Overt and fantasized aggression toward parents by enuretic and nonenuretic children.
This study compared the amount and direction of overt and fantasized aggression of enuretic and nonenuretic children. Following the dynamic approach, it was hypothesized that enuretic children would differ from nonenuretics in having more difficulty in expressing overt aggression toward their mothers than toward a neutral figure. In fantasy, enuretic children were expected to express more aggression feelings toward their parents than control subjects. Twenty-eight enuretic subjects and a matched group of control subjects were induced to aggress toward their mothers and toward a neutral figure. The experimental situation was a variation of the Buss (1961) technique for eliciting and measuring aggression. Aggressive fantasies were assessed, using Bene and Anthony's Family Relation Test (1957). A significant interaction was obtained between enuresis/nonenuresis and target figures. Enuretic subjects expressed more aggression toward a neutral figure than toward the mother (p = .05) and differed from the control group in expressing less aggression toward the mother (p = .10). On the fantasy level, a significantly opposite trend to the predicted one emerged: Enuretic subjects showed less aggression toward both parents. The results were discussed with respect to the dynamic and the behavioristic approach to enuresis, and further research directions were suggested.


Quantum Spin Hall States in Stanene/Ge(111).
For topological insulators to be implemented in practical applications, it is a prerequisite to select suitable substrates that are required to leave insulators' nontrivial properties and sizable opened band gaps (due to spin-orbital couplings) unaltered. Using ab initio calculations, we predict that Ge(111) surface qualified as a candidate to support stanene sheets, because the band structure of √3 × √3 stanene/Ge(111) (2 × 2) surface displays a typical Dirac cone at Γ point in the vicinity of the Fermi level. Aided with the result of Z2 invariant calculations, a √3 × √3 stanene/Ge(111) (2 × 2) system has been proved to sustain the nontrivial topological phase, with the prove being confirmed by the edge state calculations of stanene ribbons. This finding can serve as guidance for epitaxial growth of stanene on substrate and render stanene feasible for practical use as a topological insulator.


Relationship between CHA(2)DS(2)-VASc scores and ischemic stroke/cardiovascular events in Japanese patients with paroxysmal atrial fibrillation not receiving anticoagulant therapy.
The CHA(2)DS(2)-VASc score has been newly proposed for stratifying patients with nonvalvular atrial fibrillation (AF) according to the risk of ischemic stroke in the 2010 European Society of Cardiology guideline. However, there is little information about its usefulness for predicting long-term prognosis of cardiovascular events in Japanese patients with paroxysmal AF. This study retrospectively included 332 paroxysmal AF patients (224 men, mean age 65±13 years, mean follow-up period 53±35 months) without receiving anticoagulant therapy between June 1995 and August 2008 who were categorized into risk stratification on the basis of CHA(2)DS(2)-VASc score. The distribution of CHA(2)DS(2)-VASc scores was 0, 1, 2, 3, 4, 5, 6, and 7 points in 76 (23%), 60 (18%), 69 (21%), 69 (21%), 28 (8%), 23 (7%), 6 (2%), and 1 (0.3%) patients, respectively. The annual rates of symptomatic ischemic stroke were 0%, 0.60%, 0.95%, 1.96%, 5.45%, 9.06%, and 13.7% when the CHA(2)DS(2)-VASc score was 0, 1, 2, 3, 4, 5, and ≥6 points, respectively (p<0.001) and those of cardiovascular events including hospitalization for thromboembolism, heart failure and cardiovascular death were 0%, 1.43%, 1.50%, 2.52%, 10.14%, 12.85%, and 17.13% when the CHA(2)DS(2)-VASc score was 0, 1, 2, 3, 4, 5 and ≥6 points, respectively (p<0.001). Higher CHA(2)DS(2)-VASc scores were associated with greater annual rates of ischemic stroke and cardiovascular events. In a multivariate logistic regression analysis adjusted for the potentially confounding variables, the CHA(2)DS(2)-VASc score was associated with symptomatic ischemic stroke (odds ratio 7.051, 95% confidence interval 3.76-13.22, p<0.001) and cardiovascular events (odds ratio 3.448, 95% confidence interval 2.33-5.11, p<0.001). In Japanese patients with paroxysmal AF, the CHA(2)DS(2)-VASc score is a useful scheme for risk stratification of ischemic stroke and cardiovascular events.


Graft-preserving treatment for vascular graft infected with Staphylococcus aureus with antibiotic-releasing porous apatite ceramic in the rabbit.
This study was undertaken to investigate whether infection of a vascular graft with Staphylococcus aureus can be treated in situ by applying antibiotic-loaded porous apatite ceramic, in a rabbit model. Teicoplanin (TEIC) was loaded onto a beta-tricalcium phosphate (TCP) block, a type of porous apatite ceramic. The activity of TEIC released from the antibiotic-loaded TCP block was examined in vivo. A vascular graft was patched onto the abdominal aorta in 24 rabbits, and S aureus was applied directly on it. Seven days postoperatively, each rabbit underwent repeat laparotomy, and retroperitoneal abscess around the prosthetic vascular patch was debrided. Animals were divided into four groups of 6 rabbits each. In group 1 only debridement was carried out. In groups 2 and 3, solution containing 40 or 60 mg of TEIC, respectively, was applied to the prosthetic vascular patch. In group 4, an antibiotic-loaded TCP block (63 +/- 6.6 mg of TEIC) was placed around the graft. Three weeks after the second operation, the graft, the tissue around it, and arterial blood were collected and cultured. TEIC activity was maintained for 28 days in vivo. In group 1, bacterial cultures of the prosthetic vascular graft and the tissue around it were positive in 5 animals and negative in 1 animal (infection rate, 83%). In both groups 2 and 3, cultures were positive in 3 animals and negative in 3 animals (infection rate, 50%). In group 4, cultures were negative in all animals (infection rate, 0%). Blood cultures were negative in all animals. Infection rate in group 4 was significantly lower than that in group 1 (P =.03), and was also lower than that in groups 2 and 3, but the difference was not significant. Use of slow-release antibiotic loaded onto a TCP block, along with debridement, may control infection in vascular grafts in situ, averting the necessity to remove the graft.


Multi-Omics Methods Applied to Flower Development.
Developmental processes in multicellular organisms depend on the proficiency of cells to orchestrate different gene expression programs. Over the past years, several studies of reproductive organ development have considered genomic analyses of transcription factors and global gene expression changes, modeling complex gene regulatory networks. Nevertheless, the dynamic view of developmental processes requires, as well, the study of the proteome in its expression, complexity, and relationship with the transcriptome. In this chapter, we describe a dual extraction method-for protein and RNA-for the characterization of genome expression at proteome level and its correlation to transcript expression data. We also present a shotgun proteomic procedure (LC-MS/MS) followed by a pipeline for the imputation of missing values in mass spectrometry results.


Bacteriological Profile in Attico-antral type of Chronic Suppurative Otitis Media.
Chronic suppurative otitis media is defined as a chronic inflammation of the middle ear cleft, which presents with recurrent ear discharge through a tympanic membrane perforation. The purpose of this study was to find pattern of bacteriology in patients of atticoantral type of chronic suppurative otitis media as it will help the clinician to decide the effective antibiotics to be prescribed. This prospective and observational study was conducted in the Department of ENT in collaboration with Department of Microbiology, Government Medical College and Hospital, Chandigarh. The ear discharge specimen of all patients meeting the inclusion criteria were collected and sent for microbial examination. Culture positive samples were subjected to antibiotic sensitivity. A total of one hundred ears (mean age 27.33 years) clinically diagnosed with chronic suppurative otitis media, atticoantral type were included in this study based on the preset inclusion and exclusion. The male: female ratio in our patients was 0.94:1. Ninety-seven (96.9%) patients had unilateral disease, while 3 (3.1%) patients had bilateral disease. Twenty-eight percent of the total samples were sterile. The most common bacteria isolated were Pseudomonas aeruginosa (27.1%), Methicillin sensitive Staphylococcus aureus (23.3%) and Proteur mirabilis (6.5%). was sensitive to polymyxin B (100%) followed by ciprofloxacin (46.4%), neomycin (42.9%) and gentamicin (42.9%). Polymyxin B is the most effective antibiotic against the cultured bacteria followed by gentamicin, ciprofloxacin and neomycin.


Determination of 2-hydroxypropyl-gamma-cyclodextrin in plasma of cynomolgus monkeys after oral administration by gas chromatography-mass spectrometry.
This report describes a specific and highly sensitive gas chromatography-mass spectrometry (GC-MS) assay for the analysis of industrially produced 2-hydroxypropyl-gamma-cyclodextrin, a heterogeneous mixture of homologues and isomers, in plasma of cynomolgus monkeys. Instead of analyzing the polysaccharide mixture as a whole, in a first step the HP-gamma-cyclodextrin mixture, together with the internal standard (2,6-di-O-methyl-beta-cyclodextrin), was deuteromethylated, and in a second step hydrolyzed with hydrochloric acid to the respective monosaccharides. The resulting reaction mixture was trimethylsilylated to 1,4-bis(O-trimethylsilyl)-2,3-bis-O-deuteromethyl-6-O-2'-deuter omethoxypropylglucose (representative for HP-gamma-CD) and 1,4-bis-(O-trimethylsilyl)-bis-2,6-O-methyl-3-O-deuteromethylglucose+ ++ (representative for the internal standard), respectively, and analyzed by GC-MS. The limit of quantification of this assay was 20 nmol/l.


