Collagen type I of rat cortical and trabecular bone differs in the extent of posttranslational modifications.
This study sought to evaluate whether the architecture of the matrix of cortical and trabecular bone is exactly the same. For this purpose we analyzed the extent of some posttranslational modifications of type I collagen, which is the major component of bone matrix. Ten female and 10 male 100-day-old rats were sacrificed and the content of hydroxylysine, glycosylated hydroxylysine, and pyridinium cross-links of collagen from cortical and trabecular bone was determined. The amount of each compound was expressed as a molar ratio with hydroxyproline. The collagen posttranslational modification pattern appears to be the same in both sexes but with a higher extent of differences in females compared with males. Comparing cortical and trabecular bone, the former contains a higher amount of hydroxylysine residues whereas in the latter, glycosylation of hydroxylysine is higher and pyridinium cross-link concentration is lower. Moreover, an inverse linear relationship between glycosylated hydroxylysine and pyridinium cross-links concentration was established, both for female (r = -0.455, P = 0.04) and male rats (r = -0.426; P = 0.06). This paper discusses what these findings may mean in functional terms.


Downregulation of lncRNA SNHG12 reversed IGF1R-induced osteosarcoma metastasis and proliferation by targeting miR-195-5p.
Long non-coding RNA SNHG12 (lncSNHG12) plays important roles in the onset and progression of various cancers. However, the role of lncSNHG12 in osteosarcoma (OS) remains unclear. Therefore, the aim of the present study was to determine the function of lncSNHG12 in OS. A bioinformatics website was used to predict the downstream targets of lncSNHG12. In addition, qRT-PCR was employed to assess lncSNHG12 expression in OS cells. Cell migration and proliferation in vitro were verified using the transwell migration, clone formation, and CCK8 assays. Tumor metastasis and xenograft formation were monitored in nude mice with or without downregulation of lncSNHG12. The results show that lncSNHG12 was upregulated in OS cell lines. Downregulation lncSNHG12 suppressed the metastasis and proliferation both in vitro and in vivo. Also, lncSNHG12 downregulation suppressed the expression of insulin growth factor 1 receptor (IGF1R) expression through sponging miR-195-5p, which was verified with the luciferase reporter assay and rescue experiments. These findings suggest that downregulation of lncSNHG12 may suppress aggressive OS phenotypes. Moreover, lncSNHG12 silencing inhibited OS metastasis and growth by targeting the miR-195-5p/IGF1R axis, which represents a candidate marker and target for OS treatment and management.


Heart rate and coronary flow effects on the cardiac response to sympathetic stimulation.
We studied the effects of changes in heart rate and coronary blood flow on the decay of the cardiac inotropic response to sympathetic stimulation in 10 anesthetized dogs. After we induced complete heart block, we paced the ventricles at rates of 90, 120 and 150.min-1. At each pacing frequency, we perfused the left main coronary artery with blood at a baseline flow and at a flow 85% above the baseline rate. At each combination of pacing frequency and flow, we stimulated the left ansa subclavia supramaximally at a frequency of 5 Hz for 2 min. To assess the rate of norepinephrine removal from the ventricular myocardium, we measured the 50% decay time of the left ventricular inotropic response [(dP/dt)max] immediately after cessation of sympathetic stimulation. We found that the inotropic response decayed faster (P = 0.03) when the coronary artery blood flow was high than when the flow was baseline. The effect of heart rate on the decay of the left ventricular inotropic response depended on the level of the coronary blood flow. When the blood flow was baseline, the inotropic response decayed more rapidly (P = 0.001) when the heart rate was 150.min-1 than when it was 90 or 120.min-1. However, when the flow was high, heart rate did not affect the response decay significantly. We conclude that the mechanical contraction of the ventricles facilitates the washout of norepinephrine from the cardiac interstitium and into the coronary circulation by virtue of a massaging action.


Charged amino acids conserved in the aromatic acid/H+ symporter family of permeases are required for 4-hydroxybenzoate transport by PcaK from Pseudomonas putida.
Charged amino acids in the predicted transmembrane portion of PcaK, a permease from Pseudomonas putida that transports 4-hydroxybenzoate (4-HBA), were required for 4-HBA transport, and they were also required for P. putida to have a chemotactic response to 4-HBA. An essential amino acid motif (DGXD) containing aspartate residues is located in the first transmembrane segment of PcaK and is conserved in the aromatic acid/H+ symporter family of the major facilitator superfamily of transporters.


Inverse PCR-mediated cloning of the promoter for the rat vasopressin V2 receptor gene.
The adenylyl cyclase-coupled vasopressin V2 receptor has been cloned recently and shown, in rats, to be produced from the predominant form of two alternate spliced variants. To begin to unravel the transcriptional regulation of this receptor, we have isolated the 5' flanking region of the rat vasopressin V2 receptor gene and characterized its promoter sequence. The method of inverse polymerase chain reaction (PCR), which allows the amplification of DNA fragments adjacent to a segment of known sequence, was used as an alternative approach to genomic DNA library screening. Using a probe encompassing part of the coding region, first we identified by Southern blot analysis, a single BstX I hybridizing fragment of 2.3 kilobases (kb). This size predicted a BstX I restriction site 1.5 kb upstream to the gene coding region. Cloning of this fragment was accomplished through circularization of BstX I restriction digests and inverse PCR-mediated amplification. Sequence analysis of the gene 5' flanking domain enabled the design of oligonucleotide primers with the usual forward/reverse orientation, and additional clones were generated from native genomic DNA using a high fidelity thermoresistant DNA polymerase. Reverse transcription-PCR (RT-PCR) and primer extension analysis mapped the major transcription start site 422 nucleotides upstream to the translation initiation codon. The promoter region lacks a TATA box but contains a CAAT box and a consensus binding site for transcription factor Sp1. Multiple potential binding sites for the transcription factor PEA3 are clustered in two DNA portions located 0.6 kb and 1 kb upstream to the coding region. In addition, sequences homologous to glucocorticoid response elements are present and might be responsible for the regulation by adrenal steroids of vasopressin-dependent adenylyl cyclase activity in the kidney.


Generation of a human induced pluripotent stem cell line KUMi006 from a patient with multiple myeloma.
In this study, we report the generation of a novel human induced pluripotent stem cell (hiPSC) line from bone marrow mononuclear cells of a patient with multiple myeloma, using an integrative Sendai virus vector. This pluripotent cell line has been shown to differentiate into three germ layers. Therefore, these induced pluripotent stem cells (iPSCs) will enable not only advances in cell therapy products but also the study of mechanisms.


Effects of photobiomodulation on cellular viability and cancer stem cell phenotype in oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy; it has been shown that cancer stem cells (CSC) are present in OSCC and associated with tumor growth, invasion, metastasis, and therapeutic resistance. Photobiomodulation (PBM) is an alternative tool for oncologic treatment adverse effects such as oral mucositis (OM); however, controversy exists regarding the undesirable effects of PBM on tumor or CSC. This study aimed to evaluate in vitro, the effects of PBM, with the same dosimetric parameters as those used in the clinic for OM prevention and treatment, on OSCC cellular viability, as well as PBM's effect on CSC properties and its phenotype. OSCC cell lines were submitted to single or daily PBM with 3 J/cm2 and 6 J/cm2 and then the cellular viability was evaluated by MTT, NRU (neutral red uptake), and CVS (crystal violet staining). The CSC populations were evaluated by clonogenic formation assay, flow cytometry, and RT-qPCR. The single PBM with the 3 J/cm2 group was associated with increased cellular viability. Daily PBM with 3 J/cm2 and 6 J/cm2 was associated with a significant decrease in cellular viability. Additionally, daily PBM was not able to promote CSC self-renewal or the CD44high/ESAlow and CD44high/ESAhigh cellular phenotypes. Moreover, a decrease in the number of spheres and in the expression of the CSC related gene BMI1 was observed after daily PBM with 6 J/cm2. Daily PBM with 3 J/cm2 and 6 J/cm2 showed an inhibitory effect on cellular viability and was not able to promote the CSC self-renewal or phenotype.


Molecular self-assembling and the fluorescence enhancement in morin-Al3+-cetyltrimethylammonium bromide-protein system.
Fluorescence enhancement effect of the morin-Al3+-cetyltrimethylammonium bromide (CTAB)-bovine serum albumin (BSA) system is reported here and the interaction mechanism is studied using fluorescence, resonance light scattering (RLS), absorption spectroscopy, Far-UV circular dichroism (CD) spectrum and small angle X-ray scattering (SAXS) measurement. It is considered that protein can bind with Al3+, morin and CTAB through self-assembling function with electrostatic attraction, hydrogen bond, hydrophobic interaction and Vander Waal force etc, and forms a supermolecular association with multilayer structure, in which morin-Al3+ is clamped between BSA and CTAB. In this system, the fluorescence enhancement of morin originates from both intermolecular energy transfer between BSA and morin, and the hydrophobic microenvironment provided by BSA and CTAB. Whereas Al3+ plays a key role for the enhancement of energy transfer efficiency because it provides an efficient channel for the energy transfer between BSA and morin.


