Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG).
Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) enforce an overwhelming social and economic burden on society. They are primarily characterized through the accumulation of modified proteins, which further trigger biological responses such as inflammation, oxidative stress, excitotoxicity and modulation of signalling pathways. In a hope for cure, these diseases have been studied extensively over the last decade to successfully develop symptom-oriented therapies. However, so far no definite cure has been found. Therefore, there is a need to identify a class of drug capable of reversing neural damage and preventing further neural death. This review therefore assesses the reliability of the neuroprotective benefits of epigallocatechin-gallate (EGCG) by shedding light on their biological, pharmacological, antioxidant and metal chelation properties, with emphasis on their ability to invoke a range of cellular mechanisms in the brain. It also discusses the possible use of nanotechnology to enhance the neuroprotective benefits of EGCG.


Bactericidal effects of 310 nm ultraviolet light-emitting diode irradiation on oral bacteria.
Ultraviolet (UV) light is used for phototherapy in dermatology, and UVB light (around 310 nm) is effective for treatment of psoriasis and atopic dermatitis. In addition, it is known that UVC light (around 265 nm) has a bactericidal effect, but little is known about the bactericidal effect of UVB light. In this study, we examined the bactericidal effects of UVB-light emitting diode (LED) irradiation on oral bacteria to explore the possibility of using a 310 nm UVB-LED irradiation device for treatment of oral infectious diseases. We prepared a UVB (310 nm) LED device for intraoral use to examine bactericidal effects on Streptococcus mutans, Streptococcus sauguinis, Porphyromonas gingivalis, and Fusobacterium nucleatum and also to examine the cytotoxicity to a human oral epithelial cell line (Ca9-22). We also examined the production of nitric oxide and hydrogen peroxide from Ca9-22 cells after irradiation with UVB-LED light. Irradiation with the 310 nm UVB-LED at 105 mJ/cm2 showed 30-50% bactericidal activity to oral bacteria, though 17.1 mJ/cm2 irradiation with the 265 nm UVC-LED completely killed the bacteria. Ca9-22 cells were strongly injured by irradiation with the 265 nm UVC-LED but were not harmed by irradiation with the 310 nm UVB-LED. Nitric oxide and hydrogen peroxide were produced by Ca9-22 cells with irradiation using the 310 nm UVB-LED. P. gingivalis was killed by applying small amounts of those reactive oxygen species (ROS) in culture, but other bacteria showed low sensitivity to the ROS. Narrowband UVB-LED irradiation exhibited a weak bactericidal effect on oral bacteria but showed low toxicity to gingival epithelial cells. Its irradiation also induces the production of ROS from oral epithelial cells and may enhance bactericidal activity to specific periodontopathic bacteria. It may be useful as a new adjunctive therapy for periodontitis.


Antipermeability and antiproliferative effects of standard and frozen bevacizumab on choroidal endothelial cells.
Bevacizumab is an antiangiogenic compound developed to target tumour vessels. Its off-label use in ophthalmology requires in vitro testing on ocular cells. To quantify the antipermeability and antiproliferative effects of bevacizumab on cultured choroidal endothelial cells (CECs). It was examined whether deep-freezing of bevacizumab attenuates its antiangiogenic activity. Porcine CECs were cultured in permeable insert systems. Permeability of the cell monolayers was quantified by a fluorescent isothiocyanate-dextran assay after treatment with vascular endothelial growth factor (VEGF; 20-100 ng/ml) alone and in combination with bevacizumab (0.1-1 mg/ml). Proliferation of the CECs was tested using a "wound scratch" assay. The experiments were repeated with bevacizumab after freezing at -20 degrees C for 5 days. Bevacizumab significantly reduced VEGF-induced permeability in a dose-dependant manner. A molar ratio of 2.6:1 of bevacizumab to VEGF was required for complete blocking of VEGF-induced rise in permeability. CEC proliferation was significantly blocked by bevacizumab (0.5 mg/ml). Thawed bevacizumab after deep freezing showed a moderate, but not statistically significant loss in activity. Bevacizumab significantly reduces VEGF-induced permeability and proliferation of CECs. Freezing and thawing of bevacizumab will affect its biological activity.


Preparation and characterisation of core-shell CNTs@MIPs nanocomposites and selective removal of estrone from water samples.
This paper reports the preparation of carbon nanotubes (CNTs) functionalized with molecularly imprinted polymers (MIPs) for advanced removal of estrone. CNTs@Est-MIPs nanocomposites with a well-defined core-shell structure were obtained using a semi-covalent imprinting strategy, which employed a thermally reversible covalent bond at the surface of silica-coated CNTs for a large-scale production. The morphology and structure of the products were characterised by transmission electron microscopy and Fourier transform infrared spectroscopy. The adsorption properties were demonstrated by equilibrium rebinding experiments and Scatchard analysis. The results demonstrate that the imprinted nanocomposites possess favourable selectivity, high capacity and fast kinetics for template molecule uptake, yielding an adsorption capacity of 113.5 μmol/g. The synthetic process is quite simple, and the different batches of synthesized CNTs@Est-MIPs nanocomposites showed good reproducibility in template binding. The feasibility of removing estrogenic compounds from environmental water using the CNTs@Est-MIPs nanocomposites was demonstrated using water samples spiked with estrone.


Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.
Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk.


Large Duplications Can Be Benign Copy Number Variants: A Case of a 3.6-Mb Xq21.33 Duplication.
Segmental aneusomies are usually associated with clinical consequences, but an increasing number of nonpathogenic cytogenetically visible as well as large cryptic chromosomal imbalances have been reported. Here, we report a 3.6-Mb Xq21.33 microduplication detected prenatally on a female fetus which was inherited from a phenotypically normal mother and grandfather. It is assumed that male patients harboring Xq or Xp duplication present with syndromic intellectual disability because of functional disomy of the corresponding genes. Female carriers are generally asymptomatic because of preferential inactivation of the abnormal X. In the present case, the 3.6-Mb-duplicated segment encompasses only 2 genes, DIAPH2 and RPL4A. Since the asymptomatic grandfather carries the duplication, we hypothesize that these genes are not dosage sensitive and/or involved in cognitive function. Our observation further illustrates that large copy number variants can be associated with a normal phenotype, especially where gene density is low. Reporting rare cases of large genomic imbalances without a phenotypic effect can be very helpful, especially for genetic counseling in the prenatal setting.


Association study between the TNXB locus and schizophrenia in a Japanese population.
The chromosome 6p21-24 region, which contains the human leukocyte antigen (HLA) region, has been suggested as an important locus for a susceptibility gene for schizophrenia. Recently, a significant association between schizophrenia and the TNXB locus, located immediately telomeric of the NOTCH4 locus in the HLA region, was observed. Few studies have further investigated the region in schizophrenia. In the present study, we investigated the region in a Japanese population. Subjects included 241 patients with schizophrenia and 290 controls. Twenty-six single nucleotide polymorphisms (SNPs) and the corresponding haplotypes were analyzed. As a result, exactly the same SNPs in the TNXB locus (rs1009382 and rs204887) as in the previous study were associated with schizophrenia (P = 0.034 and 0.034, respectively, uncorrected). A SNP (rs2071287) in the NOTCH4 locus and haplotype around it were also suggested to associate with the disease, consistent with another previous study (P = 0.041 and permutation P = 0.024, respectively, uncorrected). Although these associations became insignificant after Bonferroni correction, the findings might provide support for the association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia.


Activity of ceftaroline and comparators against pathogens isolated from skin and soft tissue infections in Latin America - results of AWARE surveillance 2012.
As part of the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program in 2012 the in vitro activity of ceftaroline and relevant comparator antimicrobials was evaluated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Venezuela) against pathogens isolated from patients with hospital associated skin and soft tissue infections (SSTIs). The study documented that ceftaroline was highly active (MIC90 0.25mg/L/% susceptible 100%) against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MIC90 2mg/L/% susceptible 83.3%) and β-hemolytic streptococci (MIC90 0.008-0.015mg/L/% susceptible 100%). The activity of ceftaroline against selected species of Enterobacteriaceae was dependent upon the presence or absence of extended-spectrum β-lactamases (ESBLs). Against ESBL screen-negative Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca the MIC90 and percent susceptible for ceftaroline were (0.5mg/L/94.1%), (0.5mg/L/99.0%) and (0.5mg/L/91.5%), respectively. Ceftaroline demonstrated potent activity against a recent collection of pathogens associated with SSTI in six Latin American countries in 2012.


Ebola: what it tells us about medical ethics.
Good medical ethics needs to look more to the resources of public health ethics and use more societal, population or community values and perspectives, rather than defaulting to the individualistic values that currently dominate discussion. In this paper I argue that we can use the recent response to Ebola as an example of a major failure of the global community in three ways. First, the focus has been on the treatment of individuals rather than seeing that the priority ought to be public health measures. Second, the advisory committee on experimental interventions set up by the WHO has focused on ethical issues related to individuals and their guidance has been unclear. Third, the Ebola issue can be seen as a symptom of a massive failure of the global community to take sufficient notice of global injustice.


Diagnosis and risk stratification of women with stable ischemic heart disease.
Although mortality rates for cardiovascular disease are on the decline, it remains the leading cause of death among men and women in the United States. Until recently, more women died of heart disease every year than men. Significant effort has been focused on increasing the awareness of cardiovascular disease among women, but ethnic disparities in awareness still exist. Early symptom recognition, risk assessment, and diagnosis of CAD are paramount in reducing cardiovascular morbidity and mortality in women. This review will highlight the unique risk factors for CAD in women, variability in clinical presentation for ischemic heart disease, and risk stratification for CAD in symptomatic women.


