Antioxidant and hepatoprotective potential of essential oils of coriander (Coriandrum sativum L.) and caraway (Carum carvi L.) (Apiaceae).
Essential oils of Coriandrum sativum L. and Carum carvi L. fruits were analyzed by gas chromatography-mass spectrometry and assayed for their in vitro and in vivo antioxidant activity and hepatoprotective effect against carbon tetrachloride (CCl(4)) damage. The in vitro antioxidant activity was evaluated as a free radical scavenging capacity (RSC), measured as scavenging activity of the essential oils on 2,2-diphenyl-1-picrylhydrazyl (DPPH(*)) and OH radicals and effects on lipid peroxidation (LP) in two systems of induction. Some liver biochemical parameters were determined in animals pretreated with essential oils and later intoxicated with CCl(4) to assess in vivo hepatoprotective effect. Tested essential oils were able to reduce the stable DPPH(*) in a dose-dependent manner and to neutralize H(2)O(2), reaching 50% neutralization with IC(50) values of <2.5 microL/mL for Carvi aetheroleum and 4.05 microL/mL for Coriandri aetheroleum . Caraway essential oil strongly inhibited LP in both systems of induction, whereas coriander essential oil exhibited prooxidant activity. In vivo investigation conferred leak of antioxidative capacity of coriander essential oil, whereas the essential oil of caraway appeared promising for safe use in folk medicine and the pharmaceutical and food industries.


Physiological and morphological characterization of honeybee olfactory neurons combining electrophysiology, calcium imaging and confocal microscopy.
The insect antennal lobe is the first brain structure to process olfactory information. Like the vertebrate olfactory bulb the antennal lobe is substructured in olfactory glomeruli. In insects, glomeruli can be morphologically identified, and have characteristic olfactory response profiles. Local neurons interconnect glomeruli, and output (projection) neurons project to higher-order brain centres. The relationship between their elaborate morphology and their physiology is not understood. We recorded electrophysiologically from antennal lobe neurons, and iontophoretically injected a calcium-sensitive dye. We then measured their spatio-temporal calcium responses to a variety of odours. Finally, we confocally reconstructed the neurons, and identified the innervated glomeruli. An increase or decrease in spiking frequency corresponded to an intracellular calcium increase or decrease in the cell. While intracellular recordings generally lasted between 10 and 30 min, calcium imaging was stable for up to 2 h, allowing a more detailed physiological analysis. The responses indicate that heterogeneous local neurons get input in the glomerulus in which they branch most strongly. In many cases, the physiological response properties of the cells corresponded to the known response profile of the innervated glomerulus. In other words, the large variety of response profiles generally found when comparing antennal lobe neurons is reduced to a more predictable response profile when the innervated glomerulus is known.


Extracephalic stabbing pain temporally related to cephalic ones.
A 23-year-old woman consulted with the complaint of short-lasting, severe stabbing headaches and mild-to-moderate degree near-daily migrainous headaches. Further questioning revealed that she also had stabbing pain on both ipsilateral hand and calf. Stabs on the hand were time-locked to cephalic ones and stabs in the calf were alternating with the ones in the hand. Dizziness and scotomas were accompanying symptoms to cephalic ones and paresthesia was the accompanying symptom in the hand. Patient's cephalic and extracephalic stabbing pains responded to indomethacine and daily headaches responded to prophylactic sodium valproate therapy. The stabs were felt in the head; hand and calf are considered as the parts of a whole. Along with its accompanying symptoms, stabbing pain may be the result of complex interactions in central nervous system.


Bleeding complications during cardiac electronic device implantation in patients receiving antithrombotic therapy: is there any value of local tranexamic acid?
The perioperative use of antithrombotic therapy is associated with increased bleeding risk after cardiac implantable electronic device (CIED) implantation. Topical application of tranexamic acid (TXA) is effective in reducing bleeding complications after various surgical operations. However, there is no information regarding local TXA application during CIED procedures. The purpose of our study was to evaluate bleeding complications rates during CIED implantation with and without topical TXA use in patients receiving antithrombotic treatment. We conducted a retrospective analysis of consecutive patients undergoing CIED implantation while receiving warfarin or dual antiplatelet (DAPT) or warfarin plus DAPT treatment. Study population was classified in two groups according to presence or absence of topical TXA use during CIED implantation. Pocket hematoma (PH), major bleeding complications (MBC) and thromboembolic events occuring within 90 days were compared. A total of 135 consecutive patients were identified and included in the analysis. The mean age was 60 ± 11 years old. Topical TXA application during implantation was reported in 52 patients (TXA group). The remaining 83 patients were assigned to the control group. PH occurred in 7.7 % patients in the TXA group and 26.5 % patients in the control group (P = 0.013). The MBC was reported in 5.8 % patients in the TXA and 20.5 % patients in control group (P = 0.024). Univariate logistic regression analysis identified age, history of recent stent implantation, periprocedural spironolactone use, periprocedural warfarin use, perioperative warfarin plus DAPT use, cardiac resynchronization therapy, and topical TXA application during CIED implantation as predicting factors of PH. Multivariate analysis showed that perioperative warfarin plus DAPT use (OR = 10.874, 95 % CI: 2.496-47.365, P = 0.001) and topical TXA application during CIED procedure (OR = 0.059, 95 % CI: 0.012-0.300, P = 0.001) were independent predictors of PH. Perioperative warfarin plus DAPT use and topical TXA application were also found to be independent predictors of MBC in multivariate analyses. No thromboembolic complications was recorded in the study group. The present study demonstrated that the topical TXA application during CIED implantation is associated with reduced PH and MBC in patients with high bleeding risk.


Exact interior reconstruction with cone-beam CT.
Using the backprojection filtration (BPF) and filtered backprojection (FBP) approaches, respectively, we prove that with cone-beam CT the interior problem can be exactly solved by analytic continuation. The prior knowledge we assume is that a volume of interest (VOI) in an object to be reconstructed is known in a subregion of the VOI. Our derivations are based on the so-called generalized PI-segment (chord). The available projection onto convex set (POCS) algorithm and singular value decomposition (SVD) method can be applied to perform the exact interior reconstruction. These results have many implications in the CT field and can be extended to other tomographic modalities, such as SPECT/PET, MRI.


Temperature of maximum density and excess properties of short-chain alcohol aqueous solutions: A simplified model simulation study.
We perform an extensive computational study of binary mixtures of water and short-chain alcohols resorting to two-scale potential models to account for the singularities of hydrogen bonded liquids. Water molecules are represented by a well studied core softened potential which is known to qualitatively account for a large number of water's characteristic anomalies. Along the same lines, alcohol molecules are idealized by dimers in which the hydroxyl groups interact with each other and with water with a core softened potential as well. Interactions involving non-polar groups are all deemed purely repulsive. We find that the qualitative behavior of excess properties (excess volume, enthalpy, and constant pressure heat capacity) agrees with that found experimentally for alcohols such as t-butanol in water. Moreover, we observe that our simple solute under certain conditions acts as a "structure-maker," in the sense that the temperature of maximum density of the bulk water model increases as the solute is added, i.e., the anomalous behavior of the solvent is enhanced by the solute.


Genetic and environmental determinants of peak bone mass in young men and women.
Peak bone mass is an important risk factor for the development of osteoporosis in later life. Previous work has suggested that genetic, intrauterine, and environmental factors all contribute to the regulation of bone mass, but the ways in which they interact with each other to do so remain poorly understood. In this study, we investigated the relationship between peak bone mass and polymorphisms of the vitamin D receptor (VDR), estrogen receptor (ER) a, and collagen type Ialpha1 (COLIA1) genes in relation to other factors such as birth weight, lifestyle diet, and exercise in a population-based cohort of 216 women and 244 men in their early 20s. Stepwise multiple regression analysis showed that body weight was the strongest predictor of bone mineral density (BMD) in women, accounting for 16.4% of the variance in spine BMD and 8.4% of the variance in femoral neck BMD. Other significant predictors were VDR genotype (3.8%) and carbohydrate intake (1.6%) at the spine and vitamin D intake (3.4%) and ER genotype (3.4%) at the femoral neck. Physical activity was the strongest predictor of BMD in men, accounting for 6.7% of the variance at the spine and 5.1% at the hip. Other significant predictors were body weight (5%) and ER PvuII genotype (2.8%) at the spine and weight (3.4%) and alcohol intake (2%) at the femoral neck. Birth weight was not a significant predictor of BMD at either site but COLIA1 genotype significantly predicted birth weight in women, accounting for 4.3% of the variance. We conclude that peak bone mass is regulated by an overlapping but distinct set of environmental and genetic influences that differ in men and women. However, much of the variance in BMD was unexplained by the variables studied here, which suggests that either most of the genes that regulate BMD remain to be discovered or major environmental influences on BMD exist that have not yet been identified.


Denosumab biosimilar in postmenopausal osteoporotic women: A randomized, assessor-blind, active-controlled clinical trial.
The study assessed the efficacy, safety, pharmacokinetic (PK), and immunogenicity profiles of denosumab-biosimilar and denosumab-reference in postmenopausal osteoporotic women from India. In this randomized, assessor-blind, active-control, multicenter trial, 114 patients were randomly allocated to receive denosumab-biosimilar (n = 58) or denosumab-reference (n = 56) at a subcutaneous dose of 60 mg every 6 months, for a year. Vitamin D and oral calcium were given daily. Lumbar spine bone mineral density (BMD) change was the primary end point. Of 114 randomized patients, 111 (denosumab-biosimilar, n = 56; denosumab-reference, n = 55) completed the study. All 114 patients were part of safety and immunogenicity analyses, 110 (denosumab-biosimilar, n = 56; denosumab-reference, n = 54) were part of efficacy analysis, and 20 (denosumab-biosimilar, n = 10; denosumab-reference, n = 10) were part of PK analysis. The bone mineral density (BMD) (lumbar spine) percent change at 1 year with denosumab-biosimilar and denosumab-reference (7.22 vs. 7.62; difference:-0.40; 95% confidence interval: -5.92, 5.12) showed no statistically relevant difference. Likewise, alkaline phosphatase (bone-specific) and PK parameters also did not show statistically relevant differences. Adverse events were reported in 44.83% of patients on denosumab-biosimilar versus 33.93% of patients on denosumab-reference; most events were mild or moderate and not related to the study drugs. No patients showed anti-denosumab antibody positivity. Denosumab-biosimilar and denosumab-reference showed biosimilarity in osteoporotic postmenopausal women. Availability of denosumab-biosimilar provides a treatment alternative for patients.