Oxalate loading test for screening steatorrhoea in diabetics.
Data presented here showed that oxalate loading test--a technique for diagnosis of steatorrhoea is not applicable if the patient is also suffering with diabetes. In vitro experiments showed that sugar interferes in oxalate assay.


A prospective study of postpartum psychoses in a high-risk group. 2. Relationships to demographic and psychiatric history characteristics.
Among 88 reproductions to women with a history of nonorganic psychosis, 25 postpartum episodes (PPPs) occurring during the total 6-month period following the current delivery were not systematically related to the woman's demographic characteristics, to her psychiatric history characteristics surrounding onset of the previous disorder or to a history of PPPs following previous reproductions. PPPs were highly significantly related to greater length of previous psychiatric hospitalization and to active mental disturbance just prior to this pregnancy, and this was true both for PPPs developing within 3 weeks of delivery and for those developing later. Considerable differences were found in the demographic characteristics that were related to development of PPPs within these Early vs. Later Onset cases, suggesting these to represent different disorders not only diagnostically but also demographically. In several diagnostic categories, selected demographic or psychiatric history characteristics identified subgroups with PPP rates as high as 75%.


Editorial Commentary: Results of Biplanar Fluoroscopy With 3-Dimensional Analysis in Patients With Rotator Cuff Tears Challenge the Concept of Superior Translation of the Humeral Head and Must Be Interpreted With Caution.
Kinematic analysis of patients with rotator cuff tears shows unexpected inferior, rather than superior, translation of the humeral head. This paradox challenges conventional thought, but limitations addressed by the authors temper the results and leave the question open for future study.


(S)-2-[(4-Fluoro-phen-yl)formamido]-3-phenyl-propanoic acid.
The title compound, C16H14FNO3, was synthesized via solid phase methods; it exhibits monoclinic (P21) symmetry at room temperature. The two independent mol-ecules that comprise the asymmetric unit display distinct torsion angles of 173.2 (2) and 72.6 (2)° along the central sp 3 C-N bond. In the crystal, hydrogen bonding through N-H⋯O contacts couples the asymmetric unit mol-ecules into pairs that align in layers extending parallel to (100) via additional O-H⋯O inter-actions. The phenyl ring of one independent mol-ecule was found to be disordered over two sets of sites in a 0.55 (3):0.45 (3) ratio.


Atrioventricular Nodal Re-entry Tachycardia in Identical Twins: A Case Report and Literature Review.
This report details the case of 17 year old identical twins who both presented with paroxysmal supraventricular tachycardia (PSVT). Electrophysiological studies revealed atrioventricular nodal reentry tachycardia (AVNRT) in both twins. Successful but technically challenging slow pathway ablation was performed in both twins. This is the first reported case of confirmed AVNRT in identical twins which adds strong evidence to heritability of the dual AV node physiology and AVNRT. A review of the current literature regarding PSVT in monozygotic twins is provided.


Analysis of colorectal cancer glyco-secretome identifies laminin β-1 (LAMB1) as a potential serological biomarker for colorectal cancer.
The high mortality rate in colorectal cancer is mostly ascribed to metastasis, but the only clinical biomarker available for disease monitoring and prognosis is the carcinoembryonic antigen (CEA). However, the prognostic utility of CEA remains controversial. In an effort to identify novel biomarkers that could be potentially translated for clinical use, we collected the secretomes from the colon adenocarcinoma cell line HCT-116 and its metastatic derivative, E1, using the hollow fiber culture system, and utilized the multilectin affinity chromatography approach to enrich for the secreted glycoproteins (glyco-secretome). The HCT-116 and E1 glyco-secretomes were compared using the label-free quantitative SWATH-MS technology, and a total of 149 glycoproteins were differentially secreted in E1 cells. Among these glycoproteins, laminin β-1 (LAMB1), a glycoprotein not previously known to be secreted in colorectal cancer cells, was observed to be oversecreted in E1 cells. In addition, we showed that LAMB1 levels were significantly higher in colorectal cancer patient serum samples as compared to healthy controls when measured using ELISA. ROC analyses indicated that LAMB1 performed better than CEA at discriminating between colorectal cancer patients from controls. Moreover, the diagnostic performance was further improved when LAMB1 was used in combination with CEA.


Binocular energy responses to natural images.
The binocular energy model provides a good description of the first stages of cortical binocular processing. Three important determinants of the responses of neurons under this model are the disparity of a stimulus, its spatial variation in disparity and its second-order luminance statistics. The influence of the latter two factors on the disparity tuning of the energy model were investigated. While each can have a significant effect on the energy response, neither presents a significant challenge when one considers the range of variation expected in natural images. The response of the energy model to natural binocular images was also investigated. The strongest responses were found for model neurons tuned to small disparities. This trend was more evident for vertical than for horizontal disparity, and flattened rapidly as image eccentricity increased. These results are predicted on the basis of simple geometrical considerations, and are reflected in both physiological and psychophysical measures of the disparity tuning of the visual system.


Relevance of leukaemia inhibitory factor to anti-melanoma differentiation-associated gene 5 antibody-positive interstitial lung disease.
Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD) is a life-threatening disease, the aetiology of which remains unclear. To detect potential diagnostic markers, a transcriptome analysis of the lung sample from a patient with anti-MDA5 antibody-positive RP-ILD was performed. RNA sequencing analyses of an autopsy lung sample from a 74-year-old woman with anti-MDA5 antibody-positive RP-ILD was performed and compared with an age- and sex-matched normal lung sample. Genes with changes of gene expression ≥5-fold were considered differentially expressed genes and analysed by Metascape. The levels of leukaemia inhibitory factor (LIF) were measured in the serum samples from 12 cases of anti-MDA5 antibody-positive ILD, 12 cases of anti-aminoacyl tRNA synthetase (ARS) antibody-positive ILD, 10 cases of anti-transcription intermediary factor 1γ/anti-Mi-2 antibody DM and 12 healthy volunteers. Gene ontology enrichment analysis on the RNA sequencing data showed a strong association with antigen binding. Upregulated expressions of IL-1β, IL-6 and LIF were also detected. Serum LIF levels were significantly elevated in anti-MDA5 antibody-positive ILD patients {median 32.4 pg/ml [interquartile range (IQR) 13.2-125.7]} when compared with anti-ARS antibody-positive ILD patients [4.9 pg/ml (IQR 3.1-19.7), P < 0.05] and DM patients [5.3 pg/ml (IQR 3.9-9.7), P < 0.05]. Our present study suggested that upregulation of LIF might be a new potential disease marker specific for anti-MDA5 antibody-positive ILD.


Visual and phonological pathways to the lexicon: evidence from Chinese readers.
In this study, we investigated the role of visual and phonological information in lexical access of Chinese characters. Homophonic English words have been the main source of stimuli for word recognition research. However, since these stimuli also often look alike, visual and phonological information may be confounded in reported experiments. In contrast, many homophonic Chinese characters are visually distinct. In addition, visually similar characters often have very different pronunciations. These characteristics allow a more controlled investigation of the roles of visual and phonological information in activation of meaning. In the present study, two types of Chinese characters were used in a semantic categorization paradigm: integrated characters, which contain strokes that are not separable; and compound characters, which contain at least two clearly identifiable components. The results show that the recognition of a Chinese integrated character depends primarily on visual information, whereas the recognition of a Chinese compound character relies on visual, phonological, and semantic information. It is concluded that visual information plays a greater role in Chinese character recognition than has previously been documented.


Subclinical eating disorders in male athletes. A study of the low weight category in rowers and wrestlers.
This study investigated the possibility that male athletes who, owing to the rules of their sport, are pressured to maintain a low weight show an elevated prevalence of subclinical eating disorders. Twenty-five wrestlers and 59 rowers in the lower weight categories were investigated using the Eating Disorder Inventory (EDI). Fifty-two percent of the athletes reported the occurrence of binging. The EDI profiles of 11% of the athletes suggested the presence of a subclinical eating disorder. These figures are clearly elevated compared with the normal male population. Low-weight wrestlers and rowers should be considered a high-risk male population for subclinical eating disorders. These findings are comparable to high-risk groups consisting mainly of women (such as ballet and modelling students). The causal relationship between the specific sport and the development of a psychogenic eating disorder is discussed.