Spatiotemporal structure of complex cell receptive fields and influence of GABAergic inhibition.
Spatiotemporal receptive field (RF) profiles were mapped with reverse correlation technique for complex cells in the striate cortex of cat. The RFs were constituted with ON and OFF subfields that overlapped much extensively in space and also largely in time. The subfields had spatial width of 1.0-4.3 degrees and temporal duration of 33-139 ms, whereas late responses were absent in most cases. When microiontophoresis of gamma-aminobutyric acid type A (GABAA) antagonist bicuculline was performed on the cells, little change occurred in width and onset time of the subfields, but the duration was prolonged in a subset of cells. These results suggest that intracortical inhibition may contribute to improve the accuracy of visual signals encoded in neuronal activities, but is unlikely critical for determining the primary structure of complex cell RF.


Interface dressings influence the delivery of topical negative-pressure therapy.
Topical negative-pressure therapy is a widely used wound management system that generates a negative pressure at the wound surface through a foam pad, which aids in wound stimulation through mechanical forces on the wound bed. System guidelines state that the foam dressing should be placed in direct apposition with the wound surface; however, an interface dressing is often inserted at this point to promote comfort at dressing changes. Topical negative-pressure dressings were applied to 40 healthy volunteers. Pressures at the skin surface under the dressing were recorded and compared with those measured by a topical negative-pressure machine using the Therapeutic Regulated Accurate Care pad system. These were repeated, inserting different types of interface dressings: petroleum jelly (Vaseline)-impregnated gauze, nonadherent silicone dressing, and mylar polyester film dressing. Pressures recorded at the skin interface with no interface dressing were close to those set on the topical negative-pressure machine (mean pressure change, -5.11 +/- 0.55 mmHg). Interposition of dressings at the skin/foam interface affected pressure transmission through the foam, and some caused significant decreases in pressures recorded at the skin surface (e.g., Vaseline-impregnated gauze: mean pressure change, -11.76 mmHg; maximum pressure change, -41 mmHg). The loss in negative pressure means that pressures designated by the machine cannot be relied on as a measure of wound pressure when certain dressings are used at the interface. This could be important in determining the outcome of some wounds under topical negative-pressure therapy treatment.


Immunomodulation with DiNAC-- a new approach to the treatment of atherosclerosis?
Not all antioxidants reduce atherosclerosis. This may be because atherosclerosis has an autoimmune, inflammatory pathogenesis. As probucol is both an antioxidant and an immunomodulatory drug, it may be the immunomodulatory effect that underlies its ability to reduce atherosclerosis. N,N-Diacetyl-L-cystine is not an antioxidant but is immunomodulatory. In the Watanabe-heritable hyperlipidaemic rabbit model of familial hypercholesterolaemia, N,N-diacetyl-L-cystine treatment does not lower lipid levels but it does reduce atherosclerosis. Immunomodulation may be a new approach to the treatment of atherosclerosis.


Stereotactic Radiation for Treating Primary and Metastatic Neoplasms of the Spinal Cord.
Stereotactic radiation treatment can be used to treat spinal cord neoplasms in patients with either unresectable lesions or residual disease after surgical resection. While treatment guidelines have been suggested for epidural lesions, the utility of stereotactic radiation for intradural and intramedullary malignancies is still debated. Prior reports have suggested that stereotactic radiation approaches can be used for effective tumor control and symptom management. Treatment-related toxicity has been documented in rare subsets of patients, though the incidences of injury are not directly correlated with higher radiation doses. Further studies are needed to assess the factors that influence the risk of radiation-induced myelopathy when treating spinal cord neoplasms with stereotactic radiation, which can include, but may not be limited to, maximum dose, dose-fractionation, irradiated volume, tumor location, histology and treatment history. This review will discuss evidence for current treatment approaches.


Bixin ameliorates high fat diet-induced cardiac injury in mice through inflammation and oxidative stress suppression.
Diabetic cardiomyopathy is known as an essential complication of diabetes, a main reason leading to mortality for diabetic patients, and novel therapeutic strategies for treatment are urgently required. Bixin (BX), isolated from the seeds of Bixa orellana, is a carotenoid, possessing anti-inflammatory, anti-tumor and anti-oxidant activities. In our study, we attempted to calculate the role of bixin in cardiac injury progression, and reveal the possible molecular mechanism. Bixin treatment ameliorated cardiac dysfunction through inhibiting fibrosis, inflammation and reactive oxygen species (ROS) generation. It reduced fibrosis levels via collagen deposition down-regulation. Inflammatory response was attenuated by reducing pro-inflammatory cytokines secretion via Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) signaling pathway inactivation in mice induced by high fat diet. Also, in in vitro studies, lipopolysaccharide (LPS)-treated cardiac muscle cells exhibits pro-inflammatory cytokines over-expression, which was reduced by bixin through blocking TLR4/NF-κB pathway. Additionally, oxidative stress triggered by high fat in vivo and LPS in vitro was down-regulated for bixin administration via nuclear factor-E2-related factor 2 (Nrf2) signaling pathway activation. Our study suggested that bixin might be a novel and protective agent with therapeutic activity against cardiac injury by suppressing fibrosis, inflammation and oxidative stress.


Femtosecond spectroscopy of carrier relaxation dynamics in type II CdSe/CdTe tetrapod heteronanostructures.
Branched nanocrystal heterostructures synthesized from CdSe and CdTe exhibit a type II band structure alignment that induces separation of charge upon photoexcitation and localizes carriers to different regions of the tetrahedral geometry. The dynamics of carrier relaxation examined with femtosecond pump-probe spectroscopy showed heterostructures having rise times and biexponential decays longer than those of nanorods with similar dimensions. This is attributed to weaker interactions with surface states and nonradiative relaxation channels afforded by the type II alignment.


Matrix protein of vesicular stomatitis virus: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation.
Malignant ascites is common in various types of cancers and is difficult to manage. Vascular endothelial growth factor (VEGF) has a pivotal role in malignant ascites. The matrix protein of vesicular stomatitis virus (VSVMP) has been shown to inhibit host gene expression and induce the apoptosis of cancer cells. The present study was designed to determine whether VSVMP suppresses the formation of ascites in ascites-producing peritoneal carcinomatosis. BALB/c female mice, 6-8 weeks old, bearing peritoneal tumors of H22 or MethA cells received an intraperitoneal administration of 50 μg VSVMP/250 μg liposome complexes, 50 μg empty plasmid/250 μg liposome complexes or 0.9% NaCl solution, respectively, every 2 days for 3 weeks. Administration of VSVMP resulted in a significant inhibition in ascites formation, improvement in health condition and prolonged survival of the treated mice. Decreased peritoneum osmolarity and reduced tumor vascularity coincided with dramatic reductions in the VEGF level in ascites fluid and plasma. Examination of floating tumor cells collected from the peritoneal wash revealed an apparently increased number of apoptotic cells and profound downregulation of VEGF mRNA in the VSVMP-treated mice. Our data indicate for the first time that in BALB/c mice bearing H22 or MethA cell peritoneal tumors, VSVMP may inhibit VEGF production and suppress angiogenesis, consequently abolishing ascites formation.


Biodiversity, population regulation, and the stability of coral-reef fish communities.
Unprecedented population declines and extinctions because of human activities, combined with a growing recognition that such losses affect the stability of ecosystems, underscore the need to better understand how populations persist naturally. We provide field experimental evidence that high biodiversity-in particular, the combined effects of predators and competitors-acts in a way that regulates the size of local fish populations within their coral-reef community. These results indicate that complex interactions among multiple species are necessary for the stability of a highly diverse community, and so forewarn that overexploiting such species may have cascading negative consequences for the entire system.


Pituitary apoplexy: a review.
The authors present a critical review of the literature on the hemorrhagic complications of pituitary adenomas, especially those leading to apoplexy. They emphasize the distinction between pituitary apoplexy, hemorrhages leading to sudden endocrine alterations, and asymptomatic hemorrhages. Moreover, they speculate upon the possible pathophysiology of pituitary apoplexy and its predisposing factors. The clinical presentation, natural history, radiological findings, and differential diagnosis are also discussed. Finally, the historical evolution of the treatment of pituitary apoplexy is reviewed, with emphasis on the surgical treatment.


[Role of bones in the physiopathology of idiopathic hypercalciuria: effect of amino-bisphosphonate alendronate].
Previous studies from our laboratory demonstrated that bone mineral content is affected in patients with idiopathic hypercalciuria and that there is a correlation between bone mineral loss and in-vitro cytokine production. At the same time we found that short term treatment with alendronate decreased urinary calcium in these subjects. In the present study we have examined the long-term effects of alendronate treatment (10 mg/day for one year) on urinary calcium, urinary hydroxyproline and bone mineral content in 18 idiopathic hypercalciuric and 8 normocalciuric stone formers. Clinical characteristics, as well as gender and age distribution were similar in both groups. Urinary calcium and hydroxyproline, were measured monthly. Calcium excretion decreased significantly at the end of the first month, and remained lower thereafter (277 +/- 28, before vs. 202 +/- 26 mg/g creatinine, after 12 months on alendronate, p < 0.01). Urinary hydroxyproline decreased significantly during the study (125.5 +/- 32.1 vs. 39.66 +/- 17.5 mg/g creatinine, p < 0.05). Serum calcium, glomerular filtration rate, and urinary sodium, did not change during the study. Lumbar spine bone density (trabecular bone) obtained with X ray absorptiometry revealed a significant increase from 1.162 +/- 0.231 to 1.197 +/- 0.248 g/cm2 (p < 0.01). These changes were associated with a significant decrease in IL-1 alpha mRNA transcription by unstimulated and lipopolysaccharide stimulated blood mononuclear cells, as tested by the reverse transcriptase polymerase chain reaction. No changes were observed in bone cortical sites (femoral neck). Normocalciuric subjects showed no significant changes in urinary calcium. In summary, the changes observed in urinary calcium excretion and different bone metabolic parameters, suggest a role of bone in the pathophysiology of idiopathic hypercalciuria.