Overnight 1-mg Dexamethasone Suppression Test for Screening Cushing Syndrome and Mild Autonomous Cortisol Secretion (MACS): What Happens when Serum Dexamethasone Is Below Cutoff? How Frequent Is it?
To determine the frequency of "invalid" 1-mg overnight dexamethasone (Dex) suppression tests (DSTs) (1-mg DST) on a large series of patients investigated for hypercortisolism and examine the interference of substances and clinical conditions that may explain low serum Dex levels. A retrospective analysis of 1300 Dex-controlled 1-mg DST applied to patients screened for Cushing syndrome or mild autonomous cortisol secretion in a single center for which there were identified invalid tests and distinctive characteristics that may have interfered with the outcome. Among all tests, 146 (11.2%) were considered invalid (serum Dex levels <140 ng/dL, 36 [24.7%] of which were undetectable [<19.5 ng/dL]). In the Dex-undetectable group, 17% failed to take Dex correctly, 25% were on glucocorticoids (GCs), and 20% were on anticonvulsants and moderate CYP3A4 inducers. In the remaining 110 tests (serum Dex 20-140 ng/dL), 6.5% did not take Dex or were using GC, 22% were on anticonvulsants or CYP3A4 inducers, and another 13% had previous gastrointestinal tract abnormalities impairing drug absorption. Inappropriately low serum Dex levels during the 1-mg DST may lead to false-positive results. This is associated with recurrent use of CYP3A4-inducing drugs and/or gastrointestinal abnormalities. When serum Dex is undetectable, the key reason is failure to take the medication or the use of GC (when cortisol is suppressed). Simultaneous measurement of serum cortisol and Dex allows for DST validation, improving its accuracy and avoiding unnecessary repetitions. Adherence to verbal/written recommendations and actual use of medication are critical for interpreting the test.


[The effect of an invasion by Trichinella spiralis and Trichinella pseudospiralis on the ultrastructure of skeletal muscle tissue in the white mouse].
The ultrastructure of striated muscular tissue was studied in experiments with three groups of white mice: those infected with T. spiralis, T. pseudospiralis, and in those uninfected (controls). There was a heterogeneity of changes in the striated muscular tissue during 35-day infection. Deep damages to the contractile, trophic, energetic, supporting, and membranous apparatuses of muscle fibers are responsible for subcellular structural changes. At the same time compensatory and adaptative processes that reflect the hyperfunction of musculoskeletal tissue develop. Generally, T. spiralis causes focal ultrastructural changes while T. pseudospiralis induces diffuse ones.


Cannabidiol affects the expression of genes involved in zinc homeostasis in BV-2 microglial cells.
Cannabidiol (CBD) has been shown to exhibit anti-inflammatory, antioxidant and neuroprotective properties. Unlike Δ(9)-tetrahydrocannabinol (THC), CBD is devoid of psychotropic effects and has very low affinity for both cannabinoid receptors, CB(1) and CB(2). We have previously reported that CBD and THC have different effects on anti-inflammatory pathways in lipopolysaccharide-stimulated BV-2 microglial cells, in a CB(1)/CB(2) independent manner. Moreover, CBD treatment of BV-2 cells, was found to induce a robust change in the expression of genes related to oxidative stress, glutathione deprivation and inflammation. Many of these genes were shown to be controlled by Nrf2 and ATF4 transcription factors. Using the Illumina MouseRef-8 BeadChip platform, DAVID Bioinformatics and Ingenuity Pathway Analysis, we identified functional sets of genes and networks affected by CBD. A subset of genes was found to be regulated by the metal responsive element (MRE)-binding transcription factor-1 (MTF-1) and is shown to be related to zinc homeostasis. We found that CBD upregulates the expression of the mRNAs for metallothionein 2 (Mt2), N-myc-downstream regulated gene 1 and matrix metalloproteinase 23 as well as of the zinc transporters ZnT1/Slc30a1 and Zip4/Slc39a4 but downregulates the expression of the mRNA for the zinc transporter Zip10/Slc39a10 as well as for the zinc finger protein 472. Among these genes, ZnT1, Mt2 and the zinc transporters ZIPs are known to function together to control the intracellular zinc concentration. These results show that CBD, but much less so THC, affects the expression of genes involved in zinc homeostasis and suggest that the regulation of zinc levels could have an important role through which CBD may exert its antioxidant and anti-inflammatory effects.


Potassium-channel blockers inhibit inositol trisphosphate-induced calcium release in the microsomal fractions isolated from the rat brain.
The ionic mechanism of inositol trisphosphate (InsP3)-induced Ca2+ release was investigated in microsomes (microsomal fractions) isolated from rat brain. InsP3 stimulated Ca2+ release from microsomes incubated in media containing 100 mM-KCl. The InsP3-induced Ca2+ release was insensitive to a variety of Ca2+-channel blockers; however, the K+-channel blockers tetraethylammonium chloride (TEA; 1 mM) and 9-tetraethylammonium chloride (9-TEA; 1 mM) blocked InsP3-induced Ca2+ release. Moreover, addition of InsP3 increased 86Rb+ influx into the microsomes. The influx of 86Rb+ also was sensitive to TEA and 9-TEA. The above results suggest that InsP3-induced Ca2+ release requires an opposite flow of K+ ions, and modulation of K+ channels by TEA and 9-TEA may underlie the inhibition of InsP3-induced Ca2+ release from brain microsomes by these agents.


Panmixia across elevation in thermally sensitive Andean dung beetles.
Janzen's seasonality hypothesis predicts that organisms inhabiting environments with limited climatic variability will evolve a reduced thermal tolerance breadth compared with organisms experiencing greater climatic variability. In turn, narrow tolerance breadth may select against dispersal across strong temperature gradients, such as those found across elevation. This can result in narrow elevational ranges and generate a pattern of isolation by environment or neutral genetic differentiation correlated with environmental variables that are independent of geographic distance. We tested for signatures of isolation by environment across elevation using genome-wide SNP data from five species of Andean dung beetles (subfamily Scarabaeinae) with well-characterized, narrow thermal physiologies, and narrow elevational distributions. Contrary to our expectations, we found no evidence of population genetic structure associated with elevation and little signal of isolation by environment. Further, elevational ranges for four of five species appear to be at equilibrium and show no decay of genetic diversity at range limits. Taken together, these results suggest physiological constraints on dispersal may primarily operate outside of a stable realized niche and point to a lower bound on the spatial scale of local adaptation.


Methods for improving the properties of zinc for the application of biodegradable vascular stents.
Biodegradable stents can support vessels for an extended period, maintain vascular patency, and progressively degrade once vascular remodeling is completed, thereby reducing the constraints of traditional metal stents. An ideal degradable stent must have good mechanical properties, degradation behavior, and biocompatibility. Zinc has become a new type of biodegradable metal after magnesium and iron, owing to its suitable degradation rate and good biocompatibility. However, zinc's poor strength and ductility make it unsuitable as a vascular stent material. Therefore, this paper reviewed the primary methods for improving the overall properties of zinc. By discussing the mechanical properties, degradation behavior, and biocompatibility of various improvement strategies, we found that alloying is the most common, simple, and effective method to improve mechanical properties. Deformation processing can further improve the mechanical properties by changing the microstructures of zinc alloys. Surface modification is an important means to improve the biological activity, blood compatibility and corrosion resistance of zinc alloys. Meanwhile, structural design can not only improve the mechanical properties of the vascular stents, but also endow the stents with special properties such as negative Poisson 's ratio. Manufacturing zinc alloys with excellent degradation properties, improved mechanical properties and strong biocompatibility and exploring their mechanism of interaction with the human body remain areas for future research.


Sudden unexpected death of a young adult due to subarachnoid hemorrhage associated with polyarteritis nodosa: Clinicopathological appearance and literature review.
A 28-year-old male was found dead in his bedroom. There were no anomalies in his birth and medical history, and there was no family history of sudden unexpected death (SUD). Autopsy showed subarachnoid hemorrhage (SAH) with basilar top inflammatory pseudoaneurysm rupture accompanied by fibrinoid necrosis in the aneurysm wall. Active and healed arteritides in small- to medium-sized arteries were identified in the brain, heart, and systemic connective tissue, which was consistent with polyarteritis nodosa (PAN). Furthermore, pneumatosis cystoides intestinalis was observed in the ascending colon. Hepatitis B virus infection and anti-neutrophil nuclear antibodies were negative. Genetic investigation using whole-exome sequencing showed no mutations among autoinflammatory-related genes, including UBA1, MEFV, and ADA2. SAH due to rupture of a pseudoaneurysm formed by PAN was considered as the cause of death in the present case. Although myocardial ischemia linked to coronary arteritis is a recognized trigger for SUD in PAN, our study showed that rupture of inflammatory pseudoaneurysm in the cerebral artery can also cause SUD in younger subjects with PAN, even if prodromal symptoms are not evident before death.


A re-examination of late outward plateau currents of cardiac Purkinje fibers.
Two outward currents, IX1 and IX2, are thought to be activated by depolarization of the Purkinje fiber. One of these, IX1, is presently believed to play a critical role in repolarization of the action potential. The IX currents were originally analyzed in voltage-clamp experiments in sheep Purkinje fibers. These experiments were designed to minimize interference by other currents, and it was assumed that changes of the net current were produced entirely by the IX currents. We have tried to repeat the original experiments and the analysis that led to acceptance of the existence and roles of the IX currents, without success. Moreover, tests of how membrane current should behave if the IX current hypothesis is correct did not give satisfactory results. Our data suggest the original conclusions about IX1 and IX2 may need substantial revision.