Graduated compression stockings for the prevention of deep-vein thrombosis in postoperative surgical patients: a systematic review and economic model with a value of information analysis.
Deep-vein thrombosis (DVT) can occur in surgical patients. Routine prophylaxis can be pharmacological and/or mechanical [e.g. graduated compression stockings (GCSs)]. GCSs are available in knee length or thigh length. To establish the expected value of undertaking additional research addressing the relative effectiveness of thigh-length GCSs versus knee-length GCSs, in addition to pharmacoprophylaxis, for prevention of DVT in surgical patients. Systematic review and economic model, including value of information (VOI) analysis. Randomised controlled trials (RCTs) assessing thigh- or knee-length GCSs in surgical patients were eligible for inclusion. The primary outcome was incidence of DVT. DVT complications and GCSs adverse events were assessed. Random-effects meta-analysis was performed. To draw on a wider evidence base, a random-effects network meta-analysis (NMA) was undertaken for the outcome DVT. A review of trials and observational studies of patient adherence was also conducted. A decision-analytic model was developed to assess the cost-effectiveness of thigh- and knee-length GCSs and the VOI. Twenty-three RCTs were included in the review of effectiveness. There was substantial variation between trials in terms of the patient characteristics, interventions and methods of outcome assessment. Five trials comparing knee-length with thigh-length GCSs with or without pharmacoprophylaxis were pooled; the summary estimate of effect indicated a non-significant trend favouring thigh-length GCSs [odds ratio (OR) 1.48, 95% confidence interval (CI) 0.80 to 2.73]. Thirteen trials were included in the NMA. In the base-case analysis, thigh-length GCSs with pharmacoprophylaxis were more effective than knee-length GCSs with pharmacoprophylaxis (knee vs. thigh OR 1.76, 95% credible interval 0.82 to 3.53). Overall, thigh-length stockings with pharmacoprophylaxis was the most effective treatment, with a 0.73 probability of being the most effective treatment in a new trial of all the treatments. Patient adherence was generally higher with knee-length GCSs, and patients preferred knee-length GCSs. Thigh-length GCSs were found to be cost-effective in all but the subgroup with the lowest baseline risk, although the absolute differences in costs and effects were relatively small. The expected value of perfect information ranged from £0.2M to £178.0M depending on the scenario and subgroup. The relative effect parameters had the highest expected value of partial perfect information and ranged from £2.0M to £39.4M. The value of further research was most evident in the high-risk subgroups. There was substantial variation across the included trials in terms of patient and intervention characteristics. Many of the included trials were old and poorly reported, which reduces the reliability of the results of the review. Given that the results from both the standard meta-analysis and the NMA lacked precision (CIs were wide) owing to the heterogeneous evidence base, a new definitive trial in high-risk patients may be warranted. However, the efficiency of any further research (i.e. whether this represents value for money) is dependent on several factors, including the acquisition price of GCSs, expected compliance with thigh-length GCSs wear, and whether or not uncertainty can be resolved around possible effect modifiers, as well as the feasibility and actual cost of undertaking the proposed research. This study is registered as PROSPERO CRD42014007202. The National Institute for Health Research Health Technology Assessment programme.


Emerging roles of Sirtuins in alleviating alcoholic liver Disease: A comprehensive review.
Sirtuins (SIRTs), a NAD+ family of dependent deacetylases, are involved in the regulation of various human diseases. Recently, accumulating evidence has uncovered number of substrates and crucial roles of SIRTs in the pathogenesis of alcoholic liver disease (ALD). However, systematic reports are still lacking, so this review provides a comprehensive profile of the crucial physiological functions of SIRTs and its role in attenuating ALD, including alcoholic liver steatosis, steatohepatitis, and fibrosis. SIRTs play beneficial roles in energy/lipid metabolism, oxidative stress, inflammatory response, mitochondrial homeostasis, autophagy and necroptosis of ALD via regulating multiple signaling transduction pathways such as AMPK, LKB1, SREBP1, Lipin1, PGC-1α, PPARα/γ, FoxO1/3a, Nrf2/p62, mTOR, TFEB, RIPK1/3, HMGB1, NFATc4, NF-κB, TLR4, NLRP3, P2X7R, MAPK, TGF1β/Smads and Wnt/β-catenin. In addition, the mechanism and clinical application of natural/ synthetic SIRTs agonists in ALD are summarized, which provide a new idea for the treatment of ALD and basic foundation for further studies into target drugs.


Shoulder adhesive capsulitis: diagnostic value of active and passive range of motion with volume of gleno-humeral capsule as a reference.
The diagnosis of adhesive capsulitis is currently based on restricted range of motion (ROM) but its diagnostic value has only been rarely investigated. The aim of this study is to assess the diagnostic value of active global and passive gleno-humeral ROM to diagnose shoulder adhesive capsulitis. Cross-sectional descriptive study. One French center for Rehabilitation Medicine. Patients referred for treatment of shoulder adhesive capsulitis in our center were included. Inclusion criteria were: shoulder pain; limitation of active global ROM (abduction or flexion <180°); limitation of passive gleno-humeral ROM (abduction or flexion <90° or 25% reduction at less of lateral rotation versus the opposite shoulder); no gleno-humeral arthropathy on radiography. The volume of the gleno-humeral capsule was assessed during a procedure of arthro-distension. The reference criterion for adhesive capsulitis was a volume <12 mL. We analyzed the correlation between the parameters of mobility and the volume of the gleno-humeral capsule; and the positive predictive value (PPV) of inclusion criteria, with the reference criterion for the diagnosis of adhesive capsulitis. We included 38 patients. Passive gleno-humeral ROM in abduction only was correlated with volume of the gleno-humeral capsule: r=0.33, P=0.043. The PPV of inclusion criteria was 82% for the diagnosis of shoulder adhesive capsulitis. Rather than 90°, when we considered 80°, 60° and 40° as the threshold of passive gleno-humeral ROM in abduction, the PPV increased from 83% to 100%. Passive gleno-humeral ROM in abduction is correlated with volume of the gleno-humeral capsule. The PPV is high for active global and passive gleno-humeral ROM for diagnosis of shoulder adhesive capsulitis. Limitation of active and passive shoulder ROM, especially passive abduction gleno-humeral, is a good criterion to diagnose shoulder adhesive capsulitis, in patients with shoulder pain and no gleno-humeral arthropathy on radiography.


Medicinal herb extracts ameliorate impaired growth performance and intestinal lesion of newborn piglets challenged with the virulent porcine epidemic diarrhea virus.
The objective of this study was to evaluate effects of a combined use of extracts of medicinal herbs Taraxaumi mongolicum, Viola yedoensis Makino, Rhizoma coptidis, and Radix isatidis (MYCI) on porcine epidemic diarrhea (PED). Twenty-two 3-day-old piglets received an oral challenge with 3 × 10(3.5) TCID50 of the virulent PED virus (PEDV) in PBS or PBS only and daily oral administration of 60 mg of the MYCI mixture suspended in milk replacer or the vehicle for 7 days in a 2 × 2 factorial arrangement of treatments. Average daily gain (ADG) increased (p < 0.05) in response to the MYCI treatment in the PEDV-challenged piglets (-18 vs. 7 g for the vehicle- vs. MYCI-administered group), but not in unchallenged animals (27 vs. 28 g). Diarrhea score and fecal PEDV shedding, however, were not influenced by the MYCI treatment. The PEDV challenge caused severe intestinal villus atrophy and crypt hyperplasia, both of which were alleviated by administration of the MYCI mixture as indicated by an increase in the villus height and a decrease in the crypt depth due to the treatment. Overall, medicinal herb extracts used in this study ameliorated impaired growth performance and intestinal lesion of newborn piglets challenged with the virulent PEDV. Therefore, our results suggest that the MYCI mixture could be used as a prophylactic or therapeutic agent against PED.


M1 muscarinic agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors.
The M1 muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer's disease (AD) and the M1-selective muscarinic agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential disease modifiers. Notably, AF267B decreased cerebrospinal fluid beta-amyloid (Abeta(40) and Abeta(42)) in rabbits, decreased brain Abeta levels in hypercholesterolemic rabbits and vascular Abeta(42) deposition from the cortex in cholinotoxin-treated rabbits. In triple transgenic AD mice, AF267B reduced cognitive deficits and decreased Abeta(42) and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR activation of protein kinase C and a disintegrin and metalloproteinase domain 17 (ADAM17 or TACE) and decreased beta-site amyloid precursor protein-cleaving enzyme 1 and glycogen synthase kinase 3beta, respectively. AF267B is the first reported low-molecular-weight therapy that targets the major AD hallmarks.


HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization.
To evaluate amplification of the HER-2/neu gene by fluorescence ir situ hybridization (FISH) in tumors with weakly positive (2+) immunohistochemical staining. A total of 1556 breast tumor biopsy specimens were referred to Mayo Medical Laboratories, Rochester, Minn, for HER2 testing between August and December 2000. Immunohistochemical (IHC) analysis was performed with use of a diagnostic test for the assessment of HER2 overexpression, the HercepTest. The IHC-stained slides were interpreted and scored on a scale ranging from 0 to 3+ according to Food and Drug Administration-approved guidelines. All specimens scored as 2+ were also routinely evaluated by FISH with use of a HER-2/neu DNA probe kit (PathVysion). Specimens were determined to be amplified if the ratio of HER-2/neu signals to chromosome 17 centromere (CEP17) signals was higher than 2.0. Thirty-eight percent of the specimens evaluated with the HercepTest were scored 0, 35% were 1+, 14% were 2+, and 13% were 3+. Of the 216 tumor specimens scored as 2+, 26 (12%) had a high level of HER-2/neu gene amplification, 54 (25%) demonstrated duplication of HER2, 4 (2%) deleted HER-2/neu and/or CEP17, and 123 (57%) had no apparent HER-2/neu anomaly, no apparent CEP17 anomaly, nor apparent single gain (aneusomy) of CEP17. We recommend that all specimens with a 2+ HercepTest result be evaluated by FISH for HER-2/neu gene amplification. The results of both assays should be considered before making a decision to recommend anti-HER2 therapy.


