response to angiotensin II or isoproterenol.


Transport of solute in proximal tubules is modified by changes in medium osmolality.
To examine the hypothesis that fluid absorption is driven by transepithelial osmotic differences, we measured such differences in proximal tubules perfused under oil and attempted to increase the rate of fluid absorption (Jv) and hence the absorbate-perfusate osmotic differences by lowering the osmolality of the perfusate. We were able to consistently increase Jv in this manner only in proximal straight tubules perfused with a simple perfusate that contained no bicarbonate or amino acids. With the simple perfusate, a small but significant increase in the absorbate-perfusate osmolality difference was seen with increased Jv, which is expected if the volume absorption is driven by a transepithelial osmotic difference. In addition, lowering the perfusate osmolality from 290 to 160 mosmol/kg H2O increased the rate of solute absorption from 79 +/- 7 to 91 +/- 8 posmol . min-1 . mm-1; this increase was partly accounted for by an increase in the rate of absorption of glucose from 6.6 +/- 0.9 to 9.5 +/- 1.1 pmol . min-1 . mm-1. In contrast, with the complete perfusate in proximal straight tubules there was little or no increment in Jv, no change in transepithelial osmolality differences, and a decrease in the rate of solute transport with hypoosmolality from 136 +/- 21 to 87 +/- 22 posmol . min-1 . mm-1. In proximal convoluted tubules, similar results were obtained, but a time-dependent decline of Jv complicated the interpretation of the results in the convoluted tubules. It is hypothesized that the observed changes in solute transport with hypotonic perfusate may be the result of changes in membrane permeability that are subsequent to cell swelling.


Hansen's disease in native-born citizens of the United States.
This paper presents a statistical analysis of data on 1,309 Hansen's disease (HD) patients born in the continental United States during the 50 year period 1932-81. Fifty-six percent of them were born in Texas. The cases of 66 percent were classed as multibacillary, 31 percent were considered paucibacillary, and the type was unknown for 3 percent. Blacks and whites appeared to be equally susceptible to Hansen's disease. Thirty percent had a history of contact with Hansen's disease. The age at diagnosis has increased an average of 2.7 years per decade, and the increase has accelerated in the last two decades. If the present trend continues, Hansen's disease among native-born citizens of the United States will ultimately disappear.


Short-time Effects of Malathion Pesticide on Functional and Histological Changes of Liver and Kidney in Female Mice.
The malathion is one of the most important organophosphorus pesticides used in Iraq. The present study was designed to investigate the short-time effects of the malathion on the biochemical parameters of AST, ALT, ALP, urea, creatinine, total cholesterol, triglycerides and total protein as well as histological changes of the liver and kidneys of female laboratory mice for an interval of 6 days. The animals were divided into 3 groups, each group included 8 mice. They were injected with the pesticide in the intraperitoneal region. The 1st group (the control group) was injected with 0.1 mL of distilled water, the 2nd group (the low dose group) was injected with 0.1 mL of the pesticide solution at 3 mg/body weight while the 3rd group (the high dose group) was injected with 0.1 mL of the pesticide solution at a concentration of 6 mg/body weight. The biochemical tests of the liver and kidney showed significant elevation in serum AST, urea, creatinine and cholesterol concentrations in mice compared to control group (p<0.05). In addition, the results showed a significant decrease in the ALP, triglycerides and the total protein in serum of the treated mice. Also, the results of histological sections of the liver and kidneys included congestion, necrosis, degeneration of cytoplasm, blood congestion, apoptosis, bleeding and sloughing of epithelial cells to the renal tubular lumen. Finally, the results indicated that malathion pesticide has the ability to induce hepatic and renal toxicity in mice within 6 days.