[Study of nucleic acid synthesis in rat embryos in relation to phase-specific characteristics of teratogenic effect of chloridine].
The maximal rate of incorporation of 32P-phosphate, 14C-formate and 14C-thymidine in DNA was recorded on the 13th day of development in the rat embryos and that of 14C-formate and 32P-phosphate in RNA and nucleotides of the acid-soluble fraction on the 12th day. The maximal incorporation of 14C-formate was recorded later: on the 15-16th days. Chloridin inhibited the incorporation of 14C-formate in DNA at all developmental stages, irrespective of the sensitivity of embryos to its teratogenic effect. The period of the maximal rate of DNA synthesis coincides with that of highest teratogenic activity of the drug. A suggestion is put forward to the effect that quantitative differences in the intensity of DNA synthesis at different stages of organgenesis provide one of the main causes of differential sensitivity of embryos to the teratogenic effect of inhibitors of nucleic acid synthesis.


Structural Composition and Diversity of Bacterial Communities in High- and Low-Yielding Moso Bamboo Forests.
Bacterial communities play an important role in helping plants absorb nutrients, promoting plant development, and preventing diseases. Moso bamboo (Phyllostachys edulis [Carriere] J. Houzeau) has a long history of cultivation and important economic value. In this study, high-throughput sequencing technology was utilized to analyze the differences in the diversity of endophytic and root zone soil bacterial communities between high-yielding (HY) and low-yielding (LY) P. edulis forests in subtropical China. Notably, the soil conditions and bacterial communities in Yong'an (YA) and Jiangle (JL) differed, but the bacterial community structures in the root zone soil of both regions were similar with the dominant bacterial phyla composed of Proteobacteria, Acidobacteriota, and Actinobacteriota. The Chao1 and Shannon indices of the root zone soil and endophytic bacterial communities in the LY were higher than those in the HY. Moreover, the bacterial community structures of HY and LY were significantly different. Notably, the relative abundances of Actinobacteriota, Myxococcota, and Cyanobacteria were higher in the HY soil samples. The bacterial community differences between the tissues and root zone soil of HY and LY indicated that healthy HY P. edulis plants were enriched with specific bacterial communities, suggesting associations between yield and both endophytic and root zone soil bacterial communities. The findings of this study provide a basis to regulate artificial bacterial communities to benefit the future cultivation of HY P. edulis.


Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression.
Expression of intercellular adhesion molecule-1 (ICAM-1) is necessary for leukocyte/keratinocyte interactions. Upregulation of ICAM-1 expression in keratinocytes has been observed in several inflammatory dermatoses, such as psoriasis, atopic dermatitis, and lupus erythematosus. Inflammatory cytokines, such as interferon-gamma (IFN-gamma), upregulate ICAM-1 expression in keratinocytes. Because of potent antioxidant and anti-inflammatory properties of the French maritime pine bark extract, Pycnogenol (Horphag Research, Geneva, Switzerland), its effects were investigated on the interaction of T cells with keratinocytes after activation with IFN-gamma and the molecular mechanisms involved in such interactions. Studies were performed using a human keratinocyte cell line, HaCaT. Cell adhesion in the presence of IFN-gamma was studied using a coculture assay. Treatment of HaCaT cells with 20 U/ml IFN-gamma for 24 h markedly induced adherence of Jurkat T cells to HaCaT cells. PYC pretreatment (50 microg/ml, 12 h) significantly inhibited IFN-gamma induced adherence of T cells to HaCaT cells (p < .01). ICAM-1 plays a major role in the IFN-gamma-induced adherence of T cells to keratinocytes. Thus, the effect of PYC on IFN-gamma-induced ICAM-1 expression was investigated as well. Pretreatment of HaCaT cells with PYC significantly inhibited IFN-gamma-induced expression of ICAM-1 expression in HaCaT cells. The downregulation of inducible ICAM-1 expression by PYC was both dose and time dependent. A 50 microg/ml dose of PYC and a 12 h pretreatment time (i.e., before activation with IFN-gamma) provided maximal (approximately 70%) inhibition of inducible ICAM-1 expression in HaCaT cells. Gamma-activated sequence present on the ICAM-1 gene confers IFN-gamma responsiveness in selected cells of epithelial origin (e.g., keratinocytes) that are known to express ICAM-1 on activation with IFN-gamma. Gel-shift assays revealed that PYC inhibits IFN-gamma-mediated activation of Stat1, thus suggesting a transcriptional regulation of inducible ICAM-1 expression by PYC. These results indicate the therapeutic potential of PYC in patients with inflammatory skin disorders.


An SVD Investigation of Modeling Scatter in Multiple Energy Windows for Improved SPECT Images.
In this work singular value decomposition (SVD) techniques are used to investigate how the use of low energy photons and multiple energy windows affects the noise properties of Tc-99m SPECT imaging. We have previously shown that, when modeling scatter in the projector and backprojector of iterative reconstruction algorithms, simultaneous reconstruction from multiple energy window data can result in very different noise characteristics. Further, the properties depend upon the width and number of energy windows used. To investigate this further, we have generated photon transport matrices using models for scatter, an elliptical phantom containing cold rods of various sizes, and a number of multiple energy window acquisition schemes. Transfer matrices were also generated for the cases of perfect scatter rejection and ideal scatter subtraction. The matrices were decomposed using SVD, and signal power and projection space variance spectra were computed using the basis formed by the left singular vectors. Results indicate very different noise levels for the various energy window combinations. The perfect scatter rejection case resulted in the lowest variance spectrum, and reconstruction-based scatter compensation performed better than the scatter subtraction case. When including lower energy photons in reconstruction-based scatter compensation, using a series of multiple energy windows outperformed a single large energy window. One multiple window combination is presented which achieves a lower variance spectrum than the standard 20% energy window, indicating the potential for using low energy photons to improve the noise characteristics of SPECT images.


Corrections and clarifications.
The last two sentences of the second paragraph of the report by Peter R. Buseck et al. (10 July, p. 215) should have read, "We subsequently confirmed the presence of C(60) and C(70) by mass spectrometry. They occur within fracture-filling films in shungite, an unusual carbonaceous rock found near the town of Shunga in Karelia, Russia."


Anion Recognition Triggered Nanoribbon-Like Self-Assembly: A Fluorescent Chemosensor for Nitrate in Acidic Aqueous Solution and Living Cells.
A water-soluble π-conjugated bispyridinium phenylenevinylene-based fluorogenic probe has been developed as a novel fluorescent chemosensor for highly selective, sensitive, and rapid detection of NO3(-) anion in acidic aqueous media. This system self-assembles to a nanoribbon as a result of ionic interaction. The positively charged chemosensor generates a nearly instantaneous significant fluorescence signal (475 vs 605 nm) in response to NO3(-) in the green/yellow spectral region, with a large Stokes shift (130 nm). The fluorescence changes can be attributed to the self-aggregation of the sensor triggered by ionic interaction, which occurs as a consequence of the subtle cooperation of electrostatic ionic bonding, van der Waals forces, and π-stacking of the π-conjugated aromatic moieties. Importantly, this chemosensor has been employed for the first time for the fluorescence detection of intracellular NO3(-) anion in cultured cells.


Quantum phase transitions in skewed ladder systems.
In this brief review, we introduce a new spin ladder system called skewed spin ladders and discuss the exotic quantum phases of this system. The spin ladders studied are the 5/7, 3/4 and 3/5 systems corresponding to alternately fused 5 and 7 membered rings; 3 and 4 membered rings; and 3 and 5 membered rings. These ladders show completely different behaviour as the Hamiltonian model parameter is changed. When the Hamiltonian parameter is increased the 5/7 ladder switches from an initial singlet ground state to progressively higher spin ground state and then to a reentrant singlet state before finally settling to the highest spin ground state whose spin equals the number of unit cells in the system. The 3/4 ladder goes from a singlet ground state to a high spin ground state with each unit cell contributing spin 1 to the state, as the model parameter is increased. The 3/5 ladder shows a singlet ground state for small parameters and high spin ground state for intermediate values of the parameter and for still higher parameters, a reentrant singlet ground state. They can also show interesting magnetization plateaus as illustrated by studies on a specific spin ladder.


[Changes in subunit composition of lactate dehydrogenase at low temperatures].
Hybridization of M4- and H4-isoenzymes of lactate dehydrogenase in saline medium was studied during slow freezing down to -9.5; -23 and -30 degrees C. It is established that appearances of the enzyme hybrid forms is associated with free water freezing out and with an increase in the concentration of salts in the solution. No hybridization was observed under fast cooling of the enzyme down to -196 degrees C, under exposition in the concentrated solution of chloride and sodium phosphate without freezing and with freezing in deionized water. The mechanism of low-temperature hybridization of lactate dehydrogenase, based on concentration effects of salts which favour dissociation of a protein molecule into subunits, are under discussion. An assumption is advanced on an intensification of intermolecular interactions in liquid microphases of the frozen solution as a possible reason of the subunits recombination into hybrid isoenzymes.