Measurement of regional pulse wave velocity using very high frame rate ultrasound.
Pulse wave velocity (PWV) is the propagation velocity of the pressure wave along the artery due to the heartbeat. The PWV becomes faster with progression of arteriosclerosis and, thus, can be used as a diagnostic index of arteriosclerosis. Measurement of PWV is known as a noninvasive approach for diagnosis of arteriosclerosis and is widely used in clinical situations. In the traditional PWV method, the average PWV is calculated between two points, the carotid and femoral arteries, at an interval of several tens of centimeters. However, PWV depends on part of the arterial tree, i.e., PWVs in the distal arteries are faster than those in the proximal arteries. Therefore, measurement of regional PWV is preferable. To evaluate regional PWV in the present study, the minute vibration velocity of the human carotid arterial wall was measured at intervals of 0.2 mm at 72 points in the arterial longitudinal direction by the phased-tracking method at a high temporal resolution of 3472 Hz, and PWV was estimated by applying the Hilbert transform to those waveforms. In the present study, carotid arteries of three healthy subjects were measured in vivo. The PWVs in short segments of 14.4 mm in the arterial longitudinal direction were estimated to be 5.6, 6.4, and 6.7 m/s, which were in good agreement with those reported in the literature. Furthermore, for one of the subjects, a component was clearly found propagating from the periphery to the direction of the heart, i.e., a well known component reflected by the peripheral arteries. By using the proposed method, the propagation speed of the reflection component was also separately estimated to be -8.4 m/s. The higher magnitude of PWV for the reflection component was considered to be the difference in blood pressure at the arrivals of the forward and reflection components. Such a method would be useful for more sensitive evaluation of the change in elasticity due to progression of arteriosclerosis by measuring the regional PWV in a specific artery of interest (not the average PWV including other arteries).


Vasopressin and isoproterenol activate adenylate cyclase in the guinea pig inner ear.
Cochleas from guinea pigs were perfused by isotonic buffer after punction of the carotid artery. The cochlea tissue was removed from the bony capsule and separated from the mediolus as band with a sharp needle under the microscope. Cell membranes were prepared subsequently from whole tissue. Purified membranes from the inner ear of guinea pigs contain adenylate cyclase which functionally is coupled with membrane receptors for vasopressin and beta-receptors for isoproterenol (epinephrine), respectively. Both hormones stimulate production of cyclic AMP at 37 degrees C. Furthermore, cyclase activity is increased by addition of Gpp (NH)p, a GTP analog. Possible relationships of these molecular events to cochlear events such as glycogenolysis, ionfluxes, transport and secretion mechanisms, and synaptic transmissions are discussed.


Childhood sexual abuse and the consequences in adult women.
This paper reviews the literature on childhood sexual abuse and its implications for women. It is estimated that at least 15-38% of adults have been sexually abused as children, with figures higher for women than for men. Failure to report abuse is common, and only 20-50% of incidents may come to the attention of authorities. Although childhood sexual abuse is present in all socioeconomic groups, more severe forms of abuse appear to be associated with lower socioeconomic status. After the age of ten, a sharp increase is observed in vaginal intercourse, sexual assaults accompanied by physical violence, and abuse committed by strangers. Although fathers are frequently cited as the primary perpetrators, not all studies support this finding. Other relatives have been reported to account for 20-70% of the sexual abuse occurring within the family. A history of childhood abuse may contribute to sexual problems or multiple chronic complaints in the adult woman. Moreover, some of these women may experience depression, anxiety, and low self-esteem. The gynecologist should use empathetic questioning with all patients regarding abuse, and integrate the patient's history of abuse with current health care. Physicians who are uncomfortable with this topic or who observe ongoing distress in their patients should refer these women to a mental health practitioner who is familiar with the issues common to women who have experienced childhood sexual abuse.


A self-assembling RNA aptamer-based nanoparticle sensor for fluorometric detection of Neomycin B in milk.
To date, there are few reports regarding the development of RNA aptamer-based biosensors for the detection of small molecules. The possible reason is attributed to the weak nuclease resistance of RNA in biological environments. In this study, we have developed an RNA aptamer-based gold nanoparticle (AuNP) sensor for fluorometric detection of Neomycin B in milk. This aptasensor depends on the self-assembly of the RNA aptamer/Neomycin B complex and fluorescence quenching by AuNPs. This biosensor exhibited a low detection limit of 0.01 μM, with a linear dynamic range from 0.1 to 10 μM in milk, and a good selectivity toward Neomycin B. Specifically, because of the shorter RNA fragments and the nuclease inhibition ability of the RNA-modified AuNPs, the RNA sequences remained stable during the experiments. This work will serve as an example for the development of novel biosensors based on RNA aptamers. Graphical Abstract An RNA aptamer-based nanoparticle sensor, developed for the detection of Neomycin B in milk, shows high binding affinity and selectivity. This aptasensor depends on the self-assembly of the aptamer/ligand complex and fluorescence quenching by gold nanoparticles (AuNPs). Because of the shorter RNA fragments and the nuclease inhibition ability of RNA-modified AuNPs, RNA sequences remain stable during the detection.


Correlation of cervical cytology with high-risk HPV molecular diagnosis, genotypes, and histopathology--A four year study from the UAE.
Cervical cancer is one of the most common cancers among women in the world and in the Middle East. Its prevention and screening strategies assume great importance especially in view of the ability to identify the illness at an early stage and disrupt its progression toward neoplasia. Cervical cancer screening program of our center in UAE as well as this study is oriented in this direction. Cervical cytology data encompassing 4 years (2011-2014) was compiled and analyzed for 14,950 cases to assess the abnormal smear reporting pattern, correlation with biopsy histopathology, HPV high-risk screening data, and HPV genotype prevalence among patients with abnormal smear test, as well as in relation to the respective nationalities of patients. Abnormal smear rates as well as HPV high-risk positivity correlated well with established data. Cytology-histology correlation was good. HPV high-risk type 16 was the commonest, type 18 which is the second common type worldwide was less frequently detected, several other high risk subtypes such as 51, 31 as well as rare types such as 66, 56, and 59 were detected in a significant number of patients. Assessment of cervical cytology reporting pattern, correlation of cervical cytology with HPV molecular diagnosis, and biopsy histopathology is a useful way to audit our work and a good quality control practice. Higher prevalence of HPV HR types such as type 51, 31 as well as 66, 56, and 59 found in the present as well as many similar other studies apart from the commonest subtype 16 may imply necessity for development of more targeted and multivalent anti-HPV vaccines for protection of women in our region. HPV genotypes correlation with the nationalities of patients is useful from an epidemiological standpoint to plan preventive strategies.


Cannabinoid receptor expression at the MNTB-LSO synapse in developing rats.
The organization of developing auditory circuits depends on the elimination of aberrant connections and strengthening of appropriate ones. Endocannabinoid mediated plasticity is a proposed mechanism for this refinement. Here we investigated for the anatomical presence of cannabinoid receptors (CB1R) in the lateral superior olive (LSO) and medial nucleus of the trapezoid body (MNTB) of developing rats. We found that CB1R is present within the LSO and that it colocalized with vesicular glutamate transporter (VGLUT3), a presynaptic marker for MTNB terminals. Both before (P5) and around hearing onset (P12), the expression levels of CB1R were higher in the lateral limb of the LSO than in the medial limb. These results suggest that endocannabinoid signaling can modulate the strength of the developing MNTB-LSO synapse.


Nrf2 and Nrf2-related proteins in development and developmental toxicity: Insights from studies in zebrafish (Danio rerio).
Oxidative stress is an important mechanism of chemical toxicity, contributing to developmental toxicity and teratogenesis as well as to cardiovascular and neurodegenerative diseases and diabetic embryopathy. Developing animals are especially sensitive to effects of chemicals that disrupt the balance of processes generating reactive species and oxidative stress, and those anti-oxidant defenses that protect against oxidative stress. The expression and inducibility of anti-oxidant defenses through activation of NFE2-related factor 2 (Nrf2) and related proteins is an essential process affecting the susceptibility to oxidants, but the complex interactions of Nrf2 in determining embryonic response to oxidants and oxidative stress are only beginning to be understood. The zebrafish (Danio rerio) is an established model in developmental biology and now also in developmental toxicology and redox signaling. Here we review the regulation of genes involved in protection against oxidative stress in developing vertebrates, with a focus on Nrf2 and related cap'n'collar (CNC)-basic-leucine zipper (bZIP) transcription factors. Vertebrate animals including zebrafish share Nfe2, Nrf1, Nrf2, and Nrf3 as well as a core set of genes that respond to oxidative stress, contributing to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and the response to oxidative stress during embryolarval development. Moreover, studies in zebrafish have revealed nrf and keap1 gene duplications that provide an opportunity to dissect multiple functions of vertebrate NRF genes, including multiple sensing mechanisms involved in chemical-specific effects.


Blood- and Urine-Based Liquid Biopsy for Early-Stage Cancer Investigation: Taken Clear Renal Cell Carcinoma as a Model.
Liquid biopsy is a noninvasive technique that can provide valuable information for disease characterization by using biofluids as a source of biomarkers. Proteins found in biofluids can offer a wealth of information for understanding pathological processes. In this study, we used early-stage clear cell renal cell carcinoma (ccRCC) as a model to explore the proteomic relationships among tissue, plasma, and urine. We analyzed samples of tumor tissue, plasma, and urine from a cohort of 27 ccRCC patients with T1-2 stage and 27 matched healthy controls, using liquid chromatography-mass spectrometry (LC-MS) for proteomic analysis. We integrated the differential proteins found in the three types of samples to explore ccRCC-associated molecular changes. Our results showed that both plasma and urine proteomes could reflect functional changes in tumor tissue. In plasma, cytoskeletal proteins and metabolic enzymes were differentially expressed, while in urine, adhesion molecules and defense proteins showed differential levels. The differential proteins found in plasma and urine both reflect the binding and catalytic activity of tumor tissue. Additionally, proteins only changed in biofluids could reflect body immune response changes, with plasma proteins involved in actin cytoskeleton and oxidative stress, and urine proteins involved in granulocyte adhesion and leukocyte extravasation signaling. Plasma and urine proteins could effectively distinguish RCC from control, with good performances (plasma/urine: 92.6%/92.6% specificity, 96.3%/92.6% sensitivity, and an area under the curve of 0.981/0.97). In conclusion, biofluids could not only reflect functional changes in tumor tissue but also reflect changes in the body's immune response. These findings will benefit the understanding of body biomarkers in tumors and the discovery of potential disease biomarkers.