Longitudinal MR Spectroscopy Shows Altered Metabolism in Traumatic Brain Injury.
Brain trauma is known to result in heterogeneous patterns of tissue damage and altered neuronal and glial metabolism that evolve over time following injury; however, little is known on the longitudinal evolution of these changes. In this study, magnetic resonance spectroscopic imaging (MRSI) was used to map the distributions of altered metabolism in a single subject at five time points over a period of 28 months following injury. Magnetic resonance imaging and volumetric MRSI data were acquired in a subject that had experienced a moderate traumatic brain injury (Glasgow Coma Scale 13) at five time points, from 7 weeks to 28 months after injury. Maps of N-acetylaspartate (NAA), total choline (Cho), and total creatine signal were generated and differences from normal control values identified using a z-score image analysis method. The z-score metabolite maps revealed areas of significantly reduced NAA and increased Cho, predominately located in frontal and parietal white matter, which evolved over the complete course of the study. A map of the ratio of Cho/NAA showed the greatest sensitivity to change, which indicated additional metabolic changes throughout white matter. The metabolic changes reduced over time following injury, though with abnormal values remaining in periventricular regions. The use of z-score image analysis for MRSI provides a method for visualizing diffuse changes of tissue metabolism in the brain. This image visualization method is of particularly effective for visualizing widespread and diffuse metabolic changes, such as that due to traumatic injury.


Tertiary conformation of the template-primer and gapped DNA substrates in complexes with rat polymerase beta. Fluorescence energy transfer studies using the multiple donor-acceptor approach.
The tertiary structure of template-primer and gapped DNA substrates in the complex with rat polymerase beta (pol beta) has been examined using the fluorescence energy transfer method based on the multiple donor-acceptor approach. In these studies, we used DNA substrates labeled at the 5' end of the template strand and the 5' end of the primer with the fluorescent donor and/or acceptor. Measurements of the enzyme complex with the template-primer DNA substrate having a ten nucleotide long ssDNA extension indicate that the distance between the 5' end of the template strand and the 5' end of the primer decreases by approximately 9.8 A as compared to the free nucleic acid. Analogous experiments with the template-primer substrate, having the ssDNA extension with five nucleotide residues, show approximately 6.6 A distance decrease. Such large distance decreases indicate that the DNA is significantly bent in the binding site. Analysis of the data indicates that the bending occurs between the third and the fourth nucleotide of the ssDNA extension. The entire template strand is at the bend angle Theta(TP) = 85 +/- 7 degrees with respect to the dsDNA part of the DNA molecule. In the polymerase complex with the gapped DNA, the distance between the 5' ends of the DNA and the bend angle are 66 +/- 2.2 A and 65 +/- 6 degrees, respectively. These values are very similar to the same distance and bend angle of the gap complex in the crystal structure of the co-complex. The presence of the 5'-terminal PO(4)(-) group downstream from the primer does not affect the tertiary conformation of the gapped DNA, indicating that the effect of the phosphate group is localized at the ssDNA gap.


Amino acids and keto acids in the treatment of chronic renal failure.
Clinical trials using very low protein supply supplemented with amino acid or keto acid preparations have shown the possibility of slowing the rate of decline of renal function in patients with advanced chronic renal failure together with preservation of nutritional status. The possible mechanisms by which this effect is obtained are reviewed. The potential advantages of keto acids upon amino acids, the optimal composition of the preparations used, and the best time to start treatment in chronic uremics are discussed. Projection of recent data indicate that a prolongation of renal autonomy of about 4 years instead of a spontaneous duration of 15 months until dialysis can be expected using keto acid treatment if started when plasma creatinine reaches 500 mumol/l.


The use of molecular methods for the detection and identification of methicillin-resistant Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in many hospitals and long-term care facilities as well as in the community. To limit the spread of MRSA, early detection and proper treatment are essential. Because conventional culture as gold standard is time consuming, new techniques such as PCR-based and hybridization assays have emerged for the rapid detection of MRSA. This review will focus on the currently available molecular-based assays and on their utility and performance for detection of S. aureus, of its virulence factors and of the markers for acquired resistance.


Putting the waste out: a proposed mechanism for transmission of the mycoparasite Escovopsis between leafcutter ant colonies.
The attine ant system is a remarkable example of symbiosis. An antagonistic partner within this system is the fungal parasite Escovopsis, a genus specific to the fungal gardens of the Attini. Escovopsis parasitizes the Leucoagaricus symbiont that leaf-cutting ants (Acromyrmex, Atta) have been farming over the past 8-12 Myr. However, it has been a puzzle how Escovopsis reaches its host. During a seasonal survey of nests of Acromyrmex subterraneus subterraneus in Atlantic rainforest in Brazil, Escovopsis was detected in all the sampled fungal garden waste tips or middens (n = 111). Middens were built strategically; always below the nest entrances. Here, we report the first evidence of a putative mechanism for horizontal transmission of Escovopsis between attine colonies. It is posited that leaf-cutting ants pick up the spores from soil and litter during foraging and vector the mycoparasite between attine colonies. Field and laboratory experiments, using At. laevigata and Ac. subterraneus subterraneus, confirm that Escovopsis spores are phoretic, and have an inbuilt dormancy, broken by the presence of their Leucoagaricus host. However, in the coevolutionary arms race, Atta ants may lose out-despite most species in the genus investing in a more advanced waste disposal system-due to the insanitary habits of their Acromyrmex neighbours.


Cadmium induces apoptosis in primary rat osteoblasts through caspase and mitogen-activated protein kinase pathways.
Exposure to cadmium (Cd) induces apoptosis in osteoblasts (OBs); however, little information is available regarding the specific mechanisms of Cd-induced primary rat OB apoptosis. In this study, Cd reduced cell viability, damaged cell membranes and induced apoptosis in OBs. We observed decreased mitochondrial transmembrane potentials, ultrastructure collapse, enhanced caspase-3 activity, and increased concentrations of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 following Cd treatment. Cd also increased the phosphorylation of p38-mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK)1/2 and c-jun N-terminal kinase (JNK) in OBs. Pretreatment with the caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, ERK1/2 inhibitor (U0126), p38 inhibitor (SB203580) and JNK inhibitor (SP600125) abrogated Cd-induced cell apoptosis. Furthermore, Cd-treated OBs exhibited signs of oxidative stress protection, including increased antioxidant enzymes superoxide dismutase and glutathione reductase levels and decreased formation of reactive oxygen species. Taken together, the results of our study clarified that Cd has direct cytotoxic effects on OBs, which are mediated by caspase- and MAPK pathways in Cd-induced apoptosis of OBs.


Effect of ethanol on gastric mucus glycoprotein synthesis, translocation, transport, glycosylation, and secretion.
The effect of ethanol on mucus glycoprotein synthesis, intracellular modification, transport, glycosylation, and secretion was studied in rat gastric mucous cells. Preincubation of the in vitro translation mixture containing gastric mucous cells mRNA for 60 min with 0 to 120 mM ethanol caused a decrease in the synthesis of mucus glycoprotein apopeptide by up to 40%. The reduction in translation was time- and ethanol concentration-dependent. After 60 min, translation in the presence of 30, 60, and 120 mM ethanol decreased to 83.3 +/- 2.3%, 75.5 +/- 0.4%, and 63.6 +/- 2.6%, respectively. The experiments conducted with endoplasmic reticulum microsomes, preincubated with ethanol, and used in the studies of cotranslational translocation of the apomucin showed a 20% decrease in the transfer of mucus glycoprotein apopeptide to the lumen of endoplasmic reticulum microsomes. In the presence of ethanol, processing of mucus glycoprotein apopeptide in Golgi was also inhibited. During the initial 30 min of incubation with 0 to 120 mM ethanol, glycosylation seemed to proceed at the same rate in the samples with and without ethanol. However, during consecutive 30 min of incubation, glycosylation in the presence of 60 mM ethanol decreased by 30 to 35%, and with 120 mM ethanol was completely inhibited. Measurements of the effect of ethanol on the discharge of mucus glycoprotein from the intracellular stores revealed that, on average, the secretory output of the rat gastric mucosa exposed to ethanol liquid diet for 8 weeks decreased by 77% or more, and adherence of the glycoprotein to the gastric epithelium was weakened. Results indicate that ethanol inhibits synthesis, transport, and processing of gastric mucus glycoprotein, and that the processes taking place in different intracellular compartments contribute in the additive fashion and, are reflected in a dramatic decrease in the delivery of mucus glycoprotein to the gastric epithelial surfaces.


Oocyte and embryo preservation in wild animals: an update.
The reduction in population genetic diversity due to inbreeding depression and the negative impact of human activity on habitats ultimately generates an extinction debt. Therefore, there is always a dire need to save wild population and to protect biodiversity. Preservation of wildlife female germplasm, i.e., oocytes and embryos, is a promising biotechnological tool to conserve species' biodiversity. Other applied tools of Assisted Reproductive Technology (ART) which assure conservation of endangered species include artificial insemination (AI), embryo transfer technology (ETT), and sperm cryopreservation. Only a few studies show the possibility of adapting the cryopreservation techniques developed for domestic animal female genetic material for use with wild animals. Difficulty is encountered in getting samples, accesses to animals for study, and the standardization of protocols for cryopreservation of such genetic material. Our meta-analysis of the literature (published or in press) and on-going studies found that biobanking for the preservation of vital tissues of wild animals is possible. Somatic tissue sections, ovarian tissues, sperms, oocytes and embryos are potential materials for preservation by vitrification. As vitrification is economical and easily applied, it appears to the best option currently available for the preservation of wildlife female genetics in order to conserve species' biodiversity.


C-Au Covalently Bonded Molecular Junctions Using Nonprotected Alkynyl Anchoring Groups.
We report on an approach to realize carbon-gold (C-Au) bonded molecular junctions without the need for an additive to deprotect the alkynyl carbon as endstanding anchor group. Using the mechanically controlled break junction (MCBJ) technique, we determine the most probable conductance value of a family of alkynyl terminated oligophenylenes (OPA(n)) connected to gold electrodes through such an akynyl moiety in ambient conditions. The molecules bind to the gold leads through an sp-hybridized carbon atom at each side. Comparing our results with other families of molecules that present organometallic C-Au bonds, we conclude that the conductance of molecules contacted via an sp-hybridized carbon atom is lower than the ones using sp(3) hybridization due to strong differences in the coupling of the conducting orbitals with the gold leads.