The effectiveness of real-time PCR assay, compared with microbiologic results for the diagnosis of pulmonary tuberculosis.
The incidence of tuberculosis (TB) in Korea is relatively high compared to the other Organisation for Economic Co-operation and Development (OECD) countries, with a prevalence of 71 per 100,000 in 2012, although the incidence is declining. Real-time polymerase chain reaction (PCR) has been introduced for the rapid diagnosis of TB. Recently, its advantage lies in higher sensitivity and specificity for the diagnosis of TB. This study evaluated the clinical accuracy of real-time PCR using respiratory specimens in a clinical setting. Real-time PCR assays using sputum specimens and/or bronchoscopic aspirates from 2,877 subjects were reviewed retrospectively; 2,859 subjects were enrolled. The diagnosis of TB was determined by positive microbiology, pathological findings of TB in the lung and pleura, or clinical suspicion of active TB following anti-TB medication for more than 6 months with a favorable response. Sensitivity, specificity, and accuracy were 44%, 99%, and 86% from sputum, and 65%, 97%, and 87% from bronchoscopic aspirates, respectively. For overall respiratory specimens, sensitivity was 59%, specificity was 98%, and accuracy increased to 89%. Positivity in real-time PCR using any respiratory specimens suggests the possibility of active TB in clinically suspected cases, guiding to start anti-TB medication. Real-time PCR from selective bronchoscopic aspirates enhances the diagnostic yield much more when added to sputum examination.


Telemedicine for post-myocardial infarction patients: an observational study.
"SHL" Telemedicine (established 1987 in Israel) provides professional care to subscribers who use cardiobeepers and contact its medical call center via telecommunication networks. The extended 6-month Acute Coronary Syndrome Israel Survey (ACSIS) 2004 involved all 26 intensive cardiac care units in Israeli hospitals. We compared the 1-year survival rates of the "SHL" Telemedicine subscribers and ACSIS participants who survived hospitalization after sustaining an acute myocardial infarction. The myocardial infarction data for the ACSIS cohort (3,899 patients) and the SHL Telemedicine cohort (699 subscribers) were provided for this study by the ACSIS executive and SHL's files, respectively. One-year mortality was ascertained by telephone contacts with patients or their relatives. Mortality at 1 year was 4.4% for the "SHL" patients and 9.7% for the ACSIS patients (p < 0.0001). The "SHL" cohort was significantly older (p < 0.0001) than the ACSIS cohort (mean age [+/-SD] 69 +/- 11 versus 63 +/- 13 years), had significantly more past myocardial infarctions (p < 0.001), more past strokes (p < 0.0032), more heart failure (p < 0.0001), more hypertension (p = 0.002), and more hyperlipidemia (p < 0.0001). Gender distribution and diabetes status were similar for both groups. In spite of having more risk factors than the ACSIS subjects, the "SHL" Telemedicine subscribers had significantly higher survival rates at 1 year compared to the ACSIS patients, whose outcome is consistent with that of the Western world. Availability of medical call centers in the out-of-hospital setting for patients with suspected cardiac symptoms improves their motivation to seek timely and appropriate medical assistance.


Evidence of endoplasmic reticulum stress mediating cell death in transplanted human islets.
A key limitation to the success of islet transplantation is islet cell exhaustion and cell death during islet isolation and following transplantation. Endoplasmic reticulum (ER) stress has been identified as an important mechanism in the development of β-cell dysfunction, cell death, and diabetes. This study investigated the role of ER stress in islet loss during human islet isolation and posttransplantation in a diabetic athymic mouse model. Islets were isolated from human organ donor pancreata using intraductal enzymatic dissociation and continuous density gradient purification. ER stress mediators were assessed by Western blot and by RT-PCR. Caspase-3 activity was quantified by a bioluminescent peptide cleavage assay. Normal and streptozotocin-treated diabetic nude mice were transplanted with 2,000 IEQ of human islets under the kidney capsule and the grafts were harvested 3 or 28 days after transplantation. The grafts were analyzed for the presence for ER stress signals by immunohistochemistry. Isolated islets demonstrated higher levels of ER chaperone Bip, ER stress mediators eIF2α, ATF, spliced XBP-1, and CHOP, and also ER stress-associated apoptotic signals like JNK, caspase-3/7, and cleaved PARP. Donor pancreatic tissue did not show expression of any of these ER stress mediators. After transplantation, low expression of only protective ER stress mediators was evident in the grafts from the normal recipients. In contrast, both protective and apoptotic ER stress mediators were highly expressed in the grafts of hyperglycemic mice. ER stress mediators were induced during islet isolation and may contribute to islet apoptosis and cell death. Islet isolation activates ER stress and apoptotic pathways in isolated islets. Hyperglycemia may prolong this ER stress signal in engrafted islets, converting the protective aspects of the ER stress response to a proapoptotic response and thus contribute to deterioration of β-cell function and survival.


Milk progesterone profiles in various reproductive states in dairy buffaloes under field conditions.
Fifty-one dairy buffaloes in the last two months of gestation were selected at seven private peri-urban farms in the Peshawar district. Observations were recorded in buffaloes during normal (NBS, August to January) and low breeding seasons (LBS, February to July). After parturition, rectal examination of reproductive organs was carried out. Estrus detection was made through visual observation and the use of intact bull. Postpartum ovulation was confirmed by ovarian palpation per rectum and milk progesterone levels (MPL), determined through radio-immunoassay. MPL was higher (p < 0.01) at various intervals in NBS calves (1.97 +/- 0.30 ng/ml) as compared to LBS calves (0.68 +/- 0.08 ng/ml). During LBS, MPL remained < 0.30 ng/ml up to the third fortnight and started rising later, reaching a peak of 1.27 ng/ml during the sixth fortnight. During NBS, there was a sharp rise in MPL during the second fortnight, reaching 3.64 ng/ml during the sixth fortnight. MPL was significantly different on different experimental farms (p < 0.01). MPL reached the lowest levels on the day of estrus (0.10 ng/ml), reached it's peak on day 7 and started declining on day 17 of estrus. MPL showed two postpartum elevations. In true anestrus buffaloes, MPL remained consistently low. However, in the anestrus period, silent ovulations were also noted, as reflected by increasing MPL without estrus signs. In pregnant buffaloes, MPL remained > 1 ng/ml. Results of the study showed that the low postpartum reproductive performance in dairy buffaloes during LBS was primarily due to inadequate functioning of the corpus luteum in secreting optimum concentrations of progesterone. The higher incidence of silent estrus during LBS indicated improved management for the detection of estrus.


Gerontology research in Georgia.
Gerontology research carried out in different scientific centers of Georgia follows the basic directions of most work in this field: epidemiology, investigation of the mechanisms of aging, and finding ways to prevent senile pathologies and to prolong life. The genealogy and epidemiology of long-living peaple have been studied in areas with high occurrence of these people by considering the sex ratio and social status of the long-living, the influence of environmental factors, and the development of senile pathologies. According to the centrosome (centriole) model of aging, the centrosomes and the cytoskeleton, important structures in cellular differentiation and morphogenesis, may be involved in the initiation of the replication senescence mechanism. Our analysis of genetic studies shows that progressive chromosome heterochromatinization (condensation of eu- and heterochromatin regions) occurs in aging. Decreases in the repair processes and increases in the frequency of chromosome aberrations during aging are secondary to this progressive chromosome heterochromatinization. Chromosome heterochromatinization is a key factor in aging but may be reversible under the influence of bioregulators, some chemical substances, and heavy metal salts. The study of chromosome heterochromatinization may provide clues to the potential for prolonging the human lifespan.


Lessons from history of socioeconomic improvements: a new approach to treating multi-drug-resistant tuberculosis.
This study investigated the trends in tuberculosis mortality through time in Switzerland. Information on the decline in mortality before chemotherapies were introduced may be useful in developing countries where drug-resistant tuberculosis is now becoming a major problem. Swiss data were collected from historical records and comparative data were obtained from the literature for England and Wales, New York, Japan, Brazil and Sierra Leone. Logistic curves were fitted to examine the rate of decline before introduction of pharmacotherapies and these show that the decline would have continued without the introduction of chemical therapies, including antibiotics. In Switzerland, England and Wales and New York, the decline had occurred long before the introduction of specific anti-tuberculosis agents. In Brazil and Japan, chemical therapy was co-incident with the decline in tuberculosis mortality rates. Overall, it is suggested that the effective control of tuberculosis can be achieved through a combination of chemical interventions, conservative therapy (rest, good nutrition, ventilation, etc.) as well as public health interventions addressing hygiene, nutrition, reducing exposure to infections and educating the population about tuberculosis.


Mutagenicity of tobacco snuff: possible health implications for coal miners.
Mutagenicity of tobacco snuff extracts was studied using the Ames Salmonella/microsome assay system. No mutagenic activity was found for tobacco snuff extracts without S9 activation. However, mutagenic substances were formed from tobacco snuff extracts in an acidic environment. The mutagenic substances induced predominantly frameshift mutations and were direct-acting mutagens. Mutagenic activity of tobacco snuff extracts was enhanced in the presence of coal-dust extracts at low pH. Since tobacco snuff has been used by some coal miners to substitute for cigarettes, a possible risk for gastric cancer induction among coal miners is proposed.


Empirical Bayes factor analyses of quantitative trait loci for gestation length in Iberian × Meishan F2 sows.
The aim of this study was to investigate chromosomal regions affecting gestation length in sows. An experimental F2 cross between Iberian and Meishan pig breeds was used for this purpose and we genotyped 119 markers covering the 18 porcine autosomal chromosomes. Within this context, we have developed a new empirical Bayes factor (BF) approach to compare between nested models, with and without the quantitative trait loci (QTL) effect, and after including the location of the QTL as an unknown parameter in the model. This empirical BF can be easily calculated from the output of a Markov chain Monte Carlo sampling by averaging conditional densities at the null QTL effects. Linkage analyses were performed in each chromosome using an animal model to account for infinitesimal genetic effects. Initially, three QTL were detected at chromosomes 6, 8 and 11 although, after correcting for multiple testing, only the additive QTL located in cM 110 of chromosome 8 remained. For this QTL, the allelic effect of substitution of the Iberian allele increased gestation length in 0.521 days, with a highest posterior density region at 95% ranged between 0.121 and 0.972 days. Although future studies are necessary to confirm if detected QTL is relevant and segregating in commercial pig populations, a hot-spot on the genetic regulation of gestation length in pigs seems to be located in chromosome 8.