Effects of alkyl analogs of histamine and metiamide on gastric acid secretion.
Histamine and metiamide analogs with alkyl, methyl, ethyl or isopropyl groups on the imidazole ring in position 5, not previously tested on an in vivo preparation, were studied for their effects on gastric acid secretion in cats with gastric fistulas. Our findings confirmed that the methyl group appears to be optimal for an effect on gastric acid secretion as regards both agonism and antagonism. Ethyl substitution apparently did not change the pharmacological activity of histamine but modified the inhibitory effect of metiamide from competitive to non-competitive kinetics. Isopropyl analogs were inactive on gastric secretion under our experimental conditions.


PARP5B is required for nonhomologous end joining during tumorigenesis in vivo.
Poly(ADP-ribose) polymerases (PARP) act as DNA damage sensors that produce poly(ADP-ribose) (PAR) chains at double-strand breaks, facilitating the recruitment of repair factors. Cancers with homologous recombination defects are sensitive to small molecule PARP inhibitors. Despite PARP5B gene copy number changes in many cancers, the effects of this genetic alteration on tumor phenotype are largely unknown. To better understand this clinical finding, we characterized a PARP5B null mutation in a carcinogen-induced in vivo head and neck squamous cell carcinoma (SCC) model. Reduced PARP5B expression inhibited tumor growth, induced primary tumor differentiation and apoptosis, and inhibited cell proliferation and metastasis. Loss of PARP5B expression-induced ataxia telangiectasia and Rad3 related (ATR) activation and depleted the cancer stem cell fraction. PARP5B null tumor cells lacked 53BP1+ double-strand break foci, ATM activation, and p53 induction compared to PARP5B+/+ cancers. PARP5B null SCC expresses a multiprotein complex containing PML, pRPA, Rad50, Rad51, XRCC1, proliferating cell nuclear antigen (PCNA), and Mcm2, suggesting an HR-mediated repair mechanism at DNA replication foci. Low doses of etoposide combined with the PARP5B inhibitor XAV939 induced senescence and apoptosis in human SCC lines. NBS1 overexpression in these cells inhibited the effects of low-dose etoposide/XAV939 treatment. Our results indicate that PARP5B inhibition is new targeted cancer therapy.


Phosphate-independent glutaminase from rat kidney. Partial purification and identity with gamma-glutamyltranspeptidase.
Phosphate-independent glutaminase can be quantitatively solubilized from a microsomal preparation of rat kidney by treatment with papain. Subsequent gel filtration and chromatography on quaternary aminoethyl (QAE)-Sephadex and hydroxylapatite yield a 200-fold purified preparation of this glutaminase. The purified enzyme also hydrolyzes gamma-glutamylhydroxamate and exhibits substrate inhibition at high concentrations of either glutamine or gamma-glutamyhydroxamate, which is partially relieved by increasing concentrations of maleate. Rat kidney phosphate-independent glutaminase reaction is catalyzed by the same enzyme which catalyzes the gamma-glutamyltranspeptidase reaction. The ratio of glutaminase to transpeptidase activities remained constant throughout a 200-fold purification of this enzyme. The observation that the phosphate0independent glutaminase and gamma-glutamyltranspeptidase activities exhibit coincident mobilities during electrophoresis, both before and after extensive treatment with neuraminidase, strongly suggests that both reactions are catalyzed by the same enzyme. This conclusion is strengthened by the observation that maleate and various amino acids have reciprocal effects on the two activities. Maleate increases glutaminase activity and blocks transpeptidation, whereas amino acids activate the transpeptidase but inhibit glutaminase activity. In contrast, the addition of both maleate and alanine resulted in a strong inhibition of both activities. Both activities exhibit a similar distribution in the various regions of the kidney. Recovery of maximal activities in the outer stripe region of the medulla is consistent with previous quantitative microanalysis which indicated that this glutaminase activity is localized primarily in the proximal straight tubule cells. The glutaminase and transpeptidase activities have different pH optima. Examination of the product specificity suggests that decreasing pH also promotes glutaminase activity and that below pH 6.0, this enzyme functions strictly as a glutaminase. Because of the localization of this activity on the brush border membrane, these resuts are consistent with the possibility that the physiological conditions induced by metabolic acidosis could convert this enzyme from a broad specificity transpeptidase to a glutaminase. Therefore, this enzyme could contribute to the increased renal synthesis of ammonia from glutamine which is observed during metabolic acidosis.


Correction to: Indirect somatic embryogenesis of purple coneflower (Echinacea purpurea (L.) Moench): a medicinal‑ornamental plant: evaluation of antioxidant enzymes activity and histological study.
The article Indirect somatic embryogenesis of purple coneflower (Echinacea purpurea (L.) Moench): a medicinal‑ornamental plant: evaluation of antioxidant enzymes activity and histological study written by Maryam Dehestani-Ardakani, Mohadeseh Hejazi, Kazem Kamali Aliabad, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17 August 2020 with open access. With the author(s)' decision to step back from open choice, the copyright of the article changed on 18 November 2020 to © Springer Nature B.V. 2020 and the article is forthwith distributed under the terms of copyright. The original article has been corrected.


Stress effects on the top-down control of visuospatial attention: Evidence from cue-dependent alpha oscillations.
Stress is assumed to inhibit the top-down control of attention and to facilitate bottom-up processing. Evidence from human experiments, however, remains scarce. Previous studies have addressed how stress affects the interplay of bottom-up and top-down mechanisms of attention. A key open question is in how far such effects can actually be attributed to a stress-induced modulation of top-down attention control. We sought to isolate top-down from bottom-up effects by assessing stress effects on anticipatory changes in alpha oscillations that precede stimulus processing. Participants performed in a cued target detection task in which a cue prompted them to covertly shift their attention to left or right screen positions, 20 min after being exposed to the bilateral feet cold pressor test or a warm water control procedure. The stressor led to a substantial increase in cortisol, peaking 20 min post stressor, along with rises in heart rate, blood pressure, and subjective ratings of stress and arousal. As expected, cued attention deployment led to higher alpha power over posterior electrodes contralateral versus ipsilateral to the attended hemifield during the cue-target interval. Importantly, this purely endogenous effect was potentiated by stress, however, significant differences were restricted to the middle of the cue-target interval and thus temporally separated from the appearance of the target. These results indicate that stress does not impair top-down attentional control per se but may introduce a qualitative change modulating the way attention is deployed to meet action goals.


Free radicals and the pH of topical glaucoma medications: a lifetime of ocular chemical injury?
Preservatives in ophthalmic preparations are known to cause ocular surface damage. Excipients can also contribute to oxidative stress in the compromised ocular surface. We evaluated commonly used topical glaucoma medications to ascertain pH levels and the intrinsic presence of free radicals. Samples of 27 topical glaucoma preparations were analysed for total free radical presence using a Randox Kit for total antioxidant status. Analytical grade indicator paper was used to ascertain pH levels. Free radical concentrations for these 27 glaucoma preparations ranged from 0 to 4.54 mmol/l, with a median value of 0.66 mmol/l (mean value of 0.662 mmol/l, SD 0.839). Levels of pH ranged from 4.0 to 7.4, with a median value of 6.5 (mean 6.252, SD 0.826). There was no evidence of a direct correlation between these two variables (r=0.232, P=0.275). This study is the first to document the range of pH and concentrations of free radicals intrinsically present in commonly used glaucoma medications. Long-term exposure to preservatives, free radicals, and pH levels could all contribute to ocular surface damage. The effect of excipients could be responsible for patient intolerance when changing products in the compromised ocular surface.


Electron transfer and ROS production in brain mitochondria of intertidal and subtidal triplefin fish (Tripterygiidae).
While oxygen is essential for oxidative phosphorylation, O2 can form reactive species (ROS) when interacting with electrons of mitochondrial electron transport system. ROS is dependent on O2 pressure (PO2) and has traditionally been assessed in O2 saturated media, PO2 at which mitochondria do not typically function in vivo. Mitochondrial ROS can be significantly elevated by the respiratory complex II substrate succinate, which can accumulate within hypoxic tissues, and this is exacerbated further with reoxygenation. Intertidal species are repetitively exposed to extreme O2 fluctuations, and have likely evolved strategies to avoid excess ROS production. We evaluated mitochondrial electron leakage and ROS production in permeabilized brain of intertidal and subtidal triplefin fish species from hyperoxia to anoxia, and assessed the effect of anoxia reoxygenation and the influence of increasing succinate concentrations. At typical intracellular PO2, net ROS production was similar among all species; however at elevated PO2, brain tissues of the intertidal triplefin fish released less ROS than subtidal species. In addition, following in vitro anoxia reoxygenation, electron transfer mediated by succinate titration was better directed to respiration, and not to ROS production for intertidal species. Overall, these data indicate that intertidal triplefin fish species better manage electrons within the ETS, from hypoxic-hyperoxic transitions.