Recent developments in the molecular characterization of Barrett's esophagus.
Barrett's esophagus, or specialized intestinal metaplasia, is a common condition associated with gastroesophageal reflux and an increased risk for adenocarcinoma of the esophagus and gastric cardia. Currently, clinical surveillance for early detection of adenocarcinoma relies on the histopathological assessment of dysplasia. In this review we present data from the published literature, and combine this with results from our own research, to address what is currently known about the environmental factors and the molecular changes thought to be important in the pathogenesis of Barrett's esophagus. The most important and well-characterized molecular changes, preceding the development of dysplasia, are alterations in the p53 and erbB-2 genes and aneuploidy. These molecular changes, as well as environmental influences, such as the quality and quantity of gastroduodenal refluxate, may result in abnormal cell proliferation which in turn promotes further genetic abnormalities and deregulation of cell growth. The identification of molecular changes, in the context of predisposing environmental factors, will enhance our understanding of the malignant progression of Barrett's esophagus leading to more effective surveillance and treatment.


Clinical transplantation: current problems, possible solutions.
I have attempted to summarize the progress that has been made in organ transplantation in the past 50 years since the first identical twin transplant. For those who have worked long in this area its success has been remarkable. We currently expect patients to survive the operation and more than 90% of the graft to be functioning at a year with the half-life of the graft beyond 10 years, with some patients surviving into the fifth decade after kidney transplantation with grafts from unrelated donors and the fourth decade for liver transplants. Now the main stumbling block is shortage of organ donors and this is unlikely to be solved easily. There has been a considerable increase in donations from living volunteers and also the worry of immoral and illegal practices. In the future, we can expect considerable advances in immunosuppression with more effective, less toxic drugs and in some patients induction therapy that may approach tolerance so that no maintenance therapy will eventually be needed. Cell transplantation is likely to be developed as treatment for the clinic in the next 5-10 years, but developments of transplantation from animal to man still remains unsolved and unlikely to be successful in the clinic in the near future.


Halothane attenuates nitric oxide relaxation of rat aortas by competition for the nitric oxide receptor site on soluble guanylyl cyclase.
Endothelial cells play an important role in the regulation of vascular activity through the release of endothelium derived relaxing factor (EDRF) now believed to be nitric oxide (NO). NO and the NO donor drug nitroglycerin relax vascular smooth muscle by stimulating soluble guanylyl cyclase leading to elevation of intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP). Halothane has been shown to inhibit the action of NO on blood vessels. This study was designed to further investigate the mechanisms by which halothane attenuates NO-induced vascular relaxations. This was done by examining the effects of halothane on nitroglycerin and NO-induced relaxations in the presence and absence of the inhibitors of soluble guanylyl cyclase, methylene blue and 6-anilino-5,8-quinolinedione (LY 83583). Thoracic aortas from anesthetized male Sprague-Dawley rats were excised and cut into rings and the endothelium was removed. The aortic rings were suspended in organ baths containing Krebs solution and equilibrated at their optimal passive tension. When a stable plateau of contraction was produced by EC60 concentrations of norepinephrine, increasing concentrations of nitroglycerin or NO were added to the baths to relax the rings. This contraction-relaxation procedure was repeated three or four times. In some baths halothane was administered by a calibrated vaporizer 10 min before beginning the second procedure. Either methylene blue or LY 83583 was added to the baths 20 min before the third procedure. The combination of halothane, methylene blue or LY 83583 was added before the fourth procedure. Halothane, methylene blue or LY 83583 significantly inhibited nitroglycerin-induced relaxation individually. Halothane and LY 83583 also significantly inhibited NO-induced relaxations (5 x 10(-9)-3 x 10(-8) M and 5 x 10(-9)-3 x 10(-5) M, respectively) individually. The combination of halothane and methylene blue or halothane and LY 83583 significantly inhibited nitroglycerin-induced relaxation, also, the combination of halothane and LY 83583 significantly inhibited NO-induced relaxations. Halothane, methylene blue and LY 83583 treatment led to rightward shift in the concentration-effect curves. Halothane, in combination with methylene blue or LY 83583, produced inhibition equivalent to the sum of their individual effects. The present study demonstrates that the halothane, methylene blue and LY 83583 attenuate nitroglycerin and NO-induced relaxations of endothelium-denuded rat aortic rings. This suggests that halothane, methylene blue and LY 83583 may act through competitive antagonism at a common site of action on soluble guanylyl cyclase in the EDRF/NO relaxation pathway.


Craniofacial morphological characteristics in children with obstructive sleep apnea syndrome: a systematic review and meta-analysis.
The authors conducted a systematic review to consolidate the current knowledge regarding craniofacial morphological characteristics associated with obstructive sleep apnea syndrome (OSAS) in nonsyndromic pediatric patients. The authors included clinical studies in which participants were younger than 18 years, polysomnography was performed to determine the presence and severity of OSAS and the study group was compared with a control group or normative growth center data. The authors excluded studies with syndromic participants or participants who had received orthodontic treatment, orthognathic treatment or both previously. The authors identified nine articles. They conducted a meta-analyses of the data from all but one of the studies to evaluate the eight most common cephalometric variables in children with OSAS. The I(2) values were 79.53 percent for the angle from the basion point to the sella nasion (SN) line, 89.54 percent for the angle between the SN and palatal plane lines and 96.82 percent for the angle between the mandibular plane and SN lines (MP-SN). Therefore, for these three variables, the authors conducted a random-effect model meta-analysis. For the remaining five variables (MP-SN, the angle from SN to Apoint, the angle from SN to B point [SNB], the angle from A point to nasion point to B point [ANB] and the angle from articulare point to gonion point to gnathion point), I(2) values were all less than 40 percent, and therefore the authors conducted a fixed-effects model meta-analysis. Three of the evaluated cephalometric variables (MP-SN, SNB and ANB) had statistically significant differences in comparison with those in a control group. Although the values of these variables were increased in children with OSAS, results of the meta-analysis should be considered cautiously owing to the limited number of cephalometric variables included. Dentists who identify patients with a craniofacial morphology consistent with pediatric OSAS (retrusive chin, steep mandibular plane, vertical direction of growth and a tendency toward Class II malocclusion) should inquire further into their patients' medical histories. When the craniofacial morphology is accompanied by a history of snoring, inability to breathe through the nose, significant allergies, asthma or obesity, the dentist should refer the patient to an otolaryngologist for assessment.


Impact of cytomegalovirus serologic status on heart transplantation.
Cytomegalovirus (CMV) infection has been associated with increased risk of mortality, cardiac allograft vasculopathy, and de novo malignancy following heart transplantation in prior institutional reports. This study examines the impact of the recipient and donor CMV status on heart recipients in the United States. Adult heart transplant recipients were identified in the OPTN registry between 2005-2016. Recipients were stratified based on the recipient (R) and donor (D) CMV serologic status (+/-). The primary endpoint was survival 5-years after transplantation. The secondary endpoint was cardiac allograft vasculopathy 5-years after transplantation. Separate Cox proportional hazards regression models were developed to evaluate independent associations between CMV status and each of the study endpoints. A total of 21 878 recipients met the inclusion criteria. The breakdown of study arms by CMV serologic status was R-/D- = 3412, R+/D- = 4939; R-/D+ = 5230, and R+/D+ = 8,297. Five-year survival estimates were similar across groups (77-79%). CMV status was associated with increased mortality at 5-years (23%-41% increased risk) which was most evident in the first 3 months. The use of valganciclovir was associated with decreased risk of mortality (HR 0.56; 95% CI, 0.52-0.60). The cumulative incidence of cardiac allograft vasculopathy (R-/D- = 31%, R+/D- = 30%, R-/D+ = 31%, and R+/D+ = 30%) was similar across groups. CMV seropositivity at the time of transplantation is associated with increased long-term risk of mortality. Chemoprophylaxis with antivirals seems to mitigate this risk. There was no association with an increased risk of allograft vasculopathy.


Pharmacokinetics of intranasal amiloride in healthy volunteers.
Anxiety and panic disorders are the most common mental illnesses in the United States and lack effective treatment options. Acid-sending ion channels (ASICs) in the brain were shown to be associated with fear conditioning and anxiety responses and therefore are potential targets for treating panic disorder. Amiloride is an inhibitor of the ASICs in the brain and was shown to reduce panic symptoms in preclinical animal models. An intranasal formulation of amiloride will be highly beneficial to treat acute panic attacks due to advantages such as the rapid onset of action and patient compliance. The aim of this single-center, open-label trial was to evaluate the basic pharmacokinetics (PKs) and safety of amiloride after intranasal administration in healthy human volunteers at three doses (0.2, 0.4, and 0.6 mg). Amiloride was detected in plasma within 10 min of intranasal administration and showed a biphasic PK profile with an initial peak within 10 min of administration followed by a second peak between 4 and 8 h of administration. The biphasic PKs indicate an initial rapid absorption via the nasal pathway and later slower absorption by non-nasal pathways. Intranasal amiloride exhibited a dose-proportional increase in the area under the curve and did not exhibit any systemic toxicity. These data indicate that intranasal amiloride is rapidly absorbed and safe at the doses evaluated and can be further considered for clinical development as a portable, rapid, noninvasive, and nonaddictive anxiolytic agent to treat acute panic attacks.


Atypical Bilateral Fuchs Uveitis: Diagnostic Challenges.
Bilateral Fuchs uveitis associated with vitreous infiltration and posterior segment involvement requires a thorough diagnostic evaluation. The lack of well-defined diagnostic criteria makes identification of this entity difficult. The aim of this case report was to present the characteristics of a patient with atypical Fuchs uveitis and the procedures needed to rule out the differential diagnosis with specific attention to the utility of in vivo confocal microscopy (IVCM). One case of chronic bilateral uveitis with severe vitreous opacities is presented. After extensive systemic workup, including vitrectomy, the case had no identifiable systemic etiology. IVCM of the cornea revealed the presence of dendritiform keratic precipitates. The diagnosis of Fuchs uveitis is based on clinical findings as no confirmatory laboratory tests are available. A high index of suspicion is key to an early diagnosis, especially in the cases with vitreous opacities and posterior segment manifestations. Auxiliary tests such as IVCM may aid the clinician in the diagnosis of Fuchs uveitis.