Do orientation effects contribute to the molecular weight dependence of the free solution mobility of DNA?
The free solution mobility of DNA increases with increasing molecular weight and then levels off and becomes constant at molecular weights above approximately 400 bp (Stellwagen, N. C., Gelfi, C., Righetti, P. G., Biopolymers 1997,42, 687-703). To investigate whether the increase in mobility could be attributed to an increased orientation of the larger DNA molecules in the electric field, the free solution mobility of DNA was measured by capillary electrophoresis as a function of electric field strength. Mixtures containing 20-, 118- and 422-bp DNA molecules, and 20-, 422- and 2116-bp DNAs, were studied. If the larger DNA molecules in each mixture were oriented by the electric field, their mobilities should increase with electric field strength faster than the mobility of the 20-bp oligomer, which is too small to be oriented by the electric fields used in this study. Instead, the ratios of the mobilities of the 118-, 422- and 2116-bp fragments to the mobility of the 20-bp oligomer were independent of electric field strength. Hence, orientation effects are not important for DNA molecules up to 2 kbp in size, in electric fields up to 500 V/cm in amplitude. An explanation is suggested.


Measurement of the biliary tree volume in the rate under Tm-conditions.
Biliary tree capacities determined under Tm-conditions using 35S-sulfobromophthalein sodium 35S-sulfobromophthalein glutathione, and 14C-taurocholate sodium as markers exceeded markedly the biliary volumes reported until now. This may have been caused at least partly by a more homogenous distribution of the marker substance throughout the liver parenchyma in contrast to simple bolus injection studies.


Phosphatidylinositol 3-Phosphate 5-Kinase, FAB1/PIKfyve Kinase Mediates Endosome Maturation to Establish Endosome-Cortical Microtubule Interaction in Arabidopsis.
Phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] is an important lipid in membrane trafficking in animal and yeast systems; however, its role is still largely obscure in plants. Here, we demonstrate that the phosphatidylinositol 3-phosphate 5-kinase, formation of aploid and binucleate cells1 (FAB1)/FYVE finger-containing phosphoinositide kinase (PIKfyve), and its product, PtdIns(3,5)P2, are essential for the maturation process of endosomes to mediate cortical microtubule association of endosomes, thereby controlling proper PIN-FORMED protein trafficking in young cortical and stele cells of root. We found that FAB1 predominantly localizes on the Sorting Nexin1 (SNX1)-residing late endosomes, and a loss of FAB1 function causes the release of late endosomal proteins, Ara7, and SNX1 from the endosome membrane, indicating that FAB1, or its product PtdIns(3,5)P2, mediates the maturation process of the late endosomes. We also found that loss of FAB1 function causes the release of endosomes from cortical microtubules and disturbs proper cortical microtubule organization.


On-line information sources of toxicology in Finland.
Toxicology is relatively young as an independent discipline in Finland as in most other countries. Toxicology gradually evolved at universities as a part of pharmacology during 1960-1970s. The research institutes, with the Finnish Institute of Occupational Health being a pioneer in this respect, have contributed significantly in special research areas. The current paper highlights Finnish toxicology, and concentrates on the current status of sources of digital information and their use.


Platelet immunoglobulin and amyloid precursor protein as potential peripheral biomarkers for Alzheimer's disease: findings from a pilot study.
the diagnosis of dementia, in particular Alzheimer's disease (AD), is enhanced with the use of molecular biomarkers. Since cerebrospinal fluid analysis and molecular neuroimaging are not routinely used in many countries, blood biomarker molecules may be more readily applicable in a routine clinical setting. twenty-five subjects with a clinical diagnosis of AD and 26 control participants were assessed for cognitive and behavioural functioning. Platelet measures of amyloid protein precursor (APP), tau protein, clusterin, α-synuclein and immunoglobulin (Ig) were measured. Linear regression analysis for platelet proteins and cognitive and behavioural status were determined, and receiver operating characteristic (ROC) curves created to assess the discriminating power of each biochemical parameter between AD and control groups. both AD and control subjects had similar platelet levels of measures platelet proteins, with the exception of slightly elevated Ig levels in AD subjects (P = 0.052). The latter were not related to increasing age, or extent of cognitive impairment. APP-N measures were negatively correlated with cognitive scores. these preliminary findings suggest that platelet measures of the traditional biomarkers for AD are feasible in the periphery. The measures of platelet APP-N and Ig, in particular, merit further study in a larger cohort of AD and control subjects.


Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells.
Nanog and Oct4 are essential transcription factors that regulate self-renewal and pluripotency of ES cells. However, the mechanisms by which Nanog and Oct4 modulate ES cell fate remain unknown. Through characterization of endogenous Nanog and Oct4 protein complexes in mouse ES cells, we found that these transcription factors interact with each other and associate with proteins from multiple repression complexes, including the NuRD, Sin3A and Pml complexes. In addition, Nanog, Oct4 and repressor proteins co-occupy Nanog-target genes in mouse ES cells, suggesting that Nanog and Oct4 together may communicate with distinct repression complexes to control gene transcription. To our surprise, of the various core components in the NuRD complex with which Nanog and Oct4 interact, Mta1 was preferred, whereas Mbd3 and Rbbp7 were either absent or present at sub-stoichiometric levels. We named this unique Hdac1/2- and Mta1/2-containing complex NODE (for Nanog and Oct4 associated deacetylase). Interestingly, NODE contained histone deacetylase (HDAC) activity that seemed to be comparable to NuRD, and retained its association with Nanog and Oct4 in Mbd3(-/-) ES cells. In contrast to Mbd3 loss-of-function, knockdown of NODE subunits led to increased expression of developmentally regulated genes and ES-cell differentiation. Our data collectively suggest that Nanog and Oct4 associate with unique repressor complexes on their target genes to control ES cell fate.


A gene affecting the specificity of the chemosensory neurons of Drosophila.
The sensilla on the proboscis and tarsi of Drosophila contain five neurons, four chemosensory and one mechanosensory. The sugar-sensitive neuron, designated S, carries independent acceptor sites for pyranose, furanose and trehalose. Two others, L1 and L2, respond to salts. The fourth neuron, W, is inhibited by salts and sugars, and is believed to mediate detection of water. We describe here a gene in which mutations alter the neurons in such a way that the S cell is excited by salts. As a result, the mutant flies are strongly attracted by NaCl at concentrations which are repellent to the wild type. To our knowledge, this is the first instance of a mutation which changes the specificity of the chemosensory neurons.


Thioredoxin-interacting protein mediates high glucose-induced reactive oxygen species generation by mitochondria and the NADPH oxidase, Nox4, in mesangial cells.
Thioredoxin-interacting protein (TxNIP) is up-regulated by high glucose and is associated with oxidative stress. It has been implicated in hyperglycemia-induced β-cell dysfunction and apoptosis. As high glucose and oxidative stress mediate diabetic nephropathy (DN), the contribution of TxNIP was investigated in renal mesangial cell reactive oxygen species (ROS) generation and collagen synthesis. To determine the role of TxNIP, mouse mesangial cells (MC) cultured from wild-type C3H and TxNIP-deficient Hcb-19 mice were incubated in HG. Confocal microscopy was used to measure total and mitochondrial ROS production (DCF and MitoSOX) and collagen IV. Trx and NADPH oxidase activities were assayed and NADPH oxidase isoforms, Nox2 and Nox4, and antioxidant enzymes were determined by immunoblotting. C3H MC exposed to HG elicited a significant increase in cellular and mitochondrial ROS as well as Nox4 protein expression and NADPH oxidase activation, whereas Hcb-19 MC showed no response. Trx activity was attenuated by HG only in C3H MC. These defects in Hcb-19 MC were not due to increased antioxidant enzymes or scavenging of ROS, but associated with decreased ROS generation. Adenovirus-mediated overexpression of TxNIP in Hcb-19 MC and TxNIP knockdown with siRNA in C3H confirmed the specific role of TxNIP. Collagen IV accumulation in HG was markedly reduced in Hcb-19 cells. TxNIP is a critical component of the HG-ROS signaling pathway, required for the induction of mitochondrial and total cell ROS and the NADPH oxidase isoform, Nox4. TxNIP is a potential target to prevent DN.


The effects of cannabidiol on worry and anxiety among high trait worriers: a double-blind, randomized placebo controlled trial.
Evidence suggests cannabidiol (CBD) displays broad therapeutic potential in the context of anxiety; however, no study has examined the effects of CBD on worry, a defining, cognitive feature of anxiety. Additionally, no study has examined the effects of an acute, single dose of CBD compared to repeated CBD administration. Within a sample of 63 individuals with elevated trait worry, the current study aimed to assess the effects of an empirically-derived high dose of CBD (i.e., 300mg) compared to a commercially-derived dose of CBD (i.e., 50mg) versus placebo on worry severity and anxiety symptoms after an acute dose and after a 2-week administration period. Results indicated no effect of acute CBD dosing on worry severity or anxiety symptoms. Repeated CBD administration similarly did not impact worry severity; however, 300mg of CBD reduced anxiety symptoms across the 2-week administration period compared to placebo. Taken together, these findings suggest 300mg of oral CBD does not attenuate cognitive symptoms of anxiety (i.e., worry), following both acute and repeated administration. Some evidence for repeated administration of 300mg on physical symptoms of anxiety was obtained. Findings from the current study suggest CBD's modest anxiolytic effects may be specific to the physical aspects of anxious arousal.


Peripherally Inserted Central Catheters-associated blood stream infections-occurrence, risk factors, and pathogens, a single center study.
Peripherally inserted central catheters (PICCs) are central venous catheters inserted peripherally but terminate in great vessels. PICCs are widely used for patients requiring long-term intravenous therapy in both in-patient and out-patient settings. This study was carried out to understand PICC-related complications, specifically infections and causal pathogens, in a tertiary care hospital in Kerala, South India. A retrospective analysis of PICC insertions and follow-up during a 9 years period to look at patient demographics and infections related to PICC was carried out. The overall PICC-related complication rate is 28.1% (4.98 per 1000 PICC days). Commonest complication was thrombosis followed by infection, either PICC-associated bloodstream infection (PABSI) or local infection (LI). PABSI noted in this study was 1.34 per 1000 catheter days. The majority (85%) of PABSI were due to Gram-negative rods. The average duration of PICC days for occurrence of PABSI was 14 days and the majority occurred in in-patients. Thrombosis and infection were the commonest PICC-related complications. PABSI rate was comparable to that of previous studies.