Self-stimulation responses are altered following long-term but not short-term treatment with clorgyline.
Clorgyline (a selective monoamine oxidase-inhibiting antidepressant) given chronically facilitated hypothalamic self-stimulation in rats, while acute treatment was without effect. Furthermore, long-term but not short-term clorgyline treatment significantly attenuated the suppressive effect of the selective alpha 2-adrenergic agonist clonidine on this behavior. These findings suggest that adaptative alterations in the modulation of rewarded behavior by inhibitory presynaptic noradrenergic receptors may be involved in antidepressant efficacy.


Methylphenidate and cocaine: the same effects on gene regulation?
Methylphenidate (Ritalin), a psychostimulant used in the treatment of Attention-Deficit Hyperactivity Disorder, has pharmacological effects similar to cocaine and amphetamine. Clinical use of methylphenidate, as well as diversion and abuse, have significantly increased during the past 10-15 years, heightening concerns regarding the long-term effects of methylphenidate on the developing brain. Here we review the effects of acute and repeated methylphenidate treatment on molecules of neuronal signaling and neuroplasticity (including transcription factors, neuropeptides, and components of second messenger cascades) and compare these molecular effects with those produced by cocaine and amphetamine. Some molecular changes, such as altered transcription factor gene regulation, are similar to those of cocaine and amphetamine. Other effects, notably those on the expression of opioid peptides and postsynaptic density molecules (Homer 1a), differ between methylphenidate and cocaine or amphetamine treatment. These differences support the notion that methylphenidate produces less neuroadaptations than cocaine and amphetamine, and might provide a molecular basis for reduced addiction liability of methylphenidate compared with these other psychostimulants.


Yersinia pestis biofilm in the flea vector and its role in the transmission of plague.
Transmission by fleabite is a relatively recent evolutionary adaptation of Yersinia pestis, the bacterial agent of bubonic plague. To produce a transmissible infection, Y. pestis grows as an attached biofilm in the foregut of the flea vector. Biofilm formation both in the flea foregut and in vitro is dependent on an extracellular matrix (ECM) synthesized by the Yersinia hms gene products. The hms genes are similar to the pga and ica genes of Escherichia coli and Staphylococcus epidermidis, respectively, that act to synthesize a poly-beta-1,6-N-acetyl-d-glucosamine ECM required for biofilm formation. As with extracellular polysaccharide production in many other bacteria, synthesis of the Hms-dependent ECM is controlled by intracellular levels of cyclic-di-GMP. Yersinia pseudotuberculosis, the food- and water-borne enteric pathogen from which Y. pestis evolved recently, possesses identical hms genes and can form biofilm in vitro but not in the flea. The genetic changes in Y. pestis that resulted in adapting biofilm-forming capability to the flea gut environment, a critical step in the evolution of vector-borne transmission, have yet to be identified. During a flea bite, Y. pestis is regurgitated into the dermis in a unique biofilm phenotype, and this has implications for the initial interaction with the mammalian innate immune response.


Imaging risk features for device related pulmonary artery injury after left atrial appendage closure with Amplatzer™ Amulet™ device.
This study aimed to find imaging risk features for device related-pulmonary artery (PA) injury (DR-PAI) in patients after left atrial appendage closure (LAAC). Cardiac tamponade resulting from DR-PAI is a rare but life-threatening complication of LAAC. In vitro analysis of Amplatzer™ Amulet™ (Abbott, MN) device was done. Measurements of the distance between PA and Amplatzer lobe at its middle part, distal part, and along the stabilizing wires' trajectory (wires-to-PA distance) were taken in 100 consecutive patients on post-LAAC computed tomography (CT) studies. Clinical outcomes were collected. In vitro analysis indicated that both middle and distal lobe had to be in close PA proximity (<1.5 mm) for the stabilizing wires to cause risk for DR-PAI, configuration called ''cuddling lobe orientation''. On CT measurements middle lobe-PA distance was 4.7 mm (IQR = 2.7-9.5), with close proximity in 4 (4%) patients, and distal lobe-PA distance was 3.2 mm (IQR = 1.8-7.2 mm), with close proximity in 17 (17%) patients. Stabilizing wires were pointing toward PA in 47 patients (47%) with median wire-to-PA distance 5.7 mm (IQR = 3.6-8.5 mm). ''Cuddling'' was found in 2 (2%) patients and resulted in shorter wires-to-PA distance vs no ''cuddling'' group (2.3 vs 5.8 mm p <.01). At 2.9 ± 1.0 yrs of follow-up, the two patients with ''cuddling lobe orientation'' on post-LAAC CT scan developed late cardiac tamponades (p <.001). One of those required surgery, which confirmed DR-PAI. ''Cuddling lobe orientation'' of Amulet device with the PA was associated with short wires-to-PA distance and late pericardial effusions, including DR-PAI. Hence, such device-to-PA configuration should be avoided.


Basal cell carcinoma originating from a nevus sebaceus on the scalp of a 7-year-old boy.
Basal cell carcinoma (BCC) occurs rarely in children and is most often associated with an underlying condition that predisposes patients to the development of malignancy. There have been numerous reports of BCC developing after puberty in nevus sebaceus; however, such occurrences have rarely been described in children. We report a 7-year-old boy with BCC forming in a nevus sebaceus.


Glycosylated whey protein isolate enhances digestion behaviors and stabilities of conjugated linoleic acid oil in water emulsions.
Although conjugated linoleic acid (CLA) has various excellent physiological functions, it exhibits poor water solubility and high oxidation sensitivity, which limits its applications in food industry. To solve this problem, a stable oil in water emulsion was used for protecting CLA. In this study, glycosylated whey protein isolate (GWPI) formed by whey protein isolate (WPI) and galactose was used to produce CLA emulsion, and then its physicochemical stabilities, gastrointestinal behaviors were evaluated. The results showed that creaming index, primary oxidation products and secondary oxidation products of GWPI-stabilized emulsion at reaction time of 4 h (GWPI-4 h) decreased by 32.43%, 95.98% and 87.34% when stored for 15 days, compared with WPI-loaded CLA emulsion. Additionally, GWPI promoted lipid digestion and led to an improvement of stability and gastrointestinal fate of GWPI-stabilized CLA emulsion. These findings confirmed that GWPI established an emulsification-based delivery system for protecting CLA to exert its physiological functions.


Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury.
The lower urinary tract has two main functions, the storage and periodic expulsion of urine, which are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the pelvic floor). During urine storage the outlet is closed and the bladder is quiescent, thereby maintaining a low intravesical pressure over a wide range of bladder volumes. During micturition the outlet relaxes and the bladder contracts to promote the release of urine. This reciprocal relationship between bladder and outlet is generated by visceral reflex circuits, some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are presumably involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter functions. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. Studies in animals indicate that the recovery of bladder function after spinal cord injury is dependent in part on plasticity of bladder afferent pathways and the unmasking of reflexes triggered by capsaicin-sensitive C-fiber bladder afferent neurons. The plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons, and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs.


Acquired bladder diverticula can mimic obstructive extrabiliary jaundice.
A rare case that relates benign prostatic hyperplasia-associated bladder diverticula and obstructive uropathy to extrabiliary obstructive jaundice in an older patient is presented. Immediate decompression of the bladder allowed for prompt restoration of the biliary drainage and normalization of the creatinine within a few days. A hepatobiliary etiology was discarded through prompt radiologic and serologic testing along with computed tomography-guided liver biopsy. Long-term management included open suprapubic prostatectomy and diverticulectomy. This unusual case expands the amount of sound anatomic and pathophysiologic links between urinary and extraurinary manifestations.


Visual stimulus eccentricity affects human gamma peak frequency.
The peak frequency of neuronal gamma-band synchronization has received much attention in recent years. Gamma peak frequency shifts to higher frequency values for higher contrast, faster moving, and attended stimuli. In monkey V1, gamma peak frequency for a drifting grating is higher for a parafoveal as compared to an eccentric stimulus (Lima et al., 2010). This effect might be due to the cortical magnification factor: the higher cortical magnification for parafoveal stimuli increases the velocity with which the cortical representations of the moving grating stripes move across the cortical surface. Since faster moving stimuli lead to higher gamma frequency, a faster moving cortical representation might do the same. This explanation predicts that the eccentricity effect on gamma peak frequency is absent for stationary stimuli. To test this, we investigated the effect of eccentricity on gamma peak frequency by recording magnetoencephalography in human subjects while they viewed moving or stationary gratings. We found that both the moving and the stationary stimuli induced lower peak frequencies for larger eccentricities, arguing against an explanation based on the cortical magnification factor. We further investigated whether this eccentricity effect was explained by differences in the size or the spatial frequency of the expected cortical activation. Neither of those explained the eccentricity effect. We propose that the different stimulus and top-down factors leading to higher gamma peak frequency all result in higher stimulus salience, that salience is translated into gamma peak frequency, and that gamma peak frequency might subserve the preferential processing of neuronal activity induced by salient stimuli.