Reductive DNA cleavage induced by UVA photoirradiation of NADH without oxygen.
UVA irradiation of dihydronicotinamide coenzyme (NADH), which plays a key role in a number of biological redox processes, results in effective DNA cleavage without oxygen via photoionization of NADH and the subsequent reaction of hydrated electron with DNA as well as photoinduced electron transfer from NADH to DNA.


Cystic fibrosis newborn screening: a model for neuromuscular disease screening?
Congenital neuromuscular disorders, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease (acid maltase deficiency [AMD]), are candidates for universal newborn screening (NBS). In this article, we discuss the future path of NBS for these disorders with particular emphasis on DMD NBS, because of the likely approval of new gene-modifying treatments, the possible benefits of earlier treatment with corticosteroids, and the recently demonstrated feasibility of a 2-tiered approach to NBS with screening by creatine kinase (CK) levels in dried blood spots followed by mutation detection in those with elevated CK. The cystic fibrosis (CF) NBS program is a successful model for NBS. CF outcomes have consistently improved into adulthood following introduction of CF NBS because considerable resources have been devoted to practices that include: attention to improving laboratory screening, consistent confirmatory testing and immediate referral of all newly diagnosed infants to designated CF care centers that follow established practice guidelines, and ongoing evaluation of CF care centers via a centralized clinical database. Like CF, DMD, SMA, and infantile AMD are inexorably debilitating and require lifetime multidisciplinary clinical management. NBS would address the delays in diagnosis that prevent patients from receiving timely treatments. Standardized care following early diagnosis would reduce disparities in clinical care and outcomes. NBS in these neuromuscular disorders should be implemented, utilizing lessons learned from the past 20 years of CF NBS: standardized protocols for all patients identified by DMD NBS, longitudinal follow-up in multidisciplinary clinics, and coordinated oversight of these clinics.


Rest-activity rhythms, daytime symptoms, and functional performance among people with heart failure.
Sleep disturbance and decreased daytime activity are well-described among people with chronic heart failure (HF) who suffer from disabling daytime symptoms and poor function. Alterations in the circadian rhythmicity of rest-activity may also be associated with these outcomes. However, little is known about the associations between rest-activity rhythms (RARS), symptoms, and functional performance or the extent to which they are explained by sleep characteristics among people with HF. The purpose of this study is to evaluate parametric and non-parametric circadian characteristics of RARs and the associations between these variables, daytime symptoms, and functional performance among patients with stable heart failure (HF). We recruited adults with stable HF from HF disease management programs. Participants wore wrist actigraphs for 3 d, completed one night of unattended polysomnography and the Six Minute Walk Test, and reported daytime symptoms and physical function. We performed cosinor, non-parametric, and spectral analyses to evaluate the rest-activity rhythms and computed bivariate correlations between the rest-activity rhythm, demographics, daytime symptoms, and functional performance. We conducted multiple regression analysis to examine how RARs contribute to daytime symptoms and functional performance after controlling for insomnia and covariates. The sample included 135 participants [Mean age = 60.6 (16.1) y, n = 88 (65.2%) male]. Older age, greater comorbidity, and poorer New York Heart Association (NYHA) Class, and more EEG arousals were associated with greater intra-daily variability of the RAR. More robust rhythmicity represented by the circadian quotient was associated with better NYHA class and less sleep fragmentation. A higher circadian quotient was significantly associated with lower fatigue, depression, and sleepiness, and better functional performance after controlling for insomnia and clinical and demographic characteristics. Circadian parameters of rest-activity are associated with symptoms and functional performance among people with HF independent of insomnia or sleep disordered breathing. Interventions targeted at improving the stability and strength of rest-activity rhythms may improve symptom and functional outcomes for these patients.


[Kinetic study on the degradation of penicillin potassium at different temperature and relative humidity].
To perform a kinetic analysis and formulation of the degradation of penicillin potassium in the solid phase at different temperature and relative humidity. Penicillin potassium was incubated in a temperature-and-humidity-controlled oven at different temperature and relative humidity, and was determined by HPLC at suitable time intervals during the incubation. The reaction rate was expressed as -dc/dt=k(c0-c+B), where c is the residual concentration, k degradation rate constant, c0 original concentration and B a constant related to original concentration of degradant. Degradation curves were fitted with c=c0-Bexp (kt)+B. The k was expressed as k=Aexp(-Ea/RT)exp(mHr), where active energy E. is 77.26 kJ/mol and constant m 0.1159. The degradation of penicillin potassium could be expressed with c=c0-Bexp [Aexp (-Ea/RT)exp (mHr)t]+B.


Atomic-Resolution Cryogenic Scanning Transmission Electron Microscopy for Quantum Materials.
ConspectusThe rich physics permeating the phase diagrams of quantum materials have commanded the attention of the solid-state chemistry, materials science, and condensed-matter physics communities, sparking immense research into quantum phase transitions including superconducting, ferroic, and charge-order transitions. Many of these transitions occur at low temperatures and involve electronic, magnetic, or lattice order, which emerges on the atomic to mesoscopic scales. The complex interplay of these states and the heterogeneity that arises due to competition and intertwining of phases, however, is not fully understood and requires probes that capture ordering over multiple length scales down to the local atomic symmetries. Advances in scanning transmission electron microscopy (STEM) have enabled atomic-resolution imaging as well as mapping of functional picometer-scale atomic displacements inside materials. In this Account, we discuss our group's work to expand the reach of atomic-resolution STEM to cryogenic temperatures (cryo-STEM) to study quantum materials with focus on charge-ordered systems.Charge-ordered phases, in which electrons as well as the atomic lattice form periodic patterns that lift the translational symmetries of the crystal, are not only intertwined with superconductivity but also underlie other exotic electronic phenomena such as colossal magnetoresistance and metal-insulator transitions. The periodic lattice distortions (PLDs) modulate the positions of the crystal's nuclei, which can be readily probed by electron microscopy. In a set of examples, we demonstrate cryo-STEM as a powerful technique for probing local order, nanometer-scale heterogeneities, and topological defects in charge-ordered manganites and in transition metal dichalcogenide charge density wave (CDW) systems.With the nearly commensurate-to-commensurate CDW transition upon cooling in 1T-TaS2, we show that nanoscale lattice textures in CDW phases can be revealed through direct imaging. These early atomic-resolution results, however, also highlighted the need for improvements in cryo-STEM imaging, which led to a push to advance data collection and analysis for direct spatial mapping and quantification of PLDs. By introducing an image registration algorithm developed specifically to accommodate fast, low signal-to-noise image acquisitions of crystalline lattices, we address previous limitations due to sample drift in cryo-STEM experiments. This has enabled subangstrom cryo-STEM imaging with sufficient signal-to-noise to reveal the low temperature structure of 1T'-TaTe2. Furthermore, it allows mapping and quantification of PLD atomic displacements in the charge-ordered manganites Bi0.35Sr0.18Ca0.47MnO3 and Nd0.5Sr0.5MnO3 with picometer precision at ∼95 K to resolve not only distinct ordered phases (i.e., site- and bond-centered charge order) but also their nanoscale coexistence within the same sample.Atomic-resolution cryo-STEM opens new opportunities for understanding the microscopic underpinnings of quantum phases. In this Account, we focus on spatial mapping of lattice degrees of freedom in phases that are present at temperatures down to liquid nitrogen. Further advances in instrumentation are needed to expand the temperature range and to also enable atomic-resolution measurements that rely on weaker signals such as electron energy loss spectroscopy (EELS) for probing of electronic structure or 4D-STEM approaches to map electric and magnetic fields.


Up-regulation of OsBIHD1, a rice gene encoding BELL homeodomain transcriptional factor, in disease resistance responses.
In the present study, we cloned and identified a full-length cDNA of a rice gene, OsBIHD1, encoding a homeodomain type transcriptional factor. OsBIHD1 is predicted to encode a 642 amino acid protein and the deduced protein sequence of OsBIHD1 contains all conserved domains, a homeodomain, a BELL domain, a SKY box, and a VSLTLGL box, which are characteristics of the BELL type homedomain proteins. The recombinant OsBIHD1 protein expressed in Escherichia coli bound to the TGTCA motif that is the characteristic cis-element DNA sequence of the homeodomain transcriptional factors. Subcellular localization analysis revealed that the OsBIHD1 protein localized in the nucleus of the plant cells. The OsBIHD1 gene was mapped to chromosome 3 of the rice genome and is a single-copy gene with four exons and three introns. Northern blot analysis showed that expression of OsBIHD1 was activated upon treatment with benzothiadiazole (BTH), which is capable of inducing disease resistance. Expression of OsBIHD1 was also up-regulated rapidly during the first 6 h after inoculation with Magnaporthe grisea in BTH-treated rice seedlings and during the incompatible interaction between M. grisea and a resistant genotype. These results suggest that OsBIHD1 is a BELL type of homeodomain transcription factor present in the nucleus, whose induction is associated with resistance response in rice.


Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.
Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.