Expression of hypoxia-regulated genes and glycometabolic genes in placenta from patients with intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder unique to pregnancy that is associated with increased rates of fetal distress and demise. While acute hypoxia is believed to cause the pathophysiology of ICP, direct molecular evidence for this is lacking. Here, we analyzed expression of three hypoxia-regulated genes and several of their downstream target genes involved in glucose metabolism in placenta. Placental tissue was collected from 20 women with normal pregnancies and 20 women with ICP. RNA and protein levels of hypoxia inducible transcription factors -1α (HIF-1α), development and DNA protein damage response 1 (REDD1), mammalian target of rapamycin (mTOR), glucose transporter type 1 (GLUT1), phosphoglycerate kinase1 (PGK1) and lacticdehydrogenase (LDHA) in placental tissue were measured by reverse transcriptase real time PCR and Western Blot. Proteins were also located by immunohistochemistry. Transcript levels were similar for all genes between the two types of placental tissue. In contrast, all protein levels except that of mTOR were significantly higher in placentas from ICP patients than the controls (P < 0.05). All proteins localized to the cytotrophoblast and syncytiotrophoblast. The placenta from ICP patients is more vulnerable to acute hypoxia and ischemia reperfusion injury. In response to hypoxia stress and oxidative damage in ICP, the placenta activates HIF-1α and REDD1, which in turn may up-regulates glucose transport and anaerobic glycolysis. HIF-1α, REDD1 and mTOR may play a significant role in the reaction to hypoxia and oxidative stress and regulate glucose metabolism in the placenta of ICP patients.


[Effect of a polyvalent proteinase inhibitor from the lungs of a bull on the state of the kinin system in burn shock and acute burn toxemia].
Effect of a polyvalent inhibitor of proteinases from bovine lungs (industrial preparation -- ingitrile, commercial grade -- conntrical) on the state of kinin system was studied in blood serum of patients with extensive burns at shock periods and in acute burn toxemia. Decrease in content of kallikreinogene, which is typical for shock and acute, toxemia and which reflects the activation of kallikrein-kinin system, was less distinct in patients, treated with the inhibitor, than in patients, which were not treated with ingitrile. The early and rapid restoration in kininogene content and distinct inhibition of the total arginine-esterase activity were observed in blood serum after treatment with the inhibitor. The inhibitor did not affect the phase alterations in the carboxypeptidase N activity within the first 3 days after the burns; the distinct decrease in the enzymatic activity was confirmed within the first period of the burn shock. Within 24-48 hrs after the burns content of alpha1-antitrypsin was distinctly increased in patients treated with ingitrile as compared with the untreated group. The data obtained suggest that the polyvalent proteinase inhibitor causes a decrease in activity of the kallikreinkinin system in blood plasma and affects the enzymes participating indirectly in formation of kinins in burned patients. The data obtained are in agreement with the distinct clinical effect of the inhibitor. The doses of the inhibitor used in these studies did not cause normalizing effect on the activity of the kinin system components and on the clinical state of patients only in extremely severe cases of burn shock and in acute burn toxemia with letal outcome within the few days after the injury.


Influence of blood group on the availability of receptors for attachment of uropathogenic Escherichia coli.
Escherichia coli strains with defined receptor specificity were used as probes to analyze the individual variation in host cell receptors with respect to blood groups. The adhesins were initially characterized as mannose sensitive (MS), mannose resistant (MR), or nonagglutinating (-). The receptor specificity of the strains with MR adhesins was defined by agglutination of synthetic Gal alpha 1----4Gal beta covalently linked via a spacer arm, (CH2)2S(CH2)2CO approximately H-bovine serum albumin (BSA) to BSA-latex beads as specific for the globoseries glycolipid receptors (MR:GS). Strains with MR adhesins not reacting with Gal alpha 1----4Gal beta-BSA-latex were designated MR:nonGS. The attachment and hemagglutination of the MR:GS strains was strictly dependent on Gal alpha 1----4Gal beta-containing receptors, as shown by the absence of binding to cells from individuals of blood group P lacking these structures. Previous reports showed differences in the composition of globoseries glycolipids between erythrocytes from individuals of P1 and P2. No significant difference was found, However, in the mean adhesion to P1 and P2 epithelial cells or in the agglutination titer for P1 and P2 erythrocytes. The MR:GS receptors were equally distributed on squamous and transitional epithelial cells. In contrast, the distribution of MR:nonGS receptors was skewed. Attachment occurred mostly to squamous epithelial cells. The attachment of strains with MR:nonGS adhesins was independent of the P blood group of the cell donor. The binding ability of MR:GS and MR:nonGS adhesins appeared independent and additive. The attachment was not influenced by the ABH blood group. However, increased binding to epithelial cells from nonsecretors occurred regardless of the P blood group, suggesting a shielding of receptors by products controlled by the secretor genes. These results illustrate how individual variation in cell surface components with and without receptor activity determine the interaction of a ligand with a known receptor.


The genera in the third catalogue (1836-1837) of Dejean's Coleoptera collection.
All genus-group names first proposed or made available for the first time in the third edition of Dejean's catalogue of his beetle collection are recorded. The following 18 names are made available for the first time in Dejean's third catalogue: Batoscelis Dejean [Carabidae], Laphyra Dejean [Carabidae], Sauriodes Dejean [Staphylinidae], Abrobapta Dejean [Buprestidae], Selagis Dejean [Buprestidae], Eurhipis Dejean [Eucnemidae], Anaeretes Dejean [Scarabaeidae], Doryscelis Dejean [Scarabaeidae], Epilissus Dejean [Scarabaeidae], Hoploscelis Dejean [Scarabaeidae], Brachygenius Dejean [Tenebrionidae], Capnisa Dejean [Tenebrionidae], Heterocheira Dejean [Tenebrionidae], Selenomma Dejean [Tenebrionidae], Dactylocrepis Dejean [Curculionidae], Lophodes Dejean [Curculionidae], Heterarthron Dejean [Bostrichidae] and Homalopus Chevrolat [Chrysomelidae]. Eurhipis Dejean, 1836 is considered a junior synonym of Phyllocerus Lepeletier and Audinet-Serville, 1825 for the first time. Abrobapta Dejean, 1836 has precedence over Torresita Harold, 1869.


Amperometric detection of superoxide dismutase at cytochrome c-immobilized electrodes: xanthine oxidase and ascorbate oxidase incorporated biopolymer membrane for in-vivo analysis.
Amperometric measurement of superoxide dismutase (SOD) was carried out at cytochrome c-immobilized monolayers and ascorbate oxidase (AOD)/xanthine oxidase (XOD)/cytochrome c- and (AOD, XOD)/cytochrome c-multilayers. Cytochrome c was covalently immobilized on mercaptopropionic acid-containing self-assembled monolayers on gold. A biopolymer membrane of poly-L-lysine confining XOD and AOD was cast on the monolayer of cytochrome c. While both the cytochrome c-immobilized monolayer and multilayer electrodes show anodic current responses to the generation of superoxide radical, the sensitivity of the multilayer system for the detection of superoxide radical was high relative to that of the monolayer system. In the case of the cytochrome c-multilayer electrodes, the generation of superoxide radical near the sensing element, cytochrome c, resulted in high sensitivity for the detection of superoxide. The use of a XOD and AOD-incorporated poly-L-lysine membrane enabled the detection of the generation of superoxide radical in the presence of L-ascorbic acid. Though L-ascorbic acid could scavenge superoxide radical, the biopolymer membrane confined with AOD will oxidize any L-ascorbic acid that permeated into the membrane. By using the multilayer electrodes, one could measure the activity of SOD in the presence of L-ascorbic acid.


Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review.
Functional methionine synthase deficiency due to abnormal methylcobalamin metabolism causes megaloblastic anemia, moderate to severe developmental delay, lethargy, and anorexia in association with homocystinuria. Patients with this disorder of cobalamin metabolism can be classified into two separate groups, cblE or cblG, primarily on the basis of complementation analysis with cultured skin fibroblasts. We describe two unrelated boys, ages 3 and 5 years, with the cblG defect in methylcobalamin synthesis. Both children presented with severe developmental delay, lethargy, anorexia, and megaloblastic anemia. The diagnosis of homocystinuria was delayed in each case due to difficulties with detection of small amounts of homocystine in physiologic samples. The clinical course of cblG disease is favorably altered by treatment with intramuscular hydroxycobalamin. Megaloblastosis in the presence of adequate supplies of cobalamin and folate in the blood must alert the clinician to the possibility of functional methionine synthase deficiency and should prompt a careful search for associated biochemical hallmarks, including homocystinuria/emia.


DISR: Dental Image Segmentation and Retrieval.
In this paper, we propose novel algorithms for retrieving dental images from databases by their contents. Based on special information of dental images, for better content-based dental image retrieval and representation, the image attributes are used. We propose Dental Image Segmentation and Retrieval (DISR), a content-based image retrieval method that is robust to translation and scaling of the objects in the images. A novel model is used to calculate the features of the image. We implemented the dentition plaster casts and proposed a special technique for segmenting teeth in our dental study models. For testing the efficiency of the presented algorithm, a software system is developed and 60 dental study models are used. The models are covering different kinds of malocclusions. Our experiments show that 95% of the extracted results are accurate and the presented algorithm is efficient.


[The organization of surgical care in Russian army during 1812 Great Patriotic War].
The article considers the characteristics of surgical care to warriors of Russian army during 1812 Great Patriotic War. Such conditions are analyzed as damaging action of French weapons, types of combat wounds, organization and forces of military sanitary service of Russian troops, surgeons' support with means of supplying surgical care to the wounded and arsenal of surgical aids. On the basis of given materials analysis a preliminary conclusion is made that surgical care in Russian army in 1812 not only was on the sufficiently high level but it played a specified role in the victory of Russian weapon.