Instanton calculations of tunneling splittings in chiral molecules.
We report the ground state tunneling splittings (ΔE± ) of a number of axially chiral molecules using the ring-polymer instanton (RPI) method (J. Chem. Phys., 2011, 134, 054109). The list includes isotopomers of hydrogen dichalcogenides H2 X2 (X = O, S, Se, Te, and Po), hydrogen thioperoxide HSOH and dichlorodisulfane S2 Cl2 . Ab initio electronic-structure calculations have been performed on the level of second-order Møller-Plesset perturbation (MP2) theory either with split-valance basis sets or augmented correlation-consistent basis sets on H, O, S, and Cl atoms. Energy-consistent pseudopotential and corresponding triple zeta basis sets of the Stuttgart group are used on Se, Te, and Po atoms. The results are further improved using single point calculations performed at the coupled cluster level with iterative singles and doubles and perturbative triples amplitudes. When available for comparison, our computed values of ΔE± are found to lie within the same order of magnitude as values reported in the literature, although RPI also provides predictions for H2 Po2 and S2 Cl2 , which have not previously been directly calculated. Since RPI is a single-shot method which does not require detailed prior knowledge of the optimal tunneling path, it offers an effective way for estimating the tunneling dynamics of more complex chiral molecules, and especially those with small tunneling splittings.


Hidradenitis suppurativa: Detangling phenotypes and identifying common denominators.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a severe impact on patients' quality of life through its recurrent and painful nature, as well as its comorbidity burden. The shift in the pathogenic paradigm from a condition of the apocrine glands to an autoinflammatory disease associated with follicular destruction has rendered its understanding difficult, as there are still large gaps in pinpointing the underlying mechanisms, which cannot currently explain the existing clinical variation and as a result, translate into suboptimal therapy. Multifactorial involvement is hypothesized, with an implication of genetic mutations, microbiome dysbiosis, cytokine upregulation and environmental factors. Clinical observation is fundamental for diagnosis, however, the marked heterogeneity in presentation leads to delays in detection and challenges in treatment selection, showcasing clear limits in defining the link between genetic aspects of HS, the role of epigenetic factors and its pathogenic pathways. There have been attempts to formulate phenotypes that could aid in prognostication and management, however, current classification schemata show significant overlap and no validation through longitudinal studies. In this context, nomenclature poses a great challenge due to the lack of global agreement in the definition of lesions, which should be addressed by future research to enable simplified recognition and allow for more precise severity scoring. This could be complemented by the addition of extra dermatologic findings or paraclinical assessment in constructing phenotypes. The development of valid, predictive and reliable classifications of HS may lead to an improvement in comprehending its pathophysiology, favouring a more personalized approach in management. This could be achieved through consensus in the characterization of clinical features and data gathering, as well as validation attempts for described phenotypes. Ultimately, the genotype-endotype-phenotype correlation in HS requires targeted, systematic inquiries and should be addressed more largely to broaden the perspective on this debilitating entity.


Loss of heterozygosity analysis in ductal lavage samples from BRCA1 and BRCA2 carriers: a cautionary tale.
Loss of heterozygosity (LOH) in breast ductal lavage (DL) fluid has been reported to be a potential biomarker of malignant change. Interpretation of LOH is reliant on sufficient quality and quantity of DNA. We investigated LOH of the BRCA1/2 loci in DL samples from BRCA1/2 mutation carriers, while also assessing the effect of DNA quantity. DNA yield was estimated using quantitative real-time PCR. Allelic status of DL DNA was determined using fluorescently tagged microsatellite markers with the subject's lymphocytic DNA serving as a control. Samples were scored as consistently heterozygous or as demonstrating LOH if the same result was observed in replicate experiments. Additionally, samples were scored as "discordant LOH" if they initially showed LOH, but in replicate experiments either showed heterozygosity or LOH of the opposite allele. In 11 BRCA1 carriers, 46 ducts were assessable, and 39 ducts from 14 BRCA2 carriers were assessable. LOH was observed in 17% and 18% of ducts from BRCA1 and BRCA2, respectively. Discordant results were seen in 23 BRCA1 (50%) and 15 BRCA2 (38%) samples. DNA yield was significantly greater in samples that were consistently heterozygous than those that were either discordant or showed LOH in replicate experiments for both BRCA1 (P = 0.003) and BRCA2 (P = 0.003). DNA quantity is highly variable between DL samples, with low yields likely to detrimentally affect the interpretation of LOH. In conclusion, LOH may not be an adequate method to detect the early stages of malignant change in samples obtained via DL.