CLOCK 3111TT Genotype Is Associated with Increased Total Cholesterol and Low-Density Lipoprotein Levels in Menopausal Women with a Body Mass Index of at Least 25 kg/m2.
Lipid profile comparative analysis was performed to reveal the interdependence of lipids with Circadian locomoter output cycles protein kaput (CLOCK) 3111T/C gene polymorphism in menopausal women with/without a body mass index (BMI) of ≥25 kg/m2. Methods: A total of 193 female volunteers aged 45 to 60 years were divided into two groups: Those with BMI < 25 kg/m2 (control) and those with BMI ≥ 25 kg/m2. Each group was then divided into two subgroups: Those with the CLOCK TT-genotype and those with the CLOCK TC-, CC-genotypes. Lipid metabolism parameters were determined by the enzymatic method. Single-nucleotide polymorphisms (SNPs) were detected via polymerase chain reaction-restriction fragment length polymorphism technology. Results: There were no differences in CLOCK 3111T/C genotypes or allele frequency between the control and main groups. In addition, there were no differences in lipid profile parameters between women of the control group and different CLOCK 3111T/C genotypes. The total cholesterol (p = 0.041) and low-density lipoprotein cholesterol (p = 0.036) levels were higher in the subgroup of women with a BMI ≥ 25 kg/m2 and CLOCK TT-genotype as compared to the subgroup with a BMI ≥ 25 kg/m2 and minor allele 3111C. Conclusions: SNP 3111T/C of the CLOCK gene is not associated with BMI however, data suggest that the minor allele of the CLOCK 3111T/C gene polymorphism may have a protective role in atherogenic lipid levels in women with a BMI greater than or equal to 25 kg/m2.


Cluster C personality disorders in major depressive episodes: the relationship between hostility and suicidal behavior.
There is some evidence for an association between Cluster C Personality Disorders (CCPD) and suicidal behavior. We compared depressed inpatients with and without CCPD in terms of suicidal behavior and associated psychopathology. Cluster A or B personality disorder co-morbidity were exclusion criteria for both groups (cases and controls). Depressed inpatients with "pure" CCPD had higher levels of suicidal ideation but not more previous suicide attempts compared with patients without CCPD. Greater suicidal ideation in depressed patients with CCPD in our study was associated with more hostility. Future studies examining the relationship between suicidal ideation and hostility in CCPD may clarify whether treatment focused on hostility might be of use for decreasing suicidal ideation in depressed patients with CCPD (Spitzer, Williams, Gibbon et al., 1990).


[Diagnosis, radioiodine and radiotherapy of thyroid carcinomas].
The long-term prognosis of differentiated thyroid carcinoma depends on early diagnosis and treatment of metastases and local recurrences and is modulated by several factors, age and histology being the most relevant. This article summarizes current trends in the use of radioactive iodine (131J) and gives explicit advice on its use in the treatment of these cancers. Complications of therapy are discussed in detail. We currently recommend that all patients undergoing a subtotal or total thyroidectomy are followed up by 131J thyroid scanning approximately 4 weeks after surgery. The combined use of three diagnostic modalities (measurement of serum thyroglobulin, neck ultrasonography with ultrasound-guided biopsy for detecting recurrences of carcinoma in the neck region and 131J whole-body scintigraphy) appears to give the best results in the follow up of patients with differentiated thyroid carcinoma. If any residual uptake is detected in the neck or if the tumor extends beyond the thyroid, we recommend routine thyroid ablation with 1,5-3 GBq of radioactive 131J. External radiotherapy is always indicated in papillary and folliculary carcinoma in the pT4 stage of pTNM classification but not in those in pT1-3 pN0 stage. In the presence of lymph-node metastases and distant metastases, an individual treatment concept is recommended regarding all risk factors, especially the age and sex of the patient, the histology and grading of the tumor and the completeness of tumor resection. Finally, radiotherapy is usually not indicated in medullary carcinoma, whereas it is always indicated in anaplastic carcinoma.


Evolutionary Transcriptomics and Proteomics: Insight into Plant Adaptation.
Comparative transcriptomics and proteomics (T&P) have brought biological insight into development, gene function, and physiological stress responses. However, RNA-seq and high-throughput proteomics remain underutilised in studies of plant adaptation. These methodologies have created discovery tools with the potential to significantly advance our understanding of adaptive diversification. We outline experimental recommendations for their application. We discuss analysis models and approaches that accelerate the identification of adaptive gene sets and integrate transcriptome, proteome, phenotypic, and environmental data. Finally, we encourage widespread uptake and future developments in T&P that will advance our understanding of evolution and adaptation.


Diminished left ventricular dyssynchrony and impact of resynchronization in failing hearts with right versus left bundle branch block.
We compared mechanical dyssynchrony and the impact of cardiac resynchronization therapy (CRT) in failing hearts with a pure right (RBBB) versus left bundle branch block (LBBB). Cardiac resynchronization therapy is effective for treating failing hearts with conduction delay and discoordinate contraction. Most data pertain to LBBB delays. With RBBB, the lateral wall contracts early so that biventricular (BiV) pre-excitation may not be needed. Furthermore, the magnitude of dyssynchrony and impact of CRT in pure RBBB versus LBBB remains largely unknown. Dogs with tachypacing-induced heart failure combined with right or left bundle branch radiofrequency ablation were studied. Basal dyssynchrony and effects of single and BiV CRT on left ventricular (LV) function were assessed by pressure-volume catheter and tagged magnetic resonance imaging, respectively. Left bundle branch block and RBBB induced similar QRS widening, and LV function (ejection fraction, maximum time derivative of LV pressure [dP/dt(max)]) was similarly depressed in failing hearts with both conduction delays. Despite this, mechanical dyssynchrony was less in RBBB (circumferential uniformity ratio estimate [CURE] index: 0.80 +/- 0.03 vs. 0.58 +/- 0.09 for LBBB, p < 0.04; CURE 0-->1 is dyssynchronous-->synchronous). Cardiac resynchronization therapy had correspondingly less effect on hearts with RBBB than those with LBBB (i.e., 5.5 +/- 1.1% vs. 29.5 +/- 5.0% increase in dP/dt(max), p < 0.005), despite similar baselines. Furthermore, right ventricular-only pacing enhanced function and synchrony in RBBB as well or better than did BiV, whereas LV-only pacing worsened function. Less mechanical dyssynchrony is induced by RBBB than LBBB in failing hearts, and the corresponding impact of CRT on the former is reduced. Right ventricular-only pacing may be equally efficacious as BiV CRT in hearts with pure right bundle branch conduction delay.


Liver function tests and electrophoretic pattern of serum protein in hepatic amoebiasis.
The liver function tests and the electrophoretic pattern of serum protein in a series of 11 patients admitted to Bernhard Nocht Institut with hepatic amoebiasis were reviewed. A constant pattern of hypoalbuminaemia and elevated alpha2 globulins were demonstrated in all patients. LDH enzyme levels were raised in all cases admitted with amoebic liver abscess. The pathogenesis of these disturbances was discussed.


Group-wise registration of point sets for statistical shape models.
This paper presents a novel, fast, group-wise registration technique based on establishing soft correspondences between groups of point sets. The registration approach is used to create a statistical shape model, capable of learning the shape variations within a training set. The shape model consists of a mean shape and its transformations to all training shapes. We decouple the procedure into two steps: updating the mean shape and registering it to the training shapes. The algorithm alternates between these two steps until convergence. Following the generation of the statistical shape model, we use the soft correspondence approach to register the model to a new observation. We perform extensive experiments on two data sets: lumbar spine and hippocampi. We compare our algorithm to available state-of- the-art group-wise registration algorithms including feature-based and volume-based approaches. We demonstrate improved generalization, specificity and compactness compared to these algorithms.


Potential contribution of human papillomavirus testing to cervical cancer screening.
A prospective study was carried out to assess the clinical value of HPV DNA identification in terms of cases missed by either cytology or combined cytology and colposcopy screening methods, 231 exfoliative cytology specimens and forty-one cervical tissue samples were analysed for the presence of HPV 6, 11, 16 and 18 DNA sequences using filter in situ and Southern blot hybridisation methods, 36% of cytology specimens examined by filter in situ hybridisation method were found to carry HPV DNA sequence. Forty-nine (27%) out of 184 cases without cytological evidence of neoplasia had a positive HPV test. Simultaneous colposcopic examination of these patients showed no abnormality in 17 cases. The relevance of HPV investigations was based on the characteristic HPV prevalence in preneoplastic and normal cervical tissue samples. The results suggest that traditional cervical screening may be improved by simultaneous HPV testing. According to the presented data, only a very small portion of a random patient population can be expected to carry HPVs without cytologic or colposcopic abnormalities.


Zero trust in edge computing environment: a blockchain based practical scheme.
Edge computing offloads the data processing capacity to the user side, provides flexible and efficient computing services for the development of smart city, and brings many security challenges. Aiming at the problems of fuzzy boundary security protection and dynamic identity authentication in the edge computing environment in smart city, the zero trust architecture based on blockchain is studied, and a digital identity model and dynamic authentication scheme of edge computing nodes based on distributed ledger are proposed. Firstly, a digital identity model of two-way authentication between edge computing node and sensing terminal is established to realize fine-grained authorization and access control in edge computing. Secondly, based on the identity data and behavior log bookkeeping on the chain, the quantification of trust value, trust transmission and update are realized, and the traceability of security events is improved. Finally, based on the improved RAFT consensus algorithm, the multi-party consensus and consistency accounting in the authentication process are realized. Simulation results show that this scheme can meet the requirements of zero trust verification in edge computing environment, and has good efficiency and robustness.


The effects of environmental enrichment on voluntary physical activity and muscle mass gain in growing rats.
Introduction: Environmental enrichment (EE) for rodents involves housing conditions that facilitate enhanced sensory, cognitive, and motor stimulation relative to standard housing conditions. A recent study suggested that EE induces muscle hypertrophy. However, it remains unclear whether muscle hypertrophy in EE is associated with voluntary physical activity, and the characteristics of muscle adaptation to EE remain unclarified. Therefore, this study investigated whether muscle adaptation to EE is associated with voluntary physical activity, and assessed the changes in the muscle fiber-type distribution and fiber-type-specific cross-sectional area in response to EE. Methods: Wistar rats (6 weeks of age) were randomly assigned to either the standard environment group (n = 10) or the EE group (n = 10). The voluntary physical activity of rats housed in EE conditions was measured using a recently developed three-axis accelerometer. After exposure to the standard or enriched environment for 30 days, the tibialis anterior, extensor digitorum longus, soleus, plantaris, and gastrocnemius muscles were removed and weighed. Immunohistochemistry analysis was performed on the surface (anterior) and deep (posterior) areas of the tibialis anterior and soleus muscles. Results and discussion: The EE group showed increased voluntary physical activity during the dark period compared with the standard environment group (p = 0.005). EE induced muscle mass gain in the soleus muscle (p = 0.002) and increased the slow-twitch muscle fiber cross-sectional area of the soleus muscle (p = 0.025). EE also increased the distribution of high-oxidative type IIa fibers of the surface area (p = 0.001) and type I fibers of the deep area (p = 0.037) of the tibialis anterior muscle. These findings suggest that EE is an effective approach to induce slow-twitch muscle fiber hypertrophy through increased daily voluntary physical activity.