Controlling the time evolution of mAb N-linked glycosylation - Part II: Model-based predictions.
N-linked glycosylation is known to be a crucial factor for the therapeutic efficacy and safety of monoclonal antibodies (mAbs) and many other glycoproteins. The nontemplate process of glycosylation is influenced by external factors which have to be tightly controlled during the manufacturing process. In order to describe and predict mAb N-linked glycosylation patterns in a CHO-S cell fed-batch process, an existing dynamic mathematical model has been refined and coupled to an unstructured metabolic model. High-throughput cell culture experiments carried out in miniaturized bioreactors in combination with intracellular measurements of nucleotide sugars were used to tune the parameter configuration of the coupled models as a function of extracellular pH, manganese and galactose addition. The proposed modeling framework is able to predict the time evolution of N-linked glycosylation patterns during a fed-batch process as a function of time as well as the manipulated variables. A constant and varying mAb N-linked glycosylation pattern throughout the culture were chosen to demonstrate the predictive capability of the modeling framework, which is able to quantify the interconnected influence of media components and cell culture conditions. Such a model-based evaluation of feeding regimes using high-throughput tools and mathematical models gives rise to a more rational way to control and design cell culture processes with defined glycosylation patterns. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1135-1148, 2016.


Intra-operative anaesthetic management of older patients undergoing liver surgery.
Older patients represent a growing proportion of the general surgical caseload. This includes those undergoing liver resection, with figures rising faster than the rate of population ageing. The physiology of ageing leads to changes in all body systems which may render the provision of safe anaesthesia more challenging than in younger patients. Anaesthesia for liver surgery has specific principles, largely aimed at reducing venous bleeding from the liver, and those related to complex major surgery. This review explores the principles of anaesthesia for liver resection and describes how they may require modification in the older patient. The traditional approach of low central venous pressure anaesthesia in order to reduce bleeding may need to be altered in the presence of a cardiovascular system less able to tolerate hypotension and hypoperfusion. These changes in physiology should also lower the threshold for invasive monitoring. The provision of effective analgesia perioperatively should be tailored to minimise the surgical stress response and opiate use. Careful consideration of general principles of intra-operative care for older patients, such as positioning, drug dosing, avoidance of excessively deep anaesthesia, and maintenance of normothermia are also important given the prolonged, complex nature of liver surgery. This individualised approach, with careful attention to changes in physiology allows liver resections to be undertaken in older patients without increases in mortality.


Pattern of skin diseases among pilgrims during Hajj season in Makkah, Saudi Arabia.
Skin diseases among pilgrims are considered to be one of the possible health problems in our area. Data supporting this observation are scanty and sparse. The aim of this study was to report the most common skin diseases seen in a 15-day period. We retrospectively collected all new cases of skin diseases diagnosed during a 15-day period at King Faisal Hospital, the nearest general medical center to Mina. Pilgrims gather at Mina (which harbors more than two million pilgrims every year) to perform their Hajj. During the Hajj season in 1998, 731 new patients were seen; 63.3% were men and 36.7% were women. Of these cases, Saudi citizens represented 42.5% of the total patients. The peak age group ranged from 20 to 39 years. The incidence in Saudi patients was more than that in other nationalities. Dermatitis of various etiologies (23.6%) was found to be the most common skin disease. Pyoderma was found to be more common in Saudis and Asians than in Arabs, whereas Arabs suffered from intertrigo much more than Asians and Saudis. A high incidence of skin diseases such as pyoderma and intertrigo among pilgrims of such a large congregation is understandable. Investigating these skin infections is worthwhile because they are preventable, easily diagnosed, and are curable in the majority of patients.


How Does Alcohol Consumption Affect Perceptions of One's Own and a Drinking Partner's Ability to Consent to Sexual Activity?
In this naturalistic study, our aim was to examine the extent to which alcohol consumption affected perceptions of one's own and one's friend's ability to consent to sexual activity. We surveyed 160 adult bargoers in pairs about their own and their friends' alcohol consumption, intoxication symptoms, and ability to consent to sexual activity. On average, participants reported consuming 4.97 drinks, rated themselves at the legal limit for driving, reported one intoxication symptom, and had a blood alcohol concentration (BAC) just over .08. However, few thought they or their friend had diminished cognitive function. Accordingly, most indicated that they could consent to sex (93%) and their friend could consent to sex (87%). Number of drinks people reported consuming, self-reported intoxication levels and symptoms, and BACs were significantly correlated; however, none of these measures was significantly related to individuals' perceptions of their own or their friends' ability to consent to sexual activity. Finally, those in man-man pairs were significantly more likely than those in woman-woman pairs to indicate they would allow their friend to have sex if approached by an interested party. These findings have potential implications for prevention programming and for legal cases involving individuals who engage in sexual activity while intoxicated.


Risk of mortality and clinical outcomes associated with healthcare delay among patients with tuberculosis.
To eliminate tuberculosis (TB), World Health Organization (WHO) initiated "The End TB Strategy" with the goal of a 95% reduction in deaths. While many resources are contributed to eradicating TB, a substantial number of TB patients are still unlikely to receive timely treatment. Thus, we aimed to measure healthcare delay and its association with clinical outcomes from 2013 to 2018. We conducted a retrospective cohort study using linked data of the National Tuberculosis Surveillance Registry and the health insurance claims data of South Korea. We included incident TB patients, and healthcare delay was defined as the period between the first medical visit with TB-related symptoms and the initiation of an anti-TB regimen. We described the distribution of healthcare delay, and the study population was classified into two groups with mean as a cutoff. The association between healthcare delay and clinical outcomes (all-cause mortality, pneumonia, progression to multi/extensively drug-resistant, intensive care unit admission, and mechanical ventilation use) was evaluated using the Cox proportional hazard model. Several stratified and sensitivity analyses were also conducted. Among 39,747 patients with pulmonary TB, mean healthcare delay was 42.3 days and delayed and non-delayed groups, classified by mean (or average), were 10,680 (26.9%) and 29,067 (73.1%), respectively. Healthcare delay was associated with an increased risk of all-cause mortality (HR 1.10, 95% CI 1.03-1.17), pneumonia (HR 1.13, 95% CI 1.09-1.18), and mechanical ventilation use (HR 1.15, 95% CI 1.01-1.32). We also observed the duration-response of healthcare delay. Stratified analyses showed patients with respiratory diseases were at higher risk, and consistent results were observed in sensitivity analyses. We observed a substantial number of patients experiencing healthcare delays, and it was associated with the deterioration of clinical outcomes. Our findings suggest that attention from authorities and healthcare professionals is needed to attenuate the preventable burden caused by TB through timely treatment.


Immunolabelling of human metaphase chromosomes reveals the same banded distribution of histone H3 isoforms methylated at lysine 4 in primary lymphocytes and cultured cell lines.
Using metaphase spreads from human lymphoblastoid cell lines, we previously showed how immunofluorescence microscopy could define the distribution of histone modifications across metaphase chromosomes. We showed that different histone modifications gave consistent and clearly defined immunofluorescent banding patterns. However, it was not clear to what extent these higher level distributions were influenced by long-term growth in culture, or by the specific functional associations of individual histone modifications. Metaphase chromosome spreads from human lymphocytes stimulated to grow in short-term culture, were immunostained with antibodies to histone H3 mono- or tri-methylated at lysine 4 (H3K4me1, H3K4me3). Chromosomes were identified on the basis of morphology and reverse DAPI (rDAPI) banding. Both antisera gave the same distinctive immunofluorescent staining pattern, with unstained heterochromatic regions and a banded distribution along the chromosome arms. Karyotypes were prepared, showing the reproducibility of banding between sister chromatids, homologue pairs and from one metaphase spread to another. At the light microscope level, we detect no difference between the banding patterns along chromosomes from primary lymphocytes and lymphoblastoid cell lines adapted to long-term growth in culture. The distribution of H3K4me3 is the same across metaphase chromosomes from human primary lymphocytes and LCL, showing that higher level distribution is not altered by immortalization or long-term culture. The two modifications H3K4me1 (enriched in gene enhancer regions) and H3K4me3 (enriched in gene promoter regions) show the same distributions across human metaphase chromosomes, showing that functional differences do not necessarily cause modifications to differ in their higher-level distributions.


Inflammatory myofibroblastic tumour: case report of a rare form of bladder tumour.
Inflammatory myofibroblastic tumour (IMT) is a rare tumour with malignant potential and has been described in many major organs with the most frequent site being the lungs. However, bladder is an extremely rare location. IMT presents a unique diagnostic challenge because of the characteristics it shares with malignant neoplasms. Here we report the case of a 47-yearold male who presented with storage lower urinary tract symptoms associated with non-specific lower abdominal pain for one month duration. Contrast-enhanced computed tomography of abdomen and pelvis revealed a 6 cm tumour at the dome and left side anterior wall of the bladder. He underwent laparotomy and partial cystectomy. Histopathology results were consistent with an IMT. Even though bladder IMT is indolent in course, typical IMTs can be locally aggressive. Due to the lack of specificity in clinical symptoms, it is not easy to arrive at a precise diagnosis before surgery. Hence, the final diagnosis depends on histomorphological features and the immune histochemical profile. It can be challenging to distinguish IMT from malignant neoplasms both clinically and histologically. As such, local surgical resection with close follow-up remains the mainstay of treatment for urinary tract IMT.


Pollution status and risk assessment of trace elements in Portuguese water, soils, sediments, and associated biota: a trend analysis from the 80s to 2021.
Pollution of water bodies and sediments/soils by trace elements remains a global threat and a serious environmental hazard to biodiversity and human's health. Globalization and industrialization resulted in the increase and availability of these substances in the environment posing unpredictable adverse effects to living organisms. To determine pollution status and risk contamination by trace elements, data available in the literature of the last 40 years on trace elements occurrence in three environmental matrices (water bodies, sediments/soils, and biota) from Continental Portugal were collected (about 90 studies). Data were compared to water and sediment quality guidelines to assess potential ecological risks. Most environmentally relevant hazardous elements include Zn, Cu, Cd, Pb, and As. Various studies found trace elements at levels higher than those considered safe by environmental guidelines. In surface waters, Al, Zn, Se, and Ag were found above aquatic life limits in about 60% of the reviewed papers, while Cu, Zn, and As exceed those values in more than 60% of mining waters. Hg and Cd in sediments from mining areas exceeded aquatic life limits and potential ecological risk showed extremely high risk for most of the elements. The data compiled in this review is very heterogenous, varying in terms of sampling schemes, trace elements analysed, and spatiotemporal settings. This heterogenicity leads to data differences that make meaningful comparisons difficult. Nevertheless, the compilation of scattered environmental spatial and temporal trace elements data, of either natural sources or human activity as well as the ultimate effect on biological systems, is of the upmost importance to broaden its knowledge, risk assessment, and implementation of mitigation measures.