Republished paper: Determinants of child health and development: the contribution of ALSPAC--a personal view of the birth cohort study.
Britain has a unique experience of national longitudinal birth cohorts, but the Avon Longitudinal Study of Parents and Children differed in two major respects-it was based in one area rather than being a national sample, and it started in pregnancy rather than at birth or later in the first year. This paper outlines a personal selection of 10 topics, highlighting results from some of the 400+ papers that have already been published from this study. It indicates in particular how many childcare and domestic fashions were neither of benefit to the children (or their parents), the importance of pregnancy in regard to childhood conditions and the likely dangers of some common chemicals, whether in medications or domestic products.


Here comes the SUN: Self-assessed unmet need, worsening health outcomes, and health care inequity.
Utilization-based approaches have predominated the measurement of socioeconomic-related inequity in health care. This approach, however, can be misleading when preferences over health and health care are correlated with socioeconomic status, especially when the underlying focus is on equity of access. We examine the potential usefulness of an alternative approach to assessing inequity of access using a direct measure of possible barriers to access-self-reported unmet need (SUN)-which is documented to vary with socioeconomic status and is commonly asked in health surveys. Specifically, as part of an assessment of its external validity, we use Canadian longitudinal health data to test whether self-reported unmet need in one period is associated with a subsequent deterioration in health status in a future period, and find that it is. This suggests that SUN does reflect in part reduced access to needed health care, and therefore may have a role in assessing health system equity as a complement to utilization-based approaches.


[Role of thyroid system in adaptation to cold].
Adaptation to cold promotes an increase in blood T3 and T4 levels in men and animals. The long-term cold exposure can induce a decrease in concentration of serum total and free T3 in human due to an enhancement of this hormone clearance. Endogenous catecholamines during adaptation to cold raise iodothyronine deiodinase D2 activity in brown fat due to α1-adrenergic receptor stimulation. Triiodothyronine is an inductor of iodothyronine deiodinase expression in brown fat, liver and kidney. Iodothyronine deiodinase D2 plays an important role in adaptation of organism to cold contributing to the high adrenergic reactivity of brown fat. At adaptation to cold T3 interacts with T3Rβ, it is formed T3Rβ-RXR complex, which binds to DNA with following transcription of UCP-1 and UCP-3 genes and UCP-1 and UCP-3 protein synthesis and uncoupling oxidative phosphorylation and an increase in heat production, where T3Rβ is T3-receptor-β, RXR is retinoid X-receptor, UCP is uncoupling protein. Triiodothyronine contributes to normal response to adrenergic agents of brown fat due to T3Rα activation. Sympatho-adrenomedullary and thyroid systems act as synergists in adaptation to cold.


The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression.
Senescence is a crucial player in several metabolic disorders and chronic inflammatory diseases. Recent data prove the involvement of hepatocyte senescence in the development of NAFLD (non-alcoholic fatty liver disease). As the main energy and ROS (reactive oxygen species) producing organelle, mitochondria play the central role in accelerated senescence and diseases development. In this review, we focus on the role of regulation of mitochondrial Ca2+ homeostasis, NAD+/NADH ratio, UPRmt (mitochondrial unfolded protein response), phospholipids and fatty acid oxidation in hepatic senescence, lifespan and NAFLD disease susceptibility. Additionally, the involvement of mitochondrial and nuclear mutations in lifespan-modulation and NAFLD development is discussed. While nuclear and mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) can be used as effective diagnostic markers and targets for treatments, advanced age should be considered as an independent risk factor for NAFLD development.