Effects of the Type of Intraoperative Fluid in Living Donor Kidney Transplantation: A Single-Center Retrospective Cohort Study.
Perioperative fluid management in kidney transplant recipients is crucial to supporting the fluid, acid-base, and electrolyte balance required for graft perfusion. However, the choice of intraoperative crystalloids in kidney transplantation remains controversial. We conducted a single-center retrospective cohort study to evaluate the impact of intraoperative fluids on acid-base and electrolyte balance and graft outcomes. We included 282 living donor kidney transplant recipients from January 2010 to December 2017. Patients were classified into two groups based on the type of intraoperative crystalloids used (157 patients in the half saline group and 125 patients in the balanced crystalloid solutions group, Plasma-lyte). Compared with the half saline group, the Plasma-lyte group showed less metabolic acidosis and hyponatremia during surgery. Hyperkalemia incidence was not significantly different between the two groups. Changes in postoperative graft function assessed by blood urea nitrogen and creatinine were significantly different between the two groups. Patients in the Plasma-lyte group exhibited consistently higher glomerular filtration rates than those in the half saline group at 1 month and 1 year after transplantation after adjusting for demographic differences. Intraoperative Plasma-lyte can lead to more favorable results in terms of acid-base balance during kidney transplantation. Patients who received Plasma-lyte showed superior postoperative graft function at 1 month and 1 year after transplantation. Further studies are needed to evaluate the superiority of intraoperative Plasma-lyte over other types of crystalloids in relation to graft outcomes.


L-DOPS therapy for refractory orthostatic hypotension in autoimmune autonomic neuropathy.
The authors report a 46-year-old woman with antibodies to the nicotinic acetylcholine receptor (NiAchR) of the autonomic ganglia. She presented with severe orthostatic intolerance refractory to treatment with midodrine, fludrocortisone, erythropoietin, vasopressin, salt, and fluid loading. Addition of L-threo-3,4-dihidroxyphenylserine (L-DOPS) substantially improved blood pressure and orthostatic tolerance. L-DOPS may benefit patients with severe orthostatic intolerance and be particularly effective in patients with ganglionic NiAchR antibodies.


Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot Assay but Not CMV QuantiFERON Assay Is a Novel Biomarker To Determine Risk of Congenital CMV Infection in Pregnant Women.
Cytomegalovirus (CMV) enzyme-linked immunosorbent spot (ELISPOT) and CMV QuantiFERON assays were examined as potential biomarkers predictive of congenital CMV (cCMV) transmission. Fifty-seven pregnant women with primary CMV infection and 23 with nonprimary CMV infection were recruited in the study. Maternal age, CMV IgG avidity, viremia, and viruria were also included among the potential predictors. Spearman's statistical correlation analysis revealed a positive correlation between the CMV ELISPOT and CMV QuantiFERON assay results (P < 0.001), but only the CMV ELISPOT assay correlated with cCMV (P < 0.001). cCMV was positively correlated with maternal viremia and viruria (P < 0.05) and negatively correlated with CMV IgG avidity (P < 0.01). Maternal age and CMV QuantiFERON assay results were not statistically associated with cCMV. CMV-specific cell-mediated immunity detected by the CMV ELISPOT assay plays a critical role in cCMV.


Board certification and credentialing in nutrition.
Board certification and credentialing in nutrition for physicians are problematic issues. Many board examinations are offered, but have few candidates and poor recognition. This discussion focuses on the feasibility of establishing a single board examination body. Some key considerations were identified to improve credentialing and examination in nutrition for physicians. Increasing the number of nutrition physicians and improving recognition of their credentials should ultimately translate to better patient health and safety. Consolidation of board examinations may be in the best interest of physician nutritionists.


Modified onlay island flap versus tubularized incised plate urethroplasty for hypospadias reoperation.
This study aimed to assess the outcomes of modified onlay island flap (MOIF) urethroplasty for hypospadias reoperation. A retrospective analysis was conducted using clinical data on children reoperated with MOIF or tubularized incised plate (TIP) urethroplasty for hypospadias in the Children's Hospital of Nanjing Medical University (Nanjing, China) from December 2016 to September 2020. A total of 90 children with hypospadias who failed primary repair and were reoperated on with MOIF (MOIF group, n = 46) or TIP urethroplasty (TIP group, n = 44) were recruited. All children were postoperatively followed up for at least 6 months. Six patients with postoperative urinary fistula, 2 patients with glans dehiscence, and 1 patient with urethral diverticulum were reported in the MOIF group, while 7 patients with postoperative urinary fistula, 2 patients with urethral stricture, and 1 patient with glans dehiscence were reported in the TIP group. Postoperative infection, flap necrosis and other complications were not recorded. A total of 37 (80.4%) patients in the MOIF group and 34 (77.3%) patients in the TIP group were successfully reoperated. Although the success rates of MOIF and TIP urethroplasty are comparable, pediatricians should master different types of repair techniques for individualized hypospadias reoperation. MOIF urethroplasty can be recommended after failure of the primary repair.


Theoretical Neurobiology of Consciousness Applied to Human Cerebral Organoids.
Organoids and specifically human cerebral organoids (HCOs) are one of the most relevant novelties in the field of biomedical research. Grown either from embryonic or induced pluripotent stem cells, HCOs can be used as in vitro three-dimensional models, mimicking the developmental process and organization of the developing human brain. Based on that, and despite their current limitations, it cannot be assumed that they will never at any stage of development manifest some rudimentary form of consciousness. In the absence of behavioral indicators of consciousness, the theoretical neurobiology of consciousness being applied to unresponsive brain-injured patients can be considered with respect to HCOs. In clinical neurology, it is difficult to discern a capacity for consciousness in unresponsive brain-injured patients who provide no behavioral indicators of consciousness. In such scenarios, a validated neurobiological theory of consciousness, which tells us what the neural mechanisms of consciousness are, could be used to identify a capacity for consciousness. Like the unresponsive patients that provide a diagnostic difficulty for neurologists, HCOs provide no behavioral indicators of consciousness. Therefore, this article discusses how three prominent neurobiological theories of consciousness apply to human cerebral organoids. From the perspective of the Temporal Circuit Hypothesis, the Global Neuronal Workspace Theory, and the Integrated Information Theory, we discuss what neuronal structures and functions might indicate that cerebral organoids have a neurobiological capacity to be conscious.


Triple approach strategy for patients with locally advanced pancreatic carcinoma.
Radiofrequency ablation (RFA) is a relatively new technique, applied to metastatic solid tumours which, in recent studies, has been shown to be feasible and safe on locally advanced pancreatic carcinoma (LAPC). RFA can be combined with radio-chemotherapy (RCT) and intra-arterial plus systemic chemotherapy (IASC). The aim of this study was to investigate the impact on the prognosis of a multimodal approach to LAPC and define the best timing of RFA. This is a retrospective observational study of patients who have consecutively undergone RFA associated with multiple adjuvant approaches. Between February 2007 and December 2011, 168 consecutive patients were treated by RFA, of which 107 were eligible for at least 18 months of follow-up. Forty-seven patients (group 1) underwent RFA as an up-front treatment and 60 patients as second treatment (group 2) depending on clinician choice. The median overall survival (OS) of the whole series was 25.6 months: 14.7 months in the group 1 and 25.6 months in the group 2 (P = 0.004). Those patients who received the multimodal treatment (RFA, RCT and IASC-triple approach strategy) had an OS of 34.0 months. The multimodal approach seems to be feasible and associated with an improved longer survival rate.


Structure of the PX domain of SNX25 reveals a novel phospholipid recognition model by dimerization in the PX domain.
SNX25, a regulator of GPCR signaling-phox-homology (PX) domain containing sorting nexin (SNX) member, has been proposed to be involved in the lysosomal degradation of the transforming growth factor β receptor and the development of temporal lobe epilepsy. Targeting to the endosomal membranes by the specific binding of phosphorylated phosphatidylinositols (PIPs) through the PX domain is critical for the function of SNXs. However, the mechanism for SNX25-PX targeting to the endosomes remains unclear. Here, we demonstrate that the PX domain of zebrafish SNX25 (zSNX25-PX) is capable of binding to PI3P only in its dimeric form. We also present the crystal structure of zSNX25-PX. Combined with biochemical experiments, we further identify a potential PI3P-binding region and propose a novel PI-binding model based on dimerization in the PX domain of SNXs.


Probing the efficacy of a heterologous Leishmania/L. Viannia braziliensis recombinant enolase as a candidate vaccine to restrict the development of L. infantum in BALB/c mice.
In the present study, the Leishmania braziliensis enolase protein was evaluated as a vaccine candidate against visceral leishmaniasis (VL). The DNA sequence was cloned and the recombinant protein (rEnolase) was evaluated as a vaccine, associated with saponin, as an immune adjuvant. The protective efficacy of the rEnolase plus saponin combination was investigated in BALB/c mice against Leishmania infantum infection. The results revealed that the vaccine induced higher levels of IFN-γ, IL-12, and GM-CSF when a capture ELISA and flow cytometry were performed, as well as an antileishmanial nitrite production after using in vitro stimulation with rEnolase and an antigenic Leishmania preparation. The vaccinated animals, when compared to the control groups, showed a lower parasite burden in the liver, spleen, bone marrow, and paws' draining lymph nodes when both a limiting dilution technique and RT-PCR assay were performed. In addition, these mice showed low levels of antileishmanial IL-4, IL-10, and anti-Leishmania IgG1 isotype antibodies. Partial protection was associated with IFN-γ production, which was mainly mediated by CD4+ T cells. In conclusion, the present study's data showed that the L. braziliensis enolase protein could be considered a vaccine candidate that offers heterologous protection against VL.