Metastatic Squamous Spindle Cell Carcinoma of the conjunctiva.
Conjunctival Squamous Cell Carcinoma (CSCC) is one of the important ocular surface tumors. It is thought to be more advanced in this part of the world such as in Saudi Arabia. The Squamous Spindle Cell Carcinoma (SSCC) is a more aggressive variant. A single case of spindle squamous cell carcinoma tumor-related death due to bone and lung metastasis has been reported in Sweden in 1995. We are reporting a similar case of SSCC of the conjunctiva with eventual death because of bilateral lung metastasis in our area. Proper identification of this type of tumor by ocular pathologists and the need for future detailed clinicopathologic studies on CSCC in Saudi Arabia is emphasized.


An ensemble with the Chinese pentatonic scale using electroencephalogram from both hemispheres.
To listen to brain activity as a piece of music, we previously proposed scale-free brainwave music (SFBM) technology, which translated the scalp electroencephalogram (EEG) into musical notes according to the power law of both the EEG and music. In this study, the methodology was further extended to ensemble music on two channels from the two hemispheres. EEG data from two channels symmetrically located on the left and right hemispheres were translated into MIDI sequences by SFBM, and the EEG parameters modulated the pitch, duration and volume of each note. Then, the two sequences were filtered into an ensemble with two voices: the pentatonic scale (traditional Chinese music) or the heptatonic scale (standard Western music). We demonstrated differences in harmony between the two scales generated at different sleep stages, with the pentatonic scale being more harmonious. The harmony intervals of this brain ensemble at various sleep stages followed the power law. Compared with the heptatonic scale, it was easier to distinguish the different stages using the pentatonic scale. These results suggested that the hemispheric ensemble can represent brain activity by variations in pitch, tempo and harmony. The ensemble with the pentatonic scale sounds more consonant, and partially reflects the relations of the two hemispheres. This can be used to distinguish the different states of brain activity and provide a new perspective on EEG analysis.


Clinical characteristics of cardiovascular patients with extremely low levels of high-density lipoprotein cholesterol.
Extremely low levels of high-density lipoprotein cholesterol (HDL-C) are related to high cardiovascular mortality. The underlying mechanism is not well known. This research aims to study the clinical characteristics of cardiovascular patients with extremely low levels of HDL-C. All cardiovascular patients in a single Chinese cardiology center that were admitted from January to December 2019 were reviewed. The clinical characteristics of those with HDL-C<20 mg/dL were investigated. A total of 20,655 individuals were enrolled. Of these, 52.17 % were males, and the average age was 58.20 ± 12.98 years old. The prevalence of HDL-C<20 mg/dL was 0.47 % for all patients (N=98) and 1.05 % for inpatients. Of those with HDL-C<20 mg/dL, 88.8 % were inpatients, and 77.6 % were males. Their average age was 60.7 ± 15.1 years. Compared with matched patients with normal HDL-C, systemic inflammation (OR= 5.556, 95% CI 2.798-11.030), hypoalbuminemia (OR=5.714, 95% CI 2.702-12.085), hyperuricemia (OR=5.156, 95% CI 2.560-10.386), low T3 syndrome (OR=4.278, 95% CI 1.627-11.245), anemia (OR=3.577, 95% CI 1.680-7.617), diabetes (OR=3.534, 95% CI 1.693-7.376) and hypertriglyceridemia (OR=2.493, 95% CI 1.264-4.918) were identified as adverse concomitant factors of extremely low HDL-C. HDL-C levels were inversely correlated with the total risk scores in patients with HDL-C<20 mg/dL (r=-0.381, P<0.001) and more significantly correlated in patients with HDL-C<15 mg/dL (r=-0.511, P=0.004). Extremely low levels of HDL-C tend to occur more frequently in males, older individuals and inpatients. For cardiovascular patients, extremely low levels of HDL-C are usually due to the presence of multiple adverse factors with relatively severe conditions. This could explain the high cardiovascular mortality of individuals with extremely low levels of HDL-C.


Postoperative endophthalmitis: establishment and results of a national registry.
To determine the incidence, clinical presentation, etiology, and outcomes of postoperative endophthalmitis in Norway and to explore the potential of and establish a platform for improving diagnostics, prophylaxis, and treatment of postoperative endophthalmitis. All ophthalmic surgical units and relevant microbiology laboratories in Norway. A national registry of cases of postoperative endophthalmitis was established in 1996. All ophthalmic surgery units in Norway were asked to return forms including preoperative, perioperative, and postoperative data for each case of endophthalmitis occurring between January 1996 and December 1998 after any intraocular surgery irrespective of the time between the surgery and the onset of endophthalmitis symptoms. All microbiology laboratories in Norway were asked to return questionnaires regarding their routine handling procedures of eye specimens in cases of endophthalmitis. From 1996 to 1998, 111 suspected endophthalmitis cases were reported, all after cataract surgery. Eighty cases were culture positive, 75 with gram-positive bacteria, 4 with gram-negative bacteria, and 1 with Candida albicans. Depending on the definition, the incidence of postoperative endophthalmitis was between 0.11% and 0.16%. Thirteen percent of cases had "delayed" endophthalmitis. Twenty-nine percent of eyes had an outcome of permanent amaurosis or light perception visual acuity; 56% (47/84) retained or improved their categorized visual acuity in the affected eye compared to preoperatively. Positive bacterial growth was associated with a worse visual outcome (P =.008). The degree of inflammation when endophthalmitis was diagnosed and the visual outcomes were worse in cases with growth of streptococci than in cases with growth of staphylococci (P =.009 and P<.001, respectively). The questionnaire to the microbiology laboratories revealed a lack of consensus on how to handle the specimens. Postoperative endophthalmitis remains a serious complication of intraocular surgery, although the prognosis depends greatly on the microbe isolated. Common guidelines should be established regarding clinical and microbiological diagnosis and treatment. Further improvement of the registry would make it a suitable platform for evaluating prophylactic treatments.


Diffusion-weighted echo-planar MR imaging and ADC mapping in the differential diagnosis of ovarian cystic masses: usefulness of detecting keratinoid substances in mature cystic teratomas.
To elucidate whether apparent diffusion coefficient (ADC) values calculated from echo-planar diffusion-weighted MR imaging (EPDWI) are useful in the differential diagnosis of ovarian cystic masses. EPDWI was performed in 131 patients with ovarian cystic masses (54 mature cystic teratomas, 35 endometrial cysts, four other benign cysts, 14 benign neoplasms, and 24 malignant neoplasms). The areas of the highest signal intensity on EPDWI (b = 1000 seconds/mm(2)) and the lowest ADC values within the cystic component were evaluated. On qualitative and quantitative analyses, mature cystic teratomas tended to show higher signal intensity and had areas of lower ADC values than endometrial cysts and other benign and malignant neoplasms (P < .005). In vitro scanning of the cystic contents of mature cystic teratomas confirmed that high signal on DWI or low ADC value was attributable to the keratinoid substance within the tumors. The difference in ADC between malignant and benign lesions were significant when mature cystic teratomas and endometrial cysts were included, but was not significant when they were excluded. The ADC value may add useful information to the differential diagnosis of ovarian cystic masses in limited populations, such as those with mature cystic teratomas with a small amount of fat.


Neutrophil to lymphocyte ratio (NLR) impact on the progression-free survival and overall survival of multiple myeloma patients treated with high-dose chemotherapy and autologous stem cell transplantation.
High-dose chemotherapy with autologous stem-cell transplantation (ASCT) remains the standard of care in multiple myeloma (MM) patients. This retrospective study aimed to assess the impact of neutrophil-to-lymphocyte ratio (NLR) and other complete blood count (CBC)-based predictors on PFS and OS of transplant-eligible MM patients. The CBC-based biomarkers were evaluated in a single-center cohort of 176 MM patients at three time points: at the diagnosis, the time of ASCT, and +100 d after ASCT. Univariable and multivariable Cox's regression analyses and Kaplan-Meier estimate were used in statistical analysis. NLR at ASCT (HR 1.15, 95% CI: 1.05-1.26) and hemoglobin at ASCT (HR 0.80, 95% CI: 0.68-0.94) were independent factors influencing PFS. In the model for OS, the only statistically significant factors were NLR at ASCT (HR 1.15, 95% CI: 1.04-1.27), bortezomib administration prior to ASCT (HR 0.52, 95% CI: 0.33-0.83) and age at diagnosis (HR 1.03, 95% CI: 1.00-1.06). NLR at ASCT is an independent predictive factor in MM patients undergoing ASCT.


Prevalence and morphological analysis of dens invaginatus in anterior teeth using cone beam computed tomography: A systematic review and meta-analysis.
To evaluate the prevalence and morphological characteristics of DI using CBCT. A literature search was performed in PubMed, Embase, Scopus, and Web of Science. Inclusion criteria were randomized clinical trials, cross-sectional studies, and prospective and retrospective cohort studies evaluating the morphological characteristics of DI in anterior teeth using CBCT. Three reviewer authors independently screened the studies, applied the eligibility criteria, assessed the risk of bias, and extracted until September (2022). The risk of bias was evaluated using the Joanna Briggs Institute criteria. Meta-analyses of proportions were used for estimate the prevalence DI according to factors at participant and tooth levels. Six studies were included in the meta-analysis. Among 7373 individuals, a prevalence of 7.45 % of DI was observed (n = 258; τ2 = 0.0096; CI of 4.51-11.3; p < 0.05), with no significant influence of sex. Regarding laterality, unilateral DI showed higher mean prevalence (4.30 %; CI of 2.03-7.33). Among the 382 anterior teeth with DI (0.72 %), the most affected tooth was the upper lateral incisor (5.12 %; n = 329; CI of 2.35-8.86; p < 0.001), type I was the most prevalent (0.59 %; CI of 0.24-1.08) and the presence of open apex and periradicular pathology ranged from 4.3 % to 22.72 % and 3.5-77.92 %, respectively. The prevalence of individuals with dens invaginatus was 7.45 %, the most affect tooth was the upper lateral incisor with a prevalence of 5.12 % unilaterally and type I was the most prevalent morphology.


Molecular ion index assisted comprehensive profiling of B-type oligomeric proanthocyanidins in rhubarb by high performance liquid chromatography-tandem mass spectrometry.
Proanthocyanidins (PAs) are major anti-diarrhea constituents in rhubarb, one of the frequently used traditional medicines. However, the phytochemical investigation of PAs in rhubarb was hampered by their strenuous purification and identification. In the present study, aiming to clarify the distribution of PAs in different rhubarb species, a molecular ion index was priorly established according to the structural features of B-type PAs, which led to a series of targeted discovery of oligomeric PAs in rhubarb by the HPLC-ESI-MS/MS method. Totally, 66 oligomeric PAs including 27 dimers, 29 trimers, and 10 tetramers were tentatively identified on the basis of their MS/MS spectra from 28 rhubarb samples derived from 5 Rheum species as R. palmatum, R. tanguticum, R. officinale, R. coreanum, and R. laciniatum. It is noteworthy that 6 propelargonidins, 14 prodelphinidins, and 10 procyanidin-tetramers were identified from rhubarb for the first time. The profiling comparison of these oligomeric PAs in different rhubarb samples was achieved by visualizing their abundance in a heat map, which indicated the dominant PAs in rhubarb were procyanidin-dimer and its galloylated derivatives.


CD8+ T lymphocytes and cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome.
We compared the levels of CD8+ and CD4+ cells in human immunodeficiency virus (HIV)-seropositive patients who had normal eye examinations, microvasculopathy, or ocular infections other than cytomegalovirus retinitis to those of patients with cytomegalovirus retinitis, to determine whether lymphocyte counts other than CD4+ are predictive of cytomegalovirus retinitis. The records of HIV-positive patients who had a lymphocyte subset analysis within three months of a complete eye examination were reviewed for age, gender, mode of HIV transmission, stage of disease, ocular findings, and absolute lymphocyte counts. Data for patients without cytomegalovirus retinitis were compared with those for patients with cytomegalovirus retinitis. Ninety-three HIV-positive patients had a lymphocyte subset analysis within three months of a complete eye examination; 76 patients had no cytomegalovirus retinitis and 17 had cytomegalovirus retinitis. Patients without cytomegalovirus retinitis and those with cytomegalovirus retinitis had the following median cell counts: CD4+, 76.0 and 15.0 cells/microliters; CD8+, 634.5 and 280.0 cells/microliters, respectively. Patients with cytomegalovirus retinitis had significantly lower CD4+ and CD8+ cell counts than those without cytomegalovirus retinitis (P < .001). CD4+ and CD8+ cells are significantly correlated with each other, and the correlation is much higher in patients with cytomegalovirus retinitis (r = .80, P < .001) than in patients without cytomegalovirus retinitis (r = .57, P < .001). Stepwise logistic regression analysis showed that CD8+ cell counts were also predictive of cytomegalovirus retinitis. Patients with low CD4+ cell counts are known to be at high risk for cytomegalovirus retinitis. We showed that patients with low CD8+ cell counts are also at high risk for cytomegalovirus retinitis.


Leptin deficiency produces contrasting phenotypes in bones of the limb and spine.
Leptin is a hormone secreted by adipocytes that can regulate bone mass through a central, neuroendocrine signaling pathway. We tested the hypothesis that the response of bone tissue to altered leptin signaling is not uniform throughout the skeleton, but may vary between different skeletal regions and between cortical and trabecular moieties. We investigated the effects of leptin deficiency on muscle mass and bone architecture in obese, leptin-deficient (ob/ob) mice, and in lean controls. Results indicate that the obese mice weigh approximately twice as much as the lean mice, but the quadriceps muscles of the ob/ob mice are 40% smaller than those of controls. Leptin-deficient mice have significantly shorter femora, lower femoral bone mineral content (BMC), bone mineral density (BMD), cortical thickness, and trabecular bone volume compared to lean mice. Marrow tissue from the femora of ob/ob mice also shows a marked increase in adipocyte number compared to that of normal mice. In contrast to the pattern observed in the femur, ob/ob mice have significantly increased vertebral length, lumbar BMC, lumbar BMD, and trabecular bone volume compared to lean controls. Few adipocytes are observed in bone marrow from lumbar vertebrae of ob/ob mice, despite being numerous in marrow of the femur. However, like the femur, significant cortical thinning is also observed in the spine. These results indicate that the effects of altered leptin signaling on bone differ significantly between axial and appendicular regions, and may be mediated in part by muscle mass. The muscle hypoplasia, increased marrow adipogenesis, and decreased bone mass observed in the hindlimbs of ob/ob mice are also observed with aging in humans, suggesting that the ob/ob mouse may be a new and useful animal model for studying the relationship between bone marrow adipogenesis and osteopenia.


Listener judges and the speech intelligibility of deaf children.
Two listener groups, one experienced and the other inexperienced in listening to deaf speakers, were asked to recognize speech sounds in word contexts presented in two modes: auditory only and auditory-visual. In contrast to previous studies, the experienced and inexperienced listener groups performed similarly. The one exception occurred for speech sounds in the final position presented auditory visually where the experienced listeners' performance surpassed that of inexperienced listeners. For both groups, performance in correct phoneme identification was better in the auditory-visual mode of presentation. Furthermore, and interaction between the position-in-word and the mode of stimulus presentation was present in both groups. In the auditory-only task, listeners correctly identified more target phonemes when they were initial rather than final position in a word. With supplemental visual information, listener performance increased our phonemes in both positions within a word, although the increase was greater for final position phonemes.


Risk factors associated with hypoxemia during foreign body removal from airways in childhood.
The aim of this study was to analyze the association between variables associated with hypoxemia in children who underwent rigid bronchoscopy for foreign body removal. From April 1993 to April 2011, four hundred and one children who inhaled foreign bodies were included. Apart from descriptive statistics, univariate and multivariate analyses were performed to identify risk factors related to hypoxemia. Among the patients aged up to one year, the risk of hypoxemia was five and a half times higher than for patients aged 1 or older (OR=5.6), whereas the risk of patients who underwent foreign body removal using seed type tweezers having hypoxemia was approximately 4 times higher than that of patients who underwent this procedure with other types of tweezers (OR=3.7). Furthermore, for each additional minute in the duration of the procedure, the risk of hypoxemia reached 4% (OR=1.04). Our results suggest that children younger than 1 year who require RB seem to be vulnerable to a higher risk of hypoxemia, especially in longer procedures in which seed tweezers are used.


Effect of diet on urinary MHPG excretion in depressed patients and normal control subjects.
The authors studied the effect of a catecholamine-controlled diet on the urinary level of 3-methoxy-4-hydroxyphenylglycol (MHPG) of 6 depressed patients and 6 normal volunteers. The normal subjects showed no change in MHPG levels on or off the diet; the depressed patients showed a significant increase in MHPG while off the diet.


Incorporating Mobile App Technology in Voice Modification Protocol for Transgender Women.
Motivated by practice and feedback principles of motor learning, a hybrid clinic-home protocol for voice feminization was developed to minimize the role of SLPs to 1 of supervision and professional guidance and to maximize learning during independent practice apart from intervention sessions. The purpose was to explore the effectiveness and acceptability of the innovative service delivery. This single-subject changing criterion design included four transgender women who completed a 10-week hybrid clinic-home voice intervention program delivered via 30 -minute weekly in-clinic sessions and a technology-supported home program. The program was client-centered and capitalized on principles of motor learning in that it incorporated frequent practice with intermittent, knowledge-of-result feedback. Participants' desired outcomes were measured using acoustics, self and listener ratings of audio samples, and a program evaluation questionnaire. Average speaking fundamental frequency of phrases and picture descriptions gradually increased into the 170-220 Hz range for all except one participant. All four transgender women were perceived to sound more feminine following treatment compared to baseline. Participants found the in-clinic sessions useful, the app easy to use, and noted limited fatigue or discomfort. Four transwomen met their goals using this hybrid clinic-home service delivery format. Further investigations may elucidate key factors of the success achieved in the current study by designing comparison delivery models and including people from other populations.


Inspirational chemistry of bioabsorbable long-acting injectables.
Long-acting injectables (LAIs) have made a tremendous impact on clinical medicine. As evidence, dozens of approved LAI products are on the market. These LAI successes, in a large part, came from the clever chemistry of their materials that control drug delivery performance. Beyond their materials, what innovations and technologies led to LAI success? What were the scientific progressions and who were the people and their stories behind LAI success? The answers to these questions are interesting to hear about, learn from, and be inspired by. Many people from many diverse fields contributed to the scientific advancement, product development, and product launches of long-acting injectables. Over 50 years ago, LAI pioneers envisioned a host of new drug delivery concepts and engaged their enthusiasm to reduce their concepts to practice. In doing so, they considered a variety of materials, dosage forms, routes of administration, and manufacturing processes, and they had to devise new tools to support product development. Because of the wide technology breadth of long-acting injectables, this publication focuses on bioabsorbable LAIs formulated with polymeric excipients such as lactide/glycolide functional excipients. Their historical progression of polymer chemistry and formulation development is shared. Successes are highlighted with some backstories.


Efficacy and safety of contrast injection beyond total occlusions in acute cardiac patients: a method to confirm balloon position within coronary lumen.
To evaluate the sensitivity and safety of contrast injection beyond total occlusions in acute cardiac patients in order to ensure balloon position within the coronary lumen and occasionally to enable the estimate of occlusion length. Percutaneous therapy of total coronary occlusions is generally more challenging than the treatment of stenotic lesions. It more frequently entails the risk of irreversibly disrupting a protruding plaque, of advancing the wire through a false route, or rarely, of causing coronary perforation. Therefore, ascertaining intraluminal position prior to inflation is important. In a large group of consecutive acute cardiac patients undergoing percutaneous coronary intervention (PCI) we employed a technique of crossing the lesion with a soft-tipped guidewire supported by an over-the-wire (OTW) balloon catheter, and then injecting dilute contrast through the balloon under fluoroscopy to achieve distal lumen visualization. In 106 patients, this technique yielded a sensitivity of 94%, a specificity of 70%, a positive predictive accuracy of 97%, and a negative predictive accuracy of 54% for intraluminal position of the balloon. The technique of lumen demonstration by contrast injection through an OTW balloon beyond acute or subacute total obstructions was shown to be a safe and effective method to ascertain proper position of the angioplasty balloon. Occasionally, it enabled the estimation of lesion length or the identification of lesions distal to the obstruction. This technique was found to be valuable in doubtful situations where the determination of wire position was crucial for achieving procedural success.


The effects of developmental and current niches on oligodendrocyte precursor dynamics and fate.
Oligodendrocyte precursor cells (OPCs), whose primary function is to generate myelinating oligodendrocytes, are distributed widely throughout the developing and mature central nervous system. They originate from several defined subdomains in the embryonic germinal zones at different developmental stages and in the adult. While many phenotypic differences have been observed among OPCs in different anatomical regions and among those arising from different germinal zones, we know relatively little about the molecular and cellular mechanisms by which the historical and current niches shape the behavior of oligodendrocyte lineage cells. This minireview will discuss how the behavior of oligodendrocyte lineage cells is influenced by the developmental niches from which subpopulations of OPCs emerge, by the current niches surrounding OPCs in different regions, and in pathological states that cause deviations from the normal density of oligodendrocyte lineage cells and myelin.


The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio.
The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.


Spinal anesthesia with tetracaine--effect of added vasoconstrictors.
The effect of adding 0.2 ml of 1:1000 epinephrine or 0.5 ml of 1% phenylephrine to 1.5 ml of 1% tetracaine for spinal anesthesia was assessed in 30 patients in a double-blind study. Phenylephrine but not epinephrine produced a significant prolongation of sensory loss in the T12 dermatome. Both vasoconstrictors produced a significant prolongation of the total duration of sensory and motor blockade. These findings differ from those in previous studies in which lidocaine and bupivacaine were used.


More airway smooth muscle in males versus females in a mouse model of asthma: A blessing in disguise?
What is the central question of this study? The lung response to inhaled methacholine is reputed to be greater in male than in female mice. The underpinnings of this sex disparity are ill defined. What is the main finding and its importance? We demonstrated that male airways exhibit a greater content of airway smooth muscle than female airways. We also found that, although a more muscular airway tree in males might contribute to their greater responsiveness to inhaled methacholine than females, it might also curb the heterogeneity in small airway narrowing. Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty-four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine-induced bronchoconstriction). However, for a well-matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity.


Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes.
To assess the characteristics, treatments, risk factors and outcomes of breakthrough candidemia in children. Episodes of breakthrough candidemia in children were compared with the remaining episodes in a 13-year cohort study. Out of 319 episodes, 45 (14.1%) were breakthrough candidemia. Breakthrough candidemia occurred in patients with more acutely ill conditions, and the majority was caused by non-albicans Candida species (73.3%; 33 episodes). A total of 79.1% of breakthrough candidemia were caused by antifungal-susceptible Candida isolates and emergence of resistance was the mechanism in five cases of patients receiving fluconazole. Episodes of breakthrough candidemia had significantly higher illness severity and higher rates of fungemia-attributable mortality. Breakthrough candidemia independently contributed to unfavorable outcomes, and more aggressive treatment strategies are warranted when breakthrough candidemia is encountered.


A Pilot Study of the Maternal-Fetal Pharmacokinetics of Furosemide in Plasma, Urine, and Amniotic Fluid of Hypertensive Parturient Women Under Cesarean Section.
The third trimester of pregnancy is related to physiological changes that can modify the process of absorption, distribution, metabolism, and excretion and, consequently, the efficacy and toxicity of drugs. However, little is known about furosemide pharmacokinetics and placental transfer in pregnancy. This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of delivery. The following furosemide pharmacokinetic parameters were obtained as median (interquartile range): Cmax , 403 ng/mL (229 to 715 ng/mL); Tmax , 2.00 hours (1.50 to 4.83 hours); elimination half-life (t1/2 ), 2.50 hours (1.77 to 2.97 hours); AUC0-12 h , 1366 ng⋅h/mL (927 to 2531 ng⋅h/mL); AUC0-∞ , 1580 ng⋅h/mL (1270 to 2881 ng⋅h/mL); CL/F 25.3 L/h (13.8 to 31.4 L/h); CLR, 2.50 L/h (1.77 to 2.97 L/h); CLNR, 22.7 L/h (12.1 to 25.6 L/h); and Vd /F 82.8 L (34.4 to 173 L). The transplacental transfer of furosemide was 0.43 (0.10 to 0.73), and the amniotic fluid concentration was 11.0 ng/mL (5.51 to 14.6 ng/mL). From a clinical point of view, these results suggest that substrates of uridine diphosphate-glucuronosyltransferase isoenzymes such as furosemide may have increased clearance during pregnancy and could require dose adjustment in this population.


Features of stabbing, cough, exertional and sexual headaches in a Turkish population of headache patients.
The aim of this study was to determine the features and prevalence of primary stabbing headache, primary exertional headache, primary headache associated with sexual activity, and primary cough headache in a Turkish population of headache patients. The data for this study were obtained from 245 patients with headache. Of these patients, 55 fulfilled the International Classification of Headache Disorders (second edition) diagnostic criteria for 'other primary headaches' such as primary stabbing headache (n=31), primary cough headache (n=1), primary exertional headache (n=13), primary headache associated with sexual activity (n=4), and both primary cough headache and primary exertional headache (n=6). Primary stabbing headache was found in 12.6% of patients, primary cough headache in 0.4%, primary exertional headache in 5.3% and primary headache associated with sexual activity in 1.6%.


Cancer chemoprevention by supplemental carotenoids in animals and humans.
Experiments were carried out in mice demonstrating that dietary carotenoids (beta-carotene or canthaxanthin), starting before cancer initiation and continuing throughout the experiment, have a protective effect against indirect skin carcinogenesis induced by benzo[a]pyrene +/- UVA and breast cancer induced by 8-methoxypsoralen + UVA. Experiments in rats demonstrated that carotenoids also prevent the direct gastric carcinogenesis induced by N-methyl-N'-nitro-nitroso-guanidine. Recently, prevention by beta-carotene against colon cancer induced in mice by dimethylhydrazine, another indirect carcinogen, was confirmed by others. The prospects for carotenoid intervention with humans were based on their antitumorigenic effect, which is quite independent of pro-vitamin A activity, their lack of toxicity even after prolonged administration, and their immunostimulating activity. These facts helped to build up a rationale predicting that any epithelial cancer, after radical surgery, can be chemoprevented with supplemental carotenoids. Thus, it is expected that the remaining initiated epithelial tissue will be protected by quenching oxygen radical formation, against the onset of a second primary malignancy. This type of prevention can be envisaged in organs like the lung, urinary bladder, breast, stomach, and colon-rectum. At present, human intervention protocols with a randomized drug/placebo method are underway under the supervision of the Centro Tumori of Pavia to chemoprevent with beta-carotene second primary lung or bladder cancer after radical surgery. Preliminary observations regarding findings in humans without randomization (1980-1988) in Pavia are also reported here. This consisted of chemoprevention with beta-carotene plus canthaxanthin against recurrence of different epithelial malignancies after radical treatment (surgery +/- chemoradiotherapy). None of the 11 cases recruited, on the basis of radical nature of treatment and patient adherence, have shown any recurrence beyond their expected disease-free intervals.


Treatment of duplicated thumb using a ligamentous/periosteal flap.
Since 1975, 22 duplicated thumbs in 21 children were treated by ablation of one of the digits, elevation of a ligament and periosteal flap from the proximal bone, reduction osteotomy to narrow the widened proximal bone, centralization of the retained thumb, and stabilization of the joint by reattaching the ligament and periosteal flap. In addition to improving the cosmetic appearance by centralizing the retained thumb on the narrowed proximal bone, good joint stability was provided. Three patients had subsequent joint arthrodesis because of laxity of the contralateral collateral ligament. The procedure is preferred to the reconstruction of a single digit by using component parts of both duplicated thumbs because the described procedure is technically simpler and does not potentially interfere with physeal growth or leave a nail matrix defect.


Systematic epidemiologic theory: conceptual foundations and axiomatic elements.
Since the initial epidemiologic confrontations of chronic, non-infectious diseases during the 1940's, there has emerged a periodic concern among epidemiologists regarding disciplinary boundaries and identity. With the development of hierarchical views of the natural history of human disease, the elaboration of mutation theories of chronic, non-infectious disease, and the identification of conceptual frameworks and causal relationships applicable to both the infectious and chronic, non-infectious diseases, it has become possible to reconsider the definitions and scope of epidemiology from within the confines of general epidemiologic-pathologic theory. Based upon natural history and discipline-related concepts of causation, it is possible to integrate the epidemiological and pathological characteristics of disease into a single, coherent systematic epidemiologic theory. Within these conceptual/axiomatic frameworks, systematic epidemiology emerges as the study of disease causality and control and is generally applicable to both the infectious and the chronic, non-infectious (i.e., neoplastic) diseases. Because epidemiologic theory begins with pathologic theory, it is fitting that systematic epidemiologic theory embrace both epidemiology and pathology as complimentary conceptual approaches to the comprehension of disease. Because the interdependent efforts of epidemiology and pathology provide the conceptual basis for action, it is also fitting that systematic epidemiologic theory embrace preventive medicine and public health as operational approaches to the control of disease.