Sustained Subconjunctival Delivery of Infliximab Protects the Cornea and Retina Following Alkali Burn to the Eye.
Tumor necrosis factor (TNF)-α is upregulated in eyes following corneal alkali injury and contributes to corneal and also retinal damage. Prompt TNF-α inhibition by systemic infliximab ameliorates retinal damage and improves corneal wound healing. However, systemic administration of TNF-α inhibitors carries risk of significant complications, whereas topical eye-drop delivery is hindered by poor ocular bioavailability and the need for patient adherence. This study investigates the efficacy of subconjunctival delivery of TNF-α antibodies using a polymer-based drug delivery system (DDS). The drug delivery system was prepared using porous polydimethylsiloxane/polyvinyl alcohol composite fabrication and loaded with 85 μg of infliximab. Six Dutch-belted pigmented rabbits received ocular alkali burn with NaOH. Immediately after the burn, subconjunctival implantation of anti-TNF-α DDS was performed in three rabbits while another three received sham DDS (without antibody). Rabbits were followed with photography for 3 months. After 3 months, the device was found to be well tolerated by the host and the eyes exhibited less corneal damage as compared to eyes implanted with a sham DDS without drug. The low dose treatment suppressed CD45 and TNF-α expression in the burned cornea and inhibited retinal ganglion cell apoptosis and optic nerve degeneration, as compared to the sham DDS treated eyes. Immunolocalization revealed drug penetration in the conjunctiva, cornea, iris, and choroid, with residual infliximab in the DDS 3 months after implantation. This reduced-risk biologic DDS improves corneal wound healing and provides retinal neuroprotection, and may be applicable not only to alkali burns but also to other inflammatory surgical procedures such as penetrating keratoplasty and keratoprosthesis implantation.


Proteomic and Transcriptomic Analyses to Decipher the Chitinolytic Response of Jeongeupia spp.
In nature, chitin, the most abundant marine biopolymer, does not accumulate due to the action of chitinolytic organisms, whose saccharification systems provide instructional blueprints for effective chitin conversion. Therefore, discovery and deconstruction of chitinolytic machineries and associated enzyme systems are essential for the advancement of biotechnological chitin valorization. Through combined investigation of the chitin-induced secretome with differential proteomic and transcriptomic analyses, a holistic system biology approach has been applied to unravel the chitin response mechanisms in the Gram-negative Jeongeupia wiesaeckerbachi. Hereby, the majority of the genome-encoded chitinolytic machinery, consisting of various glycoside hydrolases and a lytic polysaccharide monooxygenase, could be detected extracellularly. Intracellular proteomics revealed a distinct translation pattern with significant upregulation of glucosamine transport, metabolism, and chemotaxis-associated proteins. While the differential transcriptomic results suggested the overall recruitment of more genes during chitin metabolism compared to that of glucose, the detected protein-mRNA correlation was low. As one of the first studies of its kind, the involvement of over 350 unique enzymes and 570 unique genes in the catabolic chitin response of a Gram-negative bacterium could be identified through a three-way systems biology approach. Based on the cumulative data, a holistic model for the chitinolytic machinery of Jeongeupia spp. is proposed.


Changes in secondary substance use after the onset of the COVID-19 pandemic among people who use cannabis: Findings from a web-based sample of adults in the United States.
The coronavirus disease 2019 (COVID-19) pandemic has had widespread impacts on mental health and substance use. Increases in cannabis use have been documented in the United States, but little is known about how other substance use has changed among people who use cannabis. We sought to examine changes in alcohol, tobacco, opioid, and stimulant use during COVID-19 and explore how these changes relate to patterns of cannabis use. Data were obtained from a web-based survey of adults in the United States who use cannabis (n = 1,471) administered in September 2020. Using data reported in retrospective (prepandemic) and time-of-survey assessment periods, we explored changes in the prevalence of regular (≥ weekly) alcohol, tobacco, opioid, and stimulant use during COVID-19 among respondents who used medical and nonmedical cannabis. We used modified Poisson regression to examine cannabis-related correlates of increasing or decreasing secondary substance use during the pandemic. There was a slight but significant increase in ≥weekly alcohol use in the medical use group only (41.4%-47.0%, p = .034). ≥ Weekly tobacco, opioid, and stimulant use did not change significantly. Pandemic-concurrent shifts in secondary substance use depended on interacting cannabis-related factors including medical cannabis use, prepandemic cannabis frequency, and pandemic-concurrent frequency changes. For example, ≥ weekly prepandemic cannabis use was significantly and positively associated with decreasing opioid use frequency among the medical cannabis use group only. Assessments of the pandemic's effects on substance use should consider relationships between cannabis and other substances, which may differ according to cannabis-specific behaviors, motives, and contexts of use. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Distribution of de novo synthesized sulfated glycosaminoglycans in the glomerular basement membrane and mesangial matrix.
The distribution of de novo synthesized heparan sulfate-glycosaminoglycan (GAG) and chondroitin sulfate-GAG of the mesangial matrix and the glomerular basement membrane was determined by a combination of biochemical and autoradiographic methods. The de novo synthesized sulfated GAGs were labeled by the ex situ organ perfusion of kidneys with [35S]sulfate for periods of time up to 7 hours. Biochemical analysis of a combined extract of the matrices revealed that both heparan sulfate-GAG and chondroitin sulfate-GAG are present at levels of approximately 90 and 10%, respectively, and that these relative levels do not change with increasing organ perfusion times. Autoradiographic analysis of the de novo synthesized sulfated GAGs in each of the matrices showed that the mesangial matrix incorporated two to three times as much of the sulfated GAGs as the glomerular basement membrane. The predominant GAG in both the matrices was heparan sulfate-GAG and chondroitin sulfate-GAG was exclusively present in the mesangial matrix, thereby indicating that these two matrices are compositionally different. These differences may be of some importance in the establishment of normal glomerular function and organization and in the alteration of that function and organization as a result of various disease processes, possibly those that are immune complex mediated.


Midazolam Premedication Facilitates Mask Ventilation During Induction of General Anesthesia: A Randomized Clinical Trial.
During induction of general anesthesia, proper mask ventilation is crucial for supplying sufficient oxygen to unconscious patients. Midazolam has a relaxing effect on airway muscles. We hypothesized that sedative premedication with midazolam would facilitate mask ventilation during anesthetic induction. Patients undergoing elective surgery under general anesthesia were randomized into 2 groups. The midazolam group received midazolam premedication at the reception area, 3 minutes before transfer to the operating room. Patients in the control group were treated with normal saline as a placebo. The primary outcome was difficulty of mask ventilation during induction, as evaluated using the Warters scales. A total of 97 patients completed the analysis: 49 in the control group and 48 in the midazolam group. The patients in the midazolam group showed a significantly lower mask ventilation difficulty score on the Warters scale than that of the control group (mean [standard deviation], 0.92 [1.13] vs 0.19 [0.57]; estimated difference [95% confidence interval], 0.73 [0.37-1.09]; P < .001). The incidence of difficult mask ventilation (≥2 Warters scale) was significantly lower in the midazolam group than in the control group (risk ratio [95% confidence interval], 0.15 [0.03-0.72]; P = .015). This randomized clinical trial demonstrated that midazolam premedication enhanced mask ventilation during induction of general anesthesia.


Cholangiocyte injury and ductopenic syndromes.
Cholangiopathies are characterized by a predominantly bile duct-directed inflammatory response that leads to bile duct injury and, if the injury is persistent, bile duct loss and the chance of developing bile duct cancer (cholangiocarcinoma). Although the cholangiopathies have broad range of etiologies and pathogenesis (e.g., inherited disorders, autoimmune disorders, infections, drug-induced, ischemia, and unknown etiology), all share the common pathogenetic target-the biliary epithelial cell (cholangiocyte). For the most part, the pathogenesis of these diseases is poorly understood, which correspondingly has restricted clinicians to nonspecific and usually ineffective therapies for these disorders. Nevertheless, significant advances toward the understanding of the mechanisms involved in cholangiocyte-directed inflammation, biliary fibrosis, cholangiocyte death, and cholangiocarcinoma have unfolded over the past 15 years that may provide us new hopes and schemes for treatment of these disorders.


A systematic review of patient-reported outcome measures patients with chronic limb-threatening ischemia.
Chronic limb-threatening ischemia (CLTI) causes significant morbidity with profound negative effects on health-related quality of life. As the prevalence of peripheral artery disease and diabetes continue to rise in our aging population, the public health impact of CLTI has escalated. Patient-reported outcome measures (PROMs) have become common and important measures for clinical evaluation in both clinical care and research. PROMs are important for the measurement of clinical effectiveness and cost effectiveness and for shared decision-making on treatment options. However, the PROMs used to describe the experience of patients with CLTI are heterogeneous, incomplete, and lack specific applicability to the underlying disease processes and diverse populations. For example, certain PROMs exist for patients with extremity wounds, and other PROMs exist for patients with pain, and still others exist for patients with vascular disease. Despite this multiplicity of tools, no single PROM encompasses all of the components necessary to describe the experiences of patients with CLTI. This significant unmet need is evident from both published reports and contemporary large-scale clinical trials in the field. In this systematic review, we review the current use of PROMs for patients with CLTI in clinical practice and in research trials and highlight the gaps that need to be addressed to develop a unifying PROM instrument for CLTI.


Ultrafast growth of submillimeter-scale single-crystal MoSe2 by pre-alloying CVD.
The synthesis of large-scale monolayer single-crystal MX2 (M = Mo, W; X = S, Se), a typical transition metal dichalcogenide (TMD), is the premise for their future applications. Compared with insulating substrates such as SiO2 and sapphire, Au is more favourable for the fast growth of TMDs by chemical vapor deposition (CVD). Recently, large-scale single-crystal WX2 was successfully grown and transferred on Au. In sharp contrast, the growth and transfer for monolayer MoX2 is still very challenging, because Au has a higher solubility of Mo and stronger interaction with MoX2 than WX2. Compared with the most studied MoS2, MoSe2 is superior in many aspects because of the narrower band gap and tunable excitonic charging effects. However, the synthesis of large-scale single-crystal MoSe2 on Au has not been reported so far. Here, a pre-alloying CVD method was developed to solve the problems for the growth and non-destructive transfer of MoX2. It has realized the ultrafast growth (30 s) of submillimeter-scale (560 μm) single-crystal MoSe2 for the first time. As-grown samples are strictly monolayers with good optical and electrical properties, which can be easily transferred without sacrificing Au foils by the electrochemical bubbling method. It was found that pre-alloying not only passivates the energetically active sites on Au but also weakens the interaction between Au and MoSe2, which is responsible for the ultrafast growth and easy transfer of MoSe2. This method is also universal for the fast growth and non-destructive transfer of other 2D TMDs.