Stigmas toward psychosis-related clinical features among the general public in Taiwan.
Stigma can be a barrier to early intervention of severe mental illnesses, especially schizophrenia, which further leads to poor outcomes. Mental health campaigns were designed to educate the general public about signs for early identification of psychosis, but the line between schizophrenia and attenuated psychosis was not well demarcated. We wonder if people would generalize their stigmas towards schizophrenia to subjects with subthreshold psychotic symptoms. A cross-sectional survey was employed which used a structured questionnaire, comprised of four case vignettes describing attenuated psychosis syndrome (APS), schizophrenia, psychotic-like experiences (PLE), or depression, and was followed by two sets of questions using the 4-point Likert scale to measure discrimination and prejudices. Participants were chosen by convenience sampling of laypersons from different backgrounds. A total of 268 subjects completed this survey. A gradient of stigmas, highest toward schizophrenia, followed by APS/depression, and lowest toward PLE was apparent across gender, all age groups, and education levels. Participants who were younger and had higher education revealed a trend of lower prejudice and discrimination. People who have visited a psychiatric hospital showed higher discrimination toward schizophrenia, APS, and depression. People who have seen mentally ill persons in public places showed lower stigma toward PLE. Our respondents posed a differentiable attitude towards PLE, APS, and schizophrenia, while exhibiting no difference between APS and depression. Certain personal attributes were correlated with stigma levels. Further investigation about mental health literacy and attitudes towards subjects with psychotic symptoms in the general public is warranted.


Ankle equinus related to trauma, and its surgical treatment: a preliminary report of three cases.
Ankle equinus specifically related to trauma has been barely touched upon in the literature. As reported by Subotnick (2) and McGlamry (1), the short-term results are impressive. In our three cases, we have had an increase in ankle joint dorsiflexion of 6 to 10 degrees; however, our longest postoperative follow up is only 9 months. We have attempted to control these patients postoperatively with functional orthoses. We have also tried to impress the patients with the fact that the orthoses should be worn during any activity to prevent recurrent arthritis.


[Exon rearrangement analysis of parkin gene in patients with isolated early-onset parkinsonism using semi-quantitative PCR].
To investigate the value of fluorescence semi-quantitative PCR in analysis of the exon rearrangement of parkin gene in Chinese patients with isolated early-onset parkinsonism (EOP). fluorescence semi-quantitative PCR was used to analyze the exon rearrangements of parkin gene in 61 isolated patients with EOP. Exon deletions in parkin gene were found in 4 of the 61 isolated patients with EOP. One of them failed to show the PCR product of exon 4 and had homozygous deletions of exon 4. The normalized ratios (NRs) of exon 2, exon 3, and exon 4 of the other 3 patients were 0.47, 0.52, and 0.49 respectively, showing that they had heterozygous deletions of exon 2, 3, and 4 respectively. No exon multiplication was found in this study. Exon rearrangement of parkin gene exists in Chinese patients with isolated EOP.


Metoclopramide in vincristine-induced ileus.
Three cases of vincristine-induced gastrointestinal toxicity were treated with metoclopramide. Two patients had severe abdominal pain and adynamic ileus, while the third had severe constipation and abdominal bloating. Rapid resolution of symptoms occurred in all three patients. Metoclopramide may, therefore, prove useful in the treatment of these not infrequent toxic effects of vinca alkaloids.


Spontaneous elimination of nerve terminals from the endplates of developing skeletal myofibers.
The development of the motor innervation of a skeletal muscle was examined in the soleus muscles of young rats. At 11 days after birth, nearly three-quarters of the endplates of individual myofibers were innervated by more than one silver stained axon. Four days later, only about 9% of the endplates remained innervated by two or more terminals. The dramatic reduction in the number of axon terminals appeared to result in large measure from the retraction of all but one of the multiple terminals. An axon interpreted as undergoing retraction was characterized by a terminal oval enlargement believed to be the site of disassembly of the fiber.


Dietary oxalate-calcium balance and the incidence of hypertension and chronic kidney disease: a prospective study among an Asian population.
The potential effects of dietary oxalate (Ox) intake on cardio-renal function have remained unestablished. We evaluated the effect of usual Ox intake and its interaction with dietary calcium (Ca) on incident hypertension (HTN) and chronic kidney disease (CKD). Adult men and women, free of HTN and CKD at baseline (2006-2008), were recruited. Dietary intakes were assessed using a validated food frequency questionnaire, and the outcomes were documented up to 2014-2017. Multivariate Cox proportional hazard regression models were used to estimate the development of HTN and CKD in relation to Ox intakes. Repeated-measures generalized estimating equation (GEE) linear regression models were used to assess possible effect of Ox-intake on the estimated glomerular filtration rate (eGFR) and blood pressure levels over eight years. Dietary Ox intakes were positively associated with incident CKD (HR = 2.59, 95% CI = 1.46-4.64) and HTN (HR = 1.79, 95% CI = 1.05-3.04). Compared to high-Ca consumers, subjects who had lower Ca intakes (< 990 vs. 1580 mg/d) had a higher incidence of CKD and HTN (HR = 2.43, 95% CI = 1.06-5.55, and HR = 1.72, 95% CI = 0.76-3.78). Participants with higher intakes of Ox (> 220 vs. < 150 mg/d) had lower eGFR values (75.3, 95% CI = 75.0-76.5 vs. 77.3, 95% CI = 76.6-78.1 mL/min/1.73m2, Ptime×group = 0.004) and higher SBP levels (112, 95% CI = 111-113 vs. 109, 95% CI = 108-110 mmHg, Ptime×group = 0.007) overtime. Higher dietary Ox intake may increase the risk of HTN and CKD. The relation between dietary Ox and risk of HTN and CKD seems to be varied by Ca intake, and subjects with lower Ca intakes may be more burdened by excessive amounts of dietary Ox.


Epigenomics of rats' liver and its cross-species functional annotation reveals key regulatory genes underlying short term heat-stress response.
Molecular responses to heat stress are multifaceted and under a complex cellular post-transcriptional control. This study explores the epigenetic and transcriptional alterations induced by heat stress (42 °C for 120 min) in the liver of rats, by integrating ATAC-seq, RNA-Seq, and WGBS information. Out of 2586 differential ATAC-seq peaks induced by heat stress, 36 up-regulated and 22 down-regulated transcript factors (TFs) are predicted, such as Cebpα, Foxa2, Foxo4, Nfya and Sp3. Furthermore, 150,189 differentially methylated regions represent 2571 differentially expressed genes (DEGs). By integrating all data, 45 DEGs are concluded as potential heat stress response markers in rats. To comprehensively annotate and narrow down predicted markers, they are integrated with GWAS results of heat stress parameters in cows, and PheWAS data in humans. Besides better understanding of heat stress responses in mammals, INSR, MAPK8, RHPN2 and BTBD7 are proposed as candidate markers for heat stress in mammals.


Anthropometric and lifestyle correlates of serum lipoprotein and apolipoprotein levels among normal non-smoking men and women.
The relationship between serologic predictors of coronary risk and anthropometric as well as lifestyle characteristics was investigated in 61 men (37.5 +/- 8.5 yrs) and 33 women (40.1 +/- 9.0 yrs). All subjects were healthy non-smokers, mostly middle-class bank employees. In bivariate analysis, among both genders the ratio of waist-to-hip circumference (WHR) was the single best predictor of levels of serum LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides (positive association) as well as HDL-cholesterol and apolipoprotein A-I (inverse association). In men, body fat as estimated from bioelectrical impedance measurement was the second best predictor of lipoprotein and apoprotein concentrations, whereas in women it was the body mass index (BMI). The additional independent predictive power of WHR and body fat for the lipid profile was tested in multivariate analysis by adding WHR and body fat sequentially to regression models containing already BMI, endurance capacity, exercise, alcohol consumption and age. For example, explained variance of triglyceride distribution rose from 26.3 to 35.1% (P = 0.01 for increase) when body fat was entered into the regression equation, or inclusion of WHR into a model already containing age, the behavioral variables, BMI, and body fat increased the explained variance of LDL/HDL-cholesterol ratio from 20.9 to 27.6% (P = 0.04 for increase). In women, the same regression models were even slightly more predictive for the serum lipid profile. Endurance capacity was related to a low atherogenic risk lipid profile in bivariate analysis but lost much of its predictive power in multivariate analysis, which confirms that the effect of fitness on lipid levels is probably mediated in part by a low body fat content. It is concluded from this cross-sectional investigation that studies which focus on associations between lifestyle and serologic predictors of atherogenic risk should possibly include the WHR and a measure of body fat, since the latter two appear to be closer correlates of serum lipoprotein and apolipoprotein levels than BMI or single behavioral factors, at least among male non-smokers.