Hypertrophic pulmonary osteoarthropathy heralding relapse of lymphoepithelioma.
Hypertrophic pulmonary osteoarthropathy is an uncommon paraneoplastic syndrome occasionally associated with nasopharyngeal lymphoepitheliomas. We treated two patients with previously diagnosed lymphoepitheliomas in whom hypertrophic pulmonary osteoarthropathy preceded the recognition of pulmonary metastases. Both patients' disabling arthritic syndromes resolved with effective therapy directed at their neoplasms.


Sexual functioning among testicular cancer survivors: a case-control study in the U.S.
Sexual function among testicular cancer survivors is a concern because affected men are of reproductive age when diagnosed. We conducted a case-control study among United States military men to examine whether testicular cancer survivors experienced impaired sexual function. A total of 246 testicular cancer cases and 236 ethnicity and age matched controls were enrolled in the study in 2008-2009. The Brief Male Sexual Function Inventory (BMSFI) was used to assess sexual function. Compared to controls, cases scored significantly lower on sex drive (5.77 vs. 5.18), erection (9.40 vs. 8.63), ejaculation (10.83 vs. 9.90), and problem assessment (10.55 vs. 9.54). Cases were significantly more likely to have impaired erection (OR 1.72; 95% CI 1.11-2.64), ejaculation (OR 2.27; 95% CI 1.32-3.91), and problem assessment (OR 2.36; 95% CI 1.43-3.90). In histology and treatment analysis, nonseminoma, chemotherapy and radiation treated cases risk of erectile dysfunction, delayed ejaculation, and/or problem assessment were greater when compared to controls. This study provides evidence that testicular cancer survivors are more likely to have impaired sexual functioning compared to demographically matched controls. The observed impaired sexual functioning appeared to vary by treatment regimen and histologic subtype.


Sirtuin deacylases: a molecular link between metabolism and immunity.
Lysine deacetylation by the NAD(+)-dependent family of sirtuins has been recognized as an important post-translational modification regulating a wide range of cellular processes. These lysine deacetylases have attracted much interest based on their ability to promote survival in response to stress. Sirtuins require NAD(+) for their enzymatic activity, suggesting that these enzymes may represent molecular links between cell metabolism and several human disorders, including diabetes and cancer. Inflammation represents a pathological situation with clear connections to metabolism and aging in humans, raising the possibility that sirtuins may also play an important role during a normal and/or a pathological immune response. A growing body of data has confirmed the immunomodulatory properties of sirtuins, although often with contrasting and opposing conclusions. These observations will be summarized herein and the possible strategies that may lead to the development of novel therapeutic approaches to treat inflammation briefly discussed.


Relationship between periodontitis and psoriasis: A two-sample Mendelian randomization study.
Observational research suggests that periodontitis affects psoriasis. However, observational studies are prone to reverse causation and confounding, which hampers drawing causal conclusions and the effect direction. We applied the Mendelian randomization (MR) method to comprehensively assess the potential bi-directional association between periodontitis and psoriasis. We used genetic instruments from the largest available genome-wide association study of European descent for periodontitis (17,353 cases, 28,210 controls) to investigate the relationship with psoriasis (13,229 cases, 21,543 controls), and vice versa. Causal Analysis Using Summary Effect (CAUSE) estimates and inverse variance-weighted (IVW) MR analyses were used for the primary analysis. Robust MR approaches were used for sensitivity analyses. Both univariable methods, CAUSE and IVW MR analyses, did not reveal any impact of periodontitis on psoriasis (CAUSE odds ratio [OR] = 1.00, p = 1.00; IVW OR = 1.02, p = .6247), or vice versa (CAUSE OR = 1.01, p = .5135; IVW OR = 1.00, p = .7070). The null association was corroborated by pleiotropy-robust methods with ORs close to 1 and p-values >.59. Overall, MR analyses did not suggest any effect of periodontitis on psoriasis. Similarly, there was no evidence to support an effect of psoriasis on periodontitis. Within the limitations of this MR study, the outcomes supported neither periodontitis affecting psoriasis nor psoriasis affecting periodontitis.


Arterial CO2 as a Potent Coronary Vasodilator: A Preclinical PET/MR Validation Study with Implications for Cardiac Stress Testing.
Myocardial blood flow (MBF) is the critical determinant of cardiac function. However, its response to increases in partial pressure of arterial CO2 (PaCO2), particularly with respect to adenosine, is not well characterized because of challenges in blood gas control and limited availability of validated approaches to ascertain MBF in vivo. Methods: By prospectively and independently controlling PaCO2 and combining it with 13N-ammonia PET measurements, we investigated whether a physiologically tolerable hypercapnic stimulus (∼25 mm Hg increase in PaCO2) can increase MBF to that observed with adenosine in 3 groups of canines: without coronary stenosis, subjected to non-flow-limiting coronary stenosis, and after preadministration of caffeine. The extent of effect on MBF due to hypercapnia was compared with adenosine. Results: In the absence of stenosis, mean MBF under hypercapnia was 2.1 ± 0.9 mL/min/g and adenosine was 2.2 ± 1.1 mL/min/g; these were significantly higher than at rest (0.9 ± 0.5 mL/min/g, P < 0.05) and were not different from each other (P = 0.30). Under left-anterior descending coronary stenosis, MBF increased in response to hypercapnia and adenosine (P < 0.05, all territories), but the effect was significantly lower than in the left-anterior descending coronary territory (with hypercapnia and adenosine; both P < 0.05). Mean perfusion defect volumes measured with adenosine and hypercapnia were significantly correlated (R = 0.85) and were not different (P = 0.12). After preadministration of caffeine, a known inhibitor of adenosine, resting MBF decreased; and hypercapnia increased MBF but not adenosine (P < 0.05). Conclusion: Arterial blood CO2 tension when increased by 25 mm Hg can induce MBF to the same level as a standard dose of adenosine. Prospectively targeted arterial CO2 has the capability to evolve as an alternative to current pharmacologic vasodilators used for cardiac stress testing.


Does capsaicin affect the thermal sensation of males during immersion in 18 degrees C and 22 degrees C?
Animals respond to acute local or systemic administration of capsaicin with strong nociceptive reactions. The present investigation examined the thermal sensation in males who were given capsaicin (CAP, 2 mg x kg(-1) body weight) vs a placebo (PL, a maltodextrin capsule) before immersion in cold water. Seven Caucasian males ages 20-28 years were immersed in 18 degrees C and 22 degrees C twice (PL vs CAP) for 120 minutes. The following were examined: metabolism (VO2; L x min(-1)), rectal temperature (Tre; degrees C), and thermal sensation (TS). For VO2 there were no significant differences between treatments (PL vs CAP) when the variables were pooled jointly over the two immersion temperatures (18 degrees C and 22 degrees C) and across time. However, for Tre there were significant differences detected across time (p = 0.01) when Tre was pooled jointly across two treatments and two immersion temperatures. Postanalysis of variance revealed specific significant differences between 5 minutes (mean +/- SE; 37.2 +/- 0.07) and 120 minutes (36.0 +/- 0.09). For TS, there was a trend (p = 0.0699) which demonstrated differences between immersion temperatures only when TS was pooled jointly over the two treatments and across time, whereby TS was lower in 18 degrees C (6.2 +/- 0.5) than in 22 degrees C (3.7 +/- 0.6). From these data it appears that although Tre differed across time and temperature, respectively, a CAP feeding did not affect differentially the TS and metabolic response of males during acute cold water immersion.


Chemical coding of submucosal type V neurons in porcine ileum.
In this study, we attempted to determine the proportion of type V neurons relative to the putative whole neuron population in the two submucosal plexuses of pigs identified by their neurofilament immunoreactivity. The total neuron number was estimated in cuprolinic blue (CB)/anti-Hu protein (HU) costained wholemounts as the sum of the number of CB+/HU+, CB+/HU- and CB-/HU+ neurons. In the external submucosal plexus (ESP), HU labelled 98.6% and CB 97.3% of neurons. In the internal submucosal plexus, HU labelled 98.3%, whereas CB only marked 92.5% of neurons. Furthermore, we investigated the chemical coding of submucosal type V neurons and searched for submucosal, non-type V neurons displaying the same chemical coding as the myenteric type V neurons described earlier, i.e. the colocalization of calcitonin gene-related peptide (CGRP) and somatostatin (SOM). In order to facilitate immunohistochemical detection of neuroactive peptides, ileal segments were pretreated with colchicine prior to fixation. Type V neurons in the ESP occurred either as single cells displaying one or few prominent dendrite(s) or within aggregates displaying a dendritic tangle. In this plexus, type V neurons amounted to between 0.9 and 1.6% of all CB-stained neurons. ESP type V neurons displayed immunoreactivities for choline acetyl transferase (95.8%) and leucine-enkephalin (73.9%). All type V neurons were negative for neuronal nitric oxide synthase. Fifty-eight percent of ESP CGRP/SOM co-immunoreactive neurons displayed type V morphology, whereas 42% were non-type V neurons. Thus, the chemical coding of ESP type V neurons is in principal similar to that of the myenteric type V neurons described earlier. In the internal submucosal plexus, we found no type V neurons. In this plexus, 0.2% of all neurons counterstained with HU displayed CGRP/SOM coreactivity. As had been observed earlier concerning the myenteric type V neurons, ESP type V neurons were also closely apposed by conspicuous accumulations of boutons reactive for the same markers as the neurons themselves. Although we cannot exclude that axons of CGRP/SOM-reactive enteric, non-type V or extrinsic neurons end synaptically on type V neurons, we suggest that the main synaptic input to type V neurons originates from other type V neurons. This presents an argument for an interneuronal role of type V neurons.


An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.
The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.