Biochemical characterization of the 2-ketoacid reductases encoded by ycdW and yiaE genes in Escherichia coli.
Glyoxylate is an important intermediate of the central microbial metabolism formed from acetate, allantoin or glycolate. Depending on the physiological conditions, glyoxylate is incorporated into the central metabolism by the combined actions of the activity of malate synthase and the D-glycerate pathway, or alternatively it can be reduced to glycolate by constitutive glyoxylate reductase activity. At present no information is available on this latter enzyme in Escherichia coli, although similar enzymes, classified as 2-hydroxyacid dehydrogenases, have been characterized in other organisms. A BLAST search using as the query sequence the hydroxypyruvate/glyoxylate reductase from Cucumis sativus identified as an orthologue the yiaE gene of E. coli encoding a ketoaldonate reductase. Use of this sequence in a subsequent BLAST search yielded the ycdW gene as a good candidate to encode glyoxylate reductase in this bacterium. Cloning and overexpression of the ycdW gene showed that its product displayed a high NADPH-linked glyoxylate reductase activity, and also catalysed the reduction of hydroxypyruvate with a lower efficiency. Disruption of the ycdW gene by a chloramphenicol acetyltransferase ('CAT') cassette did not totally abolish the glyoxylate reductase activity, indicating that another enzyme accomplished this function. The similarity with YiaE led us to test whether this protein was responsible for the remaining glyoxylate reductase activity. Purification of YcdW and YiaE proteins permitted their kinetic characterization and comparison. Analysis of the catalytic power (k(cat)/K(m)) disclosed a higher ratio of YcdW for glyoxylate and of YiaE for hydroxypyruvate.


Natural genetic transformation of Pseudomonas stutzeri in a non-sterile soil.
Natural transformation of the soil bacterium Pseudomonas stutzeri JM300 in a non-sterile brown earth microcosm was studied. For this purpose, the microcosm was loaded with purified DNA (plasmid or chromosomal DNA, both containing a high-frequency-transformation marker, his+, of the P. stutzeri genome), the non-adsorbed DNA was washed out with soil extract and then the soil was charged with competent cells (his-1). Both chromosomal and plasmid transformants were found among the P. stutzeri cells recovered from the soil. The number of plasmid transformants increased in a linear fashion with the amount of DNA added [10-600 ng (0.7 g soil)-1]. The observed efficiency of transformation, the time course of transformant formation and the complete inhibition of transformation by DNase I, when added to the soil, were similar to that seen in optimized transformations in nutrient broth. Addition of cells as late as 3 d after loading the soil with plasmid DNA still yielded 3% of the initial transforming activity. This suggests that nucleases indigenous to the soil destroyed the transforming DNA, but at a rate allowing considerable DNA persistence. Transformants were also obtained when intact P. stutzeri cells were introduced into the soil to serve as plasmid DNA donors. Apparently, DNA was released from the cells, adsorbed to the soil material and subsequently taken up by recipient cells. The results indicate that competent cells of P. stutzeri were able to find access to and take up DNA bound on soil particles in the presence of micro-organisms and DNases indigenous to the soil.


Cancer testis antigen vaccination affords long-term protection in a murine model of ovarian cancer.
Sperm protein (Sp17) is an attractive target for ovarian cancer (OC) vaccines because of its over-expression in primary as well as in metastatic lesions, at all stages of the disease. Our studies suggest that a Sp17-based vaccine can induce an enduring defense against OC development in C57BL/6 mice with ID8 cells, following prophylactic and therapeutic treatments. This is the first time that a mouse counterpart of a cancer testis antigen (Sp17) was shown to be expressed in an OC mouse model, and that vaccination against this antigen significantly controlled tumor growth. Our study shows that the CpG-adjuvated Sp17 vaccine overcomes the issue of immunologic tolerance, the major barrier to the development of effective immunotherapy for OC. Furthermore, this study provides a better understanding of OC biology by showing that Th-17 cells activation and contemporary immunosuppressive T-reg cells inhibition is required for vaccine efficacy. Taken together, these results indicate that prophylactic and therapeutic vaccinations can induce long-standing protection against OC and delay tumor growth, suggesting that this strategy may provide additional treatments of human OC and the prevention of disease onset in women with a family history of OC.


Determinants of the microbiome spatial variability in chronic rhinosinusitis.
The sinus microbiome in patients with chronic rhinosinusitis (CRS) is considered homogenous across the sinonasal cavity. The middle nasal meatus is the recommended sampling site for 16S rRNA sequencing. However, individuals with unusually high between-site variability between the middle meatus and the sinuses were identified in previous studies. This study aimed to identify which factors determine increased microbial heterogeneity between sampling sites in the sinuses. In this cross-sectional study samples for 16S rRNA sequencing were obtained from the middle meatus, the maxillary and the frontal sinus in 50 patients with CRS. The microbiome diversity between sampling sites was analysed in relation to the size of the sinus ostia and clinical metadata. In approximately 15% of study participants, the differences between sampling sites within one patient were greater than between the patient and other individuals. Contrary to a popular hypothesis, obstruction of the sinus ostium resulted in decreased dissimilarity between the sinus and the middle meatus. The dissimilarity between the sampling sites was patient-specific: greater between-sinus differences were associated with greater meatus-sinus differences, regardless of the drainage pathway patency. Decreased spatial variability was observed in patients with nasal polyps and extensive mucosal changes in the sinuses. Sampling from the middle meatus is not universally representative of the sinus microbiome. The differences between sites cannot be predicted from the patency of communication pathways between them.


Non-pharmacological cognitive enhancement.
The term "cognitive enhancement" usually characterizes interventions in humans that aim to improve mental functioning beyond what is necessary to sustain or restore good health. While the current bioethical debate mainly concentrates on pharmaceuticals, according to the given characterization, cognitive enhancement also by non-pharmacological means has to be regarded as enhancement proper. Here we summarize empirical data on approaches using nutrition, physical exercise, sleep, meditation, mnemonic strategies, computer training, and brain stimulation for enhancing cognitive capabilities. Several of these non-pharmacological enhancement strategies seem to be more efficacious compared to currently available pharmaceuticals usually coined as cognitive enhancers. While many ethical arguments of the cognitive enhancement debate apply to both pharmacological and non-pharmacological enhancers, some of them appear in new light when considered on the background of non-pharmacological enhancement. This article is part of a Special Issue entitled 'Cognitive Enhancers'.


Update on the role of genetic factors, environmental factors and allergens in canine atopic dermatitis.
Canine atopic dermatitis (cAD) is a common, complex and multifactorial disease involving, among others, genetic predisposition, environmental factors and allergic sensitisation. This review summarises the current evidence on the role of genetic and environmental factors and allergic sensitisation in the pathogenesis of cAD since the last review by ICADA in 2015. Online citation databases and proceedings from international meetings on genetic factors, environmental factors and allergens relevant to cAD that had been published between 2015 and 2022 were reviewed. Despite intensive research efforts, the detailed genetic background predisposing to cAD and the effect of a wide range of environmental factors still need more clarification. Genome-wide association studies and investigations on genetic biomarkers, such as microRNAs, have provided some new information. Environmental factors appear to play a major role. Lifestyle, especially during puppyhood, appears to have an important impact on the developing immune system. Factors such as growing up in a rural environment, large size of family, contact with other animals, and a nonprocessed meat-based diet may reduce the risk for subsequent development of cAD. It appears that Toxocara canis infection may have a protective effect against Dermatophagoides farinae-induced cAD. House dust mites (D. farinae and D. pteronyssinus) remain the most common allergen group to which atopic dogs react. Currently, the major allergens related to D. farinae in dogs include Der f 2, Der f 15, Der f 18 and Zen 1. Canine atopic dermatitis remains a complex, genetically heterogeneous disease that is influenced by multiple environmental factors. Further, well-designed studies are necessary to shed more light on the role of genetics, environmental factors and major allergens in the pathogenesis of cAD.


HIV/AIDS interventions for midlife and older adults: current status and challenges.
Drawing on both domestic and global international perspectives, this special issue is devoted to articles that confront the challenges of understanding, preventing, and intervening, with HIV/AIDS as an epidemic that carries increasingly serious consequences for a growing number of adults who are 50 years of age or older. This issue builds on papers first presented at an HIV/AIDS and aging conference sponsored in the fall of 2000 by the National Institute on Aging of the National Institutes of Health. The editors have selected articles that focus dually on what is currently known and what needs to be known to successfully address the needs of persons 50 years of age or older who are vulnerable to the virus's effects. This special issue is organized around a series of subsections representing key issues and research findings related to HIV/AIDS and aging issues, including the epidemiology of HIV/AIDS and aging, HIV/AIDS risk and risk behavior, settings and situations as social contexts of risk, clinical challenges with older populations, living with and managing HIV/AIDS, interventions and research methods, new frontiers and challenges, and strategies for action. Some articles are data driven, whereas others are reflective pieces that recount personal experiences in living with the virus or point to new directions for research and practice. In this introduction, the editors highlight findings and approaches from each article and further add to our knowledge by setting these articles within the context of major themes relevant to the study of HIV/AIDS in an aging population.