Tenofovir rescue therapy in chronic hepatitis B patients who failed previous nucleoside analogue treatment.
Tenofovir (TDF) is considered as the first line therapy for chronic hepatitis B. This study presents the results of TDF monotherapy in patients who failed previous nucleoside analogue treatment. The study included 29 patients treated with TDF 245 mg once daily for 18 months after lamivudine monotherapy (LAM arm: n = 15) or sequential therapy with lamivudine and entecavir (LAM → ETV arm: n = 14). The previous antiviral therapy was discontinued due to lack of efficacy. All patients had HBV DNA between 2.1 and 8.23 log10 IU/ml and 15 were HBeAg-positive, while 45% of patients had increased ALT activity. Undetectable HBV DNA (<20 IU/ml) at months 3, 6, 12 and 18 was the primary endpoint in the study, while HBeAg/HBsAg loss/seroconversion and ALT normalisation were secondary endpoints. Primary nonresponse to TDF was not observed. HBV DNA was undetectable in 80, 80, 80 and 93% in LAM arm and 50, 71, 86 and 86% in LAM → ETV arm patients, at 3, 6, 12 and 18 months of TDF therapy, respectively. One patient achieved anti-HBeAg seroconversion. 86.5% of patients had normal ALT activity at the end of the study. The baseline HBV DNA load, HBeAg status and the length of the duration of TDF therapy appeared significantly associated with the response to the therapy. HBV DNA clearance occurred faster in HBeAg-negative patients than in those positive for HBeAg. TDF is an effective antiviral medication in patients with previous exposure to LAM or LAM and ETV. Final proportion of patients who achieved undetectable HBV DNA and had normal ALT activity in both arms, was similar.


Letter to the Editor: CONVERGENCES AND DIVERGENCES IN THE ICD-11 VS. DSM-5 CLASSIFICATION OF MOOD DISORDERS.
Dear Editor, The chapter on mental, behavioural and neurodevelopmental disorders of the 11th revision of the International Classification of Diseases and Related Health Problems (ICD-11) has been now finalized. Reporting of health statistics by Member States to the World Health Organization (WHO) using the new diagnostic system will begin in 2022. The section on mood disorders of the ICD-11 is overall consistent with the corresponding section of the ICD-10. However, the definitions of a depressive and a manic episode have been slightly changed, making them consistent with the DSM-5 (see below), and an independent category of bipolar II disorder has been introduced. A significant effort has been made by the WHO and the American Psychiatric Association to harmonize the diagnostic systems they produce (the ICD-11 and the DSM-5). Indeed, the organizational framework ("metastructure") is now the same in the two systems. Nonetheless, several intentional differences between the two classifications remain, or have emerged as a consequence of changes made in the DSM- 5. Here we briefly summarize the convergences and the divergences between the ICD-11 and the DSM-5 regarding the section on mood disorders (see Table 1). A major convergence between the two diagnostic systems regards the minimum number of symptoms required for the diagnosis of major depression ("depressive episode" in the ICD-11). In the ICD-11, contrary to the ICD-10, the threshold for the diagnosis of depression is the same as in the DSM: at least five depressive symptoms. However, the ICD-11 requires at least five symptoms out of a list of ten (instead of nine as in the DSM-5). The additional symptom is "hopelessness", which has been found to outperform more than half of DSM symptoms in differentiating depressed from non-depressed people (McGlinchey et al. 2006). Table 1. Some Main Differences Between ICD-10, ICD-11 and DSM-5 Concerning the Diagnosis Of Mood Disorders ICD-10 ICD-11 DSM-5 Threshold for diagnosis of depressive episode At least four out of ten symptoms, two of which must be depressed mood, loss of interest and enjoyment, or increased fatigability At least five out of ten symptoms, one of which must be depressed mood or diminished interest or pleasure At least five out of nine symptoms, one of which must be depressed mood or diminished interest or pleasure The threshold for the diagnosis of depression is higher if the person is bereaved Not made explicit Yes No Antidepressant-related mania qualifies as a manic episode No Yes Yes Mixed episode is a separate diagnostic entity Yes Yes No Dysthymia is a separate diagnostic entity Yes Yes No Bipolar II disorder is a separate diagnostic entity No Yes Yes "Qualifiers" ("specifiers") for the diagnoses of mood disorders are provided No Yes Yes CONVERGENCES AND DIVERGENCES IN THE ICD-11 VS. DSM-5 CLASSIFICATION OF MOOD DISORDERS 294 The ICD-11 is also following the DSM-5 in requiring the presence of increased activity or a subjective experience of increased energy, in addition to euphoria (or irritability or expansiveness), for the diagnosis of a manic episode, in order to reduce the chance of false positive cases. The two diagnostic systems also converge in considering that a manic or hypomanic syndrome arising during antidepressant treatment, and enduring beyond the known physiological effects of that treatment, qualifies as a manic or hypomanic episode. Bipolar II disorder has become an independent category in the ICD-11 (it was just mentioned as an example of "other bipolar affective disorders" in the ICD-10). Furthermore, for the first time, the ICD follows the DSM in introducing "qualifiers" (corresponding to DSM-5 "specifiers") to the diagnoses of mood disorders, based on specific aspects of symptomatology or course. There are, however, three important aspects in which the two diagnostic systems diverge. All of them are a consequence of changes made in the DSM-5 that the relevant ICD-11 Committee has regarded as not sufficiently supported by the available research evidence. The first of these divergences concerns the issue of bereavement. In the ICD-11, in line with the DSM-IV and ICD-10 approach, it is stated that "a depressive episode should not be considered if the depressive symptoms are consistent with the normative response for grieving within the individual's religious and cultural context". However, the diagnosis of depression is not excluded if the person is bereaved; the diagnostic threshold is just raised, exactly as it happens in ordinary clinical practice. A depressive episode during bereavement is suggested by the persistence of symptoms for at least one month, and the presence of at least one symptom which is unlikely to occur in normal grief (such as extreme beliefs of low self-worth or guilt not related to the lost loved one, presence of psychotic symptoms, suicidal ideation, or psychomotor retardation). In contrast, the special status conferred by the DSM-IV to bereavement among life stressors has been eliminated in the DSM-5. However, two independent follow-up studies (Mojtabai 2011, Wakefield and Schmitz 2012) have reported that, in people with baseline bereavement-related depression, the risk for the occurrence of a further depressive episode during follow-up is significantly lower than in individuals with baseline non-bereavement-related depression, and not significantly different from the risk of people without a baseline history of depression to develop a first depressive episode during follow-up. This research evidence strongly supports the ICD-11 (and DSM-IV) approach. Furthermore, an intensive public debate has highlighted the consequences that the DSM-5 approach to the bereavement issue could have in several cultures, including a high rate of false positives and a trivialization of the concept of depression and consequently of mental disorder (Kleinman 2012). A second divergence between the ICD-11 and DSM-5 sections on mood disorders concerns mixed states. The category of mixed episode is kept in the ICD-11, defined by several prominent manic and depressive symptoms which either occur simultaneously or alternate very rapidly (from day to day or within the same day) during a period of at least two weeks. The mood state is altered throughout the episode (i.e., the mood should be depressed, dysphoric, euphoric or expansive for at least two weeks). When depressive symptoms predominate, common contrapolar symptoms are irritability, racing or crowded thoughts, increased talkativeness, and increased activity. When manic symptoms predominate, common contrapolar symptoms are dysphoric mood, expressed beliefs of worthlessness, hopelessness, and suicidal ideation. This definition is in line with the ICD-10 and completely consistent with both classic and recent research evidence, as well as with clinical experience. In contrast, the DSM-5 solution to eliminate the category of mixed episode and to introduce a specifier "with mixed features", applicable to manic, hypomanic and depressive episodes, has had the consequence to reduce the visibility of "mixity" in ordinary clinical practice (especially since the specifier is not codable, and is therefore at risk of not being recorded in clinical settings). Moreover, the DSM-5 definition of major depression with mixed features, requiring the presence of at least three "classic" manic symptoms (such as elevated mood, grandiosity, and increased involvement in risky activities) has been criticized for being inconsistent with the concept of mixed depression as delineated in both the classic and recent literature (e.g., Koukopoulos and Sani 2014). A third divergence between the two diagnostic systems consists in the fact that the ICD-11 has not followed the DSM-5 in combining dysthymic disorder and chronic major depressive disorder into a single category ("persistent depressive disorder"). In fact, the relevant ICD-11 Committee expert considered that the evidence that the two disorders represent the same condition, to be addressed therapeutically in the same way, is insufficient. The category of dysthymic disorder is kept in the ICD-11, while a qualifier "current episode persistent" is to be used when the diagnostic requirements for depressive episode have been met continuously for at least the past two years. For a discussion of other aspects of the classification of mood disorders, with the relevant therapeutic implications, as well as for information about the differences between the ICD-11 and the DSM-5 concerning other sections of the classification of mental disorders, we refer the reader to previous contributions (Demyttenaere et al. 2015, Fried et al. 2016, Haroz et al. 2017, Boschloo et al. 2019, Bryant 2019, Forbes et al. 2019, Fusar-Poli et al. 2019, Gureje et al. 2019, 295 Received: 13.09.2021, Accepted: 19.09.2021, Available Online Date: 30.11.2021 MD., University of Campania L. Vanvitelli, WHO Collaborating Centre for Research and Training in Mental Health, Naples, Italy. Dr. Arcangelo Di Cerbo, e-mail: email@example.com https://doi.org/10.5080/u26899 Reed et al. 2019, Kendall 2019, van Os et al. 2019, Cuijpers et al. 2020, Fava and Guidi 2020, Gaebel et al. 2019, 2020, Hasler 2020, Jarrett 2020, Kato et al. 2020, Maj et al. 2020, Reynolds 2020, Sanislow 2020, Stein et al. 2020). An International Advisory Group has been established to supervise the activities of translation, training of professionals and implementation of the ICD-11 chapter on mental disorders (see Giallonardo 2019, Pocai 2019, Perris 2020). The experience in the field will tell whether the above divergences from the DSM-5 in the ICD-11 classification of mood disorders are justified. Indeed, divergences in the description of the same mental health condition may sometimes be useful in order to allow the empirical comparison of different approaches to issues that are controversial. Arcangelo DI CERBO REFERENCES Boschloo L, Bekhuis E, Weitz ES et al (2019) The symptom-specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: results from an individual patient data meta-analysis. World Psychiatry 18:183-91. Bryant RA (2019) Post-traumatic stress disorder: a state-of-the-art review of evidence and challenges. World Psychiatry 18:259-69. Cuijpers P, Noma H, Karyotaki E et al (2020) A network meta-analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression. World Psychiatry 19:92-107. Demyttenaere K, Donneau AF, Albert A et al (2015) What is important in being cured from depression? Discordance between physicians and patients (1). J Affect Disord 174:390-6. Fava GA, Guidi J (2020) The pursuit of euthymia. World Psychiatry 19:40-50. Fried EI, Epskamp S, Nesse RM et al (2016) What are "good" depression symptoms? Comparing the centrality of DSM and non-DSM symptoms of depression in a network analysis. J Affect Disord 189:314-20. Forbes MK, Wright AGC, Markon KE et al (2019) The network approach to psychopathology: promise versus reality. World Psychiatry 18:272-3. Fusar-Poli P, Solmi M, Brondino N et al (2019) Transdiagnostic psychiatry: a systematic review. World Psychiatry 8:192-207. Gaebel W, Reed GM, Jakob R (2019) Neurocognitive disorders in ICD-11: a new proposal and its outcome. World Psychiatry 18:232-3. Gaebel W, Stricker J, Riesbeck M et al (2020) Accuracy of diagnostic classification and clinical utility assessment of ICD-11 compared to ICD-10 in 10 mental disorders: findings from a web-based field study. Eur Arch Psychiatry Clin Neurosci 270:281-9. Giallonardo V (2019) ICD-11 sessions within the 18th World Congress of Psychiatry. World Psychiatry 18:115-6. Gureje O, Lewis-Fernandez R, Hall BJ et al (2019) Systematic inclusion of culture-related information in ICD-11. World Psychiatry 18:357-8. Haroz EE, Ritchey M, Bass JK et al (2017) How is depression experienced around the world? A systematic review of qualitative literature. Soc Sci Med 183:151-62. Hasler G (2020) Understanding mood in mental disorders. World Psychiatry 19:56-7. Jarrett RB (2020) Can we help more? World Psychiatry 19:246-7. Kato TA, Kanba S, Teo AR (2020) Defining pathological social withdrawal: proposed diagnostic criteria for hikikomori. World Psychiatry 19:116-7. Kendall T (2019) Outcomes help map out evidence in an uncertain terrain, but they are relative. World Psychiatry 18:293-5. Kleinman A (2012) Culture, bereavement, and psychiatry. Lancet 379:608-9. Koukopoulos A, Sani G (2014) DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand 129:4-16. Kotov R, Jonas KG, Carpenter WT et al (2020) Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): I. Psychosis superspectrum. World Psychiatry 19:151-72. 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Reynolds CF 3rd (2020) Optimizing personalized management of depression: the importance of real-world contexts and the need for a new convergence paradigm in mental health. World Psychiatry 19:266-8. Sanislow CA (2020) RDoC at 10: changing the discourse for psychopathology. World Psychiatry 19:311-2. Stein DJ, Szatmari P, Gaebel W et al (2020) Mental, behavioural and neurodevelopmental disorders in the OCD-11: an international perspective on key changes and controversies. BMC Med 18:21. van Os J, Guloksuz S, Vijn TW et al (2019) The evidence-based group-level symptom-reduction model as the organizing principle for mental health care: time for change? World Psychiatry 18:88-96. Wakefield JC, Schmitz MF (2012) Recurrence of bereavement-related depression: evidence for the validity of the DSM-IV bereavement exclusion from the Epidemiologic Catchment Area Study. J Ment Dis 200:480-5.


Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne.
The emergence of oral and topical retinoids was a major advance in the clinical management of acne vulgaris. However, the benefits of these agents were somewhat limited by the degree of side effects caused by these drugs. Over the last 15 years, researchers have sought compounds that can provide the manifold therapeutic benefits obtained with tretinoin and isotretinoin while minimizing the potential for irritation and other unwanted effects. Adapalene, a naphthoic-acid derivative, is one result of this search, and it serves as an example of rational drug development: the formulation of a novel substance with specific pharmacological properties and clinical objectives in mind. These goals included enhancing stability, enhancing anti-inflammatory effects, maintaining effectiveness and minimizing cutaneous irritation. This paper reviews the history of the development of adapalene, its unique physical and biochemical properties, and the pharmacological studies that demonstrate a wide range of retinoid-receptor, genetic and anti-inflammatory effects, all of which contribute to the therapeutic efficacy and improved tolerability of adapalene observed in the clinical use of this agent for the treatment of acne.


Typical MR features and interpretation of perianal fistulas in patients with Crohn's disease.
Perianal fistulas in Crohn's disease (CD) are a poor prognostic phenotype requiring a combination of medical and surgical management. Perianal fistulas in CD are characterized by more complex and multi-branched fistulas, association with skin tags, and frequent presence of proctitis. A comprehensive approach with clinical examination, endoscopic and MR assessment is required, and in particular, MR interpretation provides detailed information on the type of fistula with its internal component and activity, secondary tracts and extension, internal, external openings, associated abscess, and presence of proctitis. Structured reporting of these items would be recommended for further discussion and management planning both at initial diagnosis and for disease monitoring during treatment follow-up. Management strategy would be individualized for each patient, and control of luminal disease activity could be an important determinant in the selection of treatment options. In this review, we provide an overview of the MRI evaluation of perianal fistulas in CD with a proposed structured MR report.


Different dimensions of hand preference that relate to skilled and unskilled activities.
Hand preference is multidimensional with two major factors and a variable number of minor factors. In the present factor analyses of hand preference, there was no evidence to support Healey, Liederman and Geschwind's (1986) suggestion that hand preference dimensions can be distinguished on the basis of those requiring movement of the distal musculature (fingers and hand) and those requiring movement of the proximal. The first factor reported here relates to "skilled" activities. Hand preference for the use of tools and manipulation of other objects is strongly lateralized in self-professed right- and left-handers. "Less skilled" activities such as picking up objects load on a second and a third factor. Preference for picking up objects including very small ones and relatively heavy ones is much less lateralized, although there appears to be a distinction between activities that involve strength and those that do not. A fourth factor relates to the use of bats and axes, a bimanual activity.


Pandemic transit: examining transit use changes and equity implications in Boston, Houston, and Los Angeles.
While the COVID-19 pandemic upended many aspects of life as we knew it, its effects on U.S. public transit were especially dramatic. Many former transit commuters began to work from home or switched to traveling via private vehicles. But for those who continued to work outside the home and could not drive-who were more likely low-income and Black or Hispanic-transit remained an important means of mobility. However, most transit agencies reduced service during the first year of the pandemic, reflecting reduced ridership demand, increasing costs, and uncertain budgets. To analyze the effects of the pandemic on transit systems and their users, we examine bus ridership changes by neighborhood in Boston, Houston, and Los Angeles from 2019 to 2020. Combining aggregated stop-level boarding data, passenger surveys, and census data, we identify associations between shifting travel patterns and neighborhoods. We find that early in the pandemic, neighborhoods with more poor and non-white households lost proportionally fewer riders; however, this gap between high- and low-ridership-loss neighborhoods shrank as the pandemic wore on. We also model ridership change controlling for multiple factors. Ridership in Houston and LA generally outperformed Boston, with built environment and demographic factors accounting for some of the observed differences. Neighborhoods with high shares of Hispanic and African American residents retained more riders in the pandemic, while those with higher levels of auto access and with more workers able to work from home lost more riders, all else equal. We conclude that transit's social service role elevated during the pandemic, and that serving travelers in disadvantaged neighborhoods will likely remain paramount emerging from it. The online version contains supplementary material available at 10.1007/s11116-022-10345-1.


Rapid Identification of DNA Fragments through Direct Sequencing with Electro-Optical Zero-Mode Waveguides.
In contrast to sequence-specific techniques such as polymerase chain reaction, DNA sequencing does not require prior knowledge of the sample for surveying DNA. However, current sequencing technologies demand high inputs for a suitable library preparation, which typically necessitates DNA