4-Amino-3-(3-meth-oxy-benz-yl)-1H-1,2,4-triazole-5(4H)-thione.
In the title mol-ecule, C10H12N4SO, the triazole ring forms a dihedral angle of 73.0 (5)° with the benzene ring. The meth-oxy group is approximtely coplanar with the benzene ring with a C C-O-Cmeth-yl torsion angle of 4.7 (3)°. In the crystal, N-H⋯S hydrogen bonds connect pairs of inversion-related mol-ecules, which are in turn connected by N-H⋯N hydrogen bonds into chains of rings along [010]. Weak C-H⋯O hydrogen bonds connect these chains into a two-dimensional network parallel to (-102).


Pre-steady-state kinetic characterization of the AP endonuclease activity of human AP endonuclease 1.
Human AP endonuclease 1 (APE1, REF1) functions within the base excision repair pathway by catalyzing the hydrolysis of the phosphodiester bond 5 ' to a baseless sugar (apurinic or apyrimidinic site). The AP endonuclease activity of this enzyme and two active site mutants were characterized using equilibrium binding and pre-steady-state kinetic techniques. Wild-type APE1 is a remarkably potent endonuclease and highly efficient enzyme. Incision 5 ' to AP sites is so fast that a maximal single-turnover rate could not be measured using rapid mixing/quench techniques and is at least 850 s(-1). The entire catalytic cycle is limited by a slow step that follows chemistry and generates a steady-state incision rate of about 2 s(-1). Site-directed mutation of His-309 to Asn and Asp-210 to Ala reduced the single turnover rate of incision 5 ' to AP sites by at least 5 orders of magnitude such that chemistry (or a step following DNA binding and preceding chemistry) and not a step following chemistry became rate-limiting. Our results suggest that the efficiency with which APE1 can process an AP site in vivo is limited by the rate at which it diffuses to the site and that a slow step after chemistry may prevent APE1 from leaving the site of damage before the next enzyme arrives to continue the repair process.


Heme as a Taste Molecule.
The sense of taste has evolved to enable the identification of appropriate substances to consume, to acquire nutrients, and to avoid consuming potential toxins. Five basic taste classes have been recognized, although there may be others, including metallic taste, which have not been well defined. The purpose of this review was to survey available data from diverse sources to determine how much was known about the molecular basis for metallic taste. Metallic taste has been studied in the context of dysgeusia, primarily using non-heme iron as an inducer of metallic taste sensation. However, recent efforts by industry to develop plant-based meat substitutes have suggested that iron in the form of heme may be the main molecule underlying the taste of meat. Little work has been done on heme as a taste molecule. Data support a primary role for heme in metallic taste that may have evolved as part of a means to consume and preserve elemental iron for physiological needs.


Molecular structure and stereoelectronic properties of herbicide sulphonylureas.
MO theoretical calculations were used with the aim to investigate the electronic properties of a number of sulphonylureas 1-8 which are employed as antifeedants. Quantum chemical descriptors [electron density, molecular electrostatic potential (MEP), the topology of frontier orbitals and reactivity index] were determined for these compounds, aimed both to obtain a deeper insight in their mechanism of action and to correlate these properties with their activity as inhibitors of ALS synthase.


Association genetics of chilling injury susceptibility in peach (Prunus persica (L.) Batsch) across multiple years.
Peach and nectarine (Prunus persica L.) are highly perishable; they ripen and deteriorate quickly at ambient temperature. Storage at low temperature (0-5 °C) is a common strategy used to slow the ripening processes and to extend shelf life. However, if susceptible varieties are held too long at a low temperature, they will not ripen properly and will develop chilling injury (CI) symptoms like mealiness (M), flesh browning (FB), and flesh bleeding (FBL). Understanding the genetic control of these traits to produce CI resistant cultivars will greatly benefit producers, shippers and consumers. In this study, we evaluated a population of 51 individuals from Pop-DG across 4 years with CI traits observed in one or two time points to detect molecular marker association with selected 960 single-nucleotide polymorphisms (SNPs) from 1,536 SNPs chip. Genotypic and phenotypic data were analyzed by general linear model and mixed linear model to see comparative results from both analyses. Among 960 SNPs used, 22 SNPs were found associated with CI susceptibility traits like M, FB, and FBL. Many SNP markers were located in or close to previously reported quantitative trait loci mapped by linkage analysis.


Lack of Galanin 3 Receptor Aggravates Murine Autoimmune Arthritis.
Neurogenic inflammation mediated by peptidergic sensory nerves has a crucial impact on the pathogenesis of various joint diseases. Galanin is a regulatory sensory neuropeptide, which has been shown to attenuate neurogenic inflammation, modulate neutrophil activation, and be involved in the development of adjuvant arthritis, but our current understanding about its targets and physiological importance is incomplete. Among the receptors of galanin (GAL1-3), GAL3 has been found to be the most abundantly expressed in the vasculature and on the surface of some immune cells. However, since there are minimal in vivo data on the role of GAL3 in joint diseases, we analyzed its involvement in different inflammatory mechanisms of the K/BxN serum transfer-model of autoimmune arthritis employing GAL 3 gene-deficient mice. After arthritis induction, GAL3 knockouts demonstrated increased clinical disease severity and earlier hindlimb edema than wild types. Vascular hyperpermeability determined by in vivo fluorescence imaging was also elevated compared to the wild-type controls. However, neutrophil accumulation detected by in vivo luminescence imaging or arthritic mechanical hyperalgesia was not altered by the lack of the GAL3 receptor. Our findings suggest that GAL3 has anti-inflammatory properties in joints by inhibiting vascular hyperpermeability and consequent edema formation.


Adverse reactions to oral retinoids. An update.
Retinoids, both naturally occurring and synthetic, are analogues of vitamin A. They represent a major advance in the treatment of acne and psoriasis, as well as rarer conditions such as the ichthyoses. The more frequent and widespread use of these drugs requires that the dermatologist be aware of the wide spectrum of adverse events that may be encountered with their use. Some are serious and irreversible, such as teratogenicity, necessitating great care if these drugs are given to women of childbearing potential. Other effects may be less severe, dose dependent and reversible. Although not devastating to the patient, appropriate advice may reduce morbidity.


Effects of sterilization and disinfection procedures on the corrosion of orthodontic ligature cutters.
The objective of our study was to investigate the corrosion resistance of orthodontic ligature cutters subjected separately to two different sterilization procedures, namely, autoclaving and chemical disinfection with main focus on the cutting section of each instrument. Twenty-four ligature cutters were obtained from three different manufacturers: Hu-Friedy, ETM, and Nadir & Co. The study included a control group (G0) and four experimental groups (G1-4). G1 was subjected to 50 autoclave sterilization cycles. G2, G3, and G4 were subjected to 50 chemical disinfection cycles using, respectively, Peridiol E, Hexanios G+R, and Steranios 2%. Manufacturer recommendations were followed. The instruments' blades were studied via SEM and X-ray microanalysis (EDX spectrum). These cutters have inserts made from various resistant alloys. SEM micrographs revealed different forms of corrosion depending on whether autoclaving or chemical disinfectant sterilization procedures were used, and depending on the alloys present. Chemical disinfection is more aggressive than autoclave sterilization, and is responsible for localized corrosion in the form of pitting. This is more detrimental to the lifespan of orthodontic cutters. Sterilization/disinfection procedures should be adapted to the chemical profile of the metal alloys present. Recommendations for use published by instrument manufacturers must be followed.


Tracing the emergence of the memorability benefit.
Some visual stimuli are consistently better remembered than others across individuals, due to variations in memorability (the stimulus-intrinsic property that determines ease of encoding into visual long-term memory (VLTM)). However, it remains unclear what cognitive processes give rise to this mnemonic benefit. One possibility is that this benefit is imbued within the capacity-limited bottleneck of VLTM encoding, namely visual working memory (VWM). More precisely, memorable stimuli may be preferentially encoded into VLTM because fewer cognitive resources are required to store them in VWM (efficiency hypothesis). Alternatively, memorable stimuli may be more competitive in obtaining cognitive resources than forgettable stimuli, leading to more successful storage in VWM (competitiveness hypothesis). Additionally, the memorability benefit might emerge post-VWM, specifically, if memorable stimuli are less prone to be forgotten (i.e., are "stickier") than forgettable stimuli after they pass through the encoding bottleneck (stickiness hypothesis). To test this, we conducted two experiments to examine how memorability benefits emerge by manipulating the stimulus memorability, set size, and degree of competition among stimuli as participants encoded them in the context of a working memory task. Subsequently, their memory for the encoded stimuli was tested in a VLTM task. In the VWM task, performance was better for memorable stimuli compared to forgettable stimuli, supporting the efficiency hypothesis. In addition, we found that when in direct competition, memorable stimuli were also better at attracting limited VWM resources than forgettable stimuli, supporting the competitiveness hypothesis. However, only the efficiency advantage translated to a performance benefit in VLTM. Lastly, we found that memorable stimuli were less likely to be forgotten after they passed through the encoding bottleneck imposed by VWM, supporting the "stickiness" hypothesis. Thus, our results demonstrate that the memorability benefit develops across multiple cognitive processes.


Increased macrophage phagocytic activity with TLR9 agonist conjugation of an anti- Borrelia burgdorferi monoclonal antibody.
Borrelia burgdorferi (Bb) infection causes Lyme disease, for which there is need for more effective therapies. Here, we sequenced the antibody repertoire of plasmablasts in Bb-infected humans. We expressed recombinant monoclonal antibodies (mAbs) representing the identified plasmablast clonal families, and identified their binding specificities. Our recombinant anti-Bb mAbs exhibit a range of activity in mediating macrophage phagocytosis of Bb. To determine if we could increase the macrophage phagocytosis-promoting activity of our anti-Bb mAbs, we generated a TLR9-agonist CpG-oligo-conjugated anti-BmpA mAb. We demonstrated that our CpG-conjugated anti-BmpA mAb exhibited increased peak Bb phagocytosis at 12-24 h, and sustained macrophage phagocytosis over 60+ hrs. Further, our CpG-conjugated anti-BmpA mAb induced macrophages to exhibit a sustained activation morphology. Our findings demonstrate the potential for TLR9-agonist CpG-oligo conjugates to enhance mAb-mediated clearance of Bb, and this approach might also enhance the activity of other anti-microbial mAbs.