The Possible Immunological Mechanisms of Pathology in Mice with Congenitally Acquired Influenza Infection.
The fact that congenitally acquired viral infection often strongly influences specific and non-specific immunoreactivity is well documented. Viral infection of pregnant female may lead to serious of pathological consequences for the offspring, namely, to mortality, developmental disorders and in less severe cases to body growth retardation, wasting syndrome and immunodeficiency. In this connection, we have studied congenitally acquired influenza infection in CII mice. The progeny of C57BL/6 female mice, which were infected with influenza virus (A/WSN) by the 3rd week of pregnancy, exhibited a profound growth retardation and major morphological lesions of central nervous system, lymphoid and other organs. We have found out that mice with congenitally acquired influenza infection had autoreactive killer T cells in their lymphoid organs. CII mice exhibited some features of chronic immune activation, namely elevated spontaneous proliferation, spontaneous development of plaque forming cells, and spontaneous inhibition of migration activity. Lymphoid cells from mice with congenitally acquired influenza infection induced an enlargement of regional lymph nodes after they had been injected into syngeneic non-infected recipient in popleteal node assay. The level of this reaction depended on the level of virus-bearing cells in donor cell population and correlated with the increase of gammadelta and CD4(+) T cells. The role of these interactions in pathology is discussed herein.


Diffusing-wave spectroscopy from head-like tissue phantoms: influence of a non-scattering layer.
We investigate the influence of a non-scattering layer on the temporal field autocorrelation function of multiple scattered light from a multilayer turbid medium such as the human head. Data from Monte Carlo simulations show very good agreement with the predictions of the correlation-diffusion equation with boundary conditions taking into account non-diffusive light transport within the non-scattering layer. Field autocorrelation functions measured at the surface of a multilayer phantom including a non-scattering layer agree well with theory and simulations when the source-receiver distance is significantly larger than the depth and the thickness of the non-scattering layer. Our results show that for source-receiver distances large enough to probe the dynamics in the human cortex, the cortical diffusion coefficient obtained by analyzing field autocorrelation functions neglecting the presence of the non-scattering cerebrospinal fluid layer is underestimated by about~$40\,\%$ in situations representative of the human head.


Incidence of nephrogenic systemic fibrosis at two large medical centers.
To determine the incidence and associated risk factors of nephrogenic systemic fibrosis (NSF) in patients who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. Institutional review board approval was obtained for retrospective review of the medical records from two hospitals to identify all cases of biopsy-confirmed NSF and all patients administered a GBCA from January 1, 1997, to June 30, 2007. Informed patient consent was not required. The incidence of NSF was calculated for patients who received a standard dose of GBCA, patients who received a high dose, and subgroups of patients with renal impairment. Fifteen patients developed NSF after gadolinium-enhanced MR imaging. All of them had an estimated glomerular filtration rate (eGFR) lower than 30 mL/min, and 11 had acute renal failure or acute deterioration of chronic renal failure. The incidence of NSF after gadolinium-enhanced MR imaging without screening for renal function was zero of 74,124 patients with the standard dose of GBCA and 15 (0.17%) of 8997 patients with the high dose (P < .001). The NSF incidence associated with a high dose of GBCA increased to 0.4% in patients in a chronic hemodialysis program and to 8.8% in those who had an eGFR lower than 15 mL/min but were not undergoing hemodialysis (P < .001). The NSF incidence in the patients with acute renal failure who received a high dose when their creatinine level was increasing was 19% (11 of 58 patients) when hemodialysis was delayed for longer than 2 days. More patients with NSF had proinflammatory events, and compared with patients without NSF, these patients had lower pH, younger age, lower eGFR, elevated serum phosphorus levels, and a longer delay between GBCA injection and hemodialysis. For patients with an eGFR lower than 15 mL/min, hemodialysis helped to prevent NSF. For patients with an eGFR lower than 30 mL/min who received a high dose of GBCA, acute renal failure, delayed hemodialysis after contrast agent injection, proinflammatory events, and hyperphosphatemia were associated with increased risk of NSF.


Gender roles and geographic location as predictors of emotional distress in Australian women.
This paper examines the emotional distress of women in urban, rural and remote areas of Queensland. A randomised telephone survey of 394 women found that geographical location was not significantly related to perceptions of life quality or distress. Contrary to expectation, urbanisation and isolation were not significant predictors of mental health and factors other than geographical location appear more influential in determining people's emotional wellbeing. One such factor, the gender role that women perceive themselves as fulfilling, was examined in this study and found to be significantly related to emotional distress. Women who saw their role as being submissive, dependent, gentle and timid reported significantly higher rates of distress and women perceiving themselves as bossy, rude and superior reported higher stress, irrespective of where they lived. Scores for the positive gender role of being sensitive, emotional and responsible grew significantly higher as the respondents became more rural/remote. Conversely, scores in the bossy, rude and superior domain were significantly higher in urban areas. This paper discusses the limitations of health research using global urban/rural classification schemes based on size of town or distance from major centres. There is mounting evidence that geographically based classification schemes are essentially minimalist and that more complex grouping variables such as gender role need to be identified.


Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors.
The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined. Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available. With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear. SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended. Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmed in vitro findings that CYP2D6 inhibition by sertraline is only moderate. (ABSTRACT TRUNCATED)


Improving door-to-balloon time by decreasing door-to-ECG time for walk-in STEMI patients.
The American Heart Association/American College of Cardiology guidelines recommend rapid door-to-electrocardiography (ECG) times for patients with ST-segment elevation myocardial infarction (STEMI). Previous quality improvement research at our institution revealed that we were not meeting this benchmark for walk-in STEMI patients. The objective is to investigate whether simple, directed changes in the emergency department (ED) triage process for potential cardiac patients could decrease door-to-ECG times and secondarily door-to-balloon times. We conducted an interventional study at a large, urban, public teaching hospital from April 2010 to June 2012. All patients who walked into the ED with a confirmed STEMI were enrolled in the study. The primary intervention involved creating a chief complaint-based "cardiac triage" designation that streamlined the evaluation of potential cardiac patients. A secondary intervention involved moving our ECG technician and ECG station to our initial triage area. The primary outcome measure was door-to-ECG time and the secondary outcome measure was door-to-balloon time. We enrolled 91 walk-in STEMI patients prior to the intervention period and 141 patients after the invention. We observed statistically significant reductions in door-to-ECG time (43±93 to 30±72 minutes, median 23 to 14 minutes p<0.01), ECG-to-activation time (87±134 to 52±82 minutes, median 43 to 31 minutes p<0.01), and door-to-balloon time (134±146 to 84±40 minutes, median 85 -75 minutes p=0.03). By creating a chief complaint-based cardiac triage protocol and by streamlining ECG completion, walk-in STEMI patients are systematically processed through the ED. This is not only associated with a decrease in door-to-balloon time, but also a decrease in the variability of the time sensitive intervals of door-to-ECG and ECG-to-balloon time.


The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites.
Specific roles of individual CDPKs vary, but in general they mediate essential biological functions necessary for parasite survival. A comparative analysis of the structure-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis calcium-dependent protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum and Toxoplasma gondii was performed by screening against 333 bumped kinase inhibitors (BKIs). Structural modelling and experimental data revealed that residues other than the gatekeeper influence compound-protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP-binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase, some library compounds exhibit activity against serine- or threonine-containing CDPKs. Divergent BKI sensitivity of CDPK homologues could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP-binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of a threonine gatekeeper in all three CDPKs.


Inotropic and electrophysiologic effects of amrinone in untreated and digitalized ventricular tissues.
The purposes of this study were to determine whether amrinone induces oscillatory afterpotentials (OAP) or aftercontractions (AC) in Purkinje tissue or myocardium, to determine whether a relationship exists between the production of OAP or AC and the inotropic effects of amrinone and to determine possible effects of amrinone on the oscillations and the positive inotropic effect produced by digitalis. Isolated canine papillary and trabecullar muscles, as well as false tendons, were exposed to 5.3 X 10(-4) M amrinone. Some of the preparations had been pretreated with acetylstrophanthidin (AS) in a dose just sufficient to induce OAP or AC. Standard electrophysiologic techniques were used to record transmembrane action potentials. Developed tension also was recorded. Amrinone by itself did not induce OAP or AC in myocardium or false tendons. This was true even when the resting membrane potential of the false tendons was reduced by means of focal current application. Amrinone increased the amplitude of AS-induced oscillations in both myocardium and false tendons. Amrinone increased strength of contraction of untreated myocardium at all basic cycle lengths and of AS-treated myocardium, especially at shorter basic cycle lengths. Amrinone decreased strength of contraction both of untreated and AS-treated false tendons at all basic cycle lengths. The results suggest that there may be important differences in the mechanisms of action of amrinone and digitalis.


Adverse surgical outcomes among patients with cognitive impairments.
To determine the factors that contributed to adverse outcomes, the records of 59 cognitively impaired patients with nonfatal complications (n = 23) or death (n = 36) on a general surgery teaching service over a 30-month period were examined retrospectively. Specific complications are reported. Patient, disease, and management factors related to mortality and morbidity are identified. Patients with cognitive impairments had a higher mortality rate (9.6 vs 6.3%) and approximately the same rate of nonfatal complications (6.1 vs 7.6%) when compared with general surgery patients as a whole. Patient characteristics including age over 70, dementia, nursing home residence, contractures, inability to communicate, need for total care, and gross malnutrition were associated with fatal outcomes. Vascular, colonic, esophageal, gastric, or duodenal conditions, emergency admission, urgent operation, and admission APACHE II scores greater than or equal to 15 were disease-related factors associated with mortality. Management risk factors were prehospital or inpatient diagnostic delays and technical or judgmental errors of surgical management. Twenty-four of 36 deaths were directly related either to a diagnostic delay (11), an operative technical error (11), or a judgmental error of postoperative airway management (2). Eighty-five per cent of diagnostic delays (11/13) and 37 per cent (11/30) of technical errors resulted in mortality. Suggestions for improving the care of these patients are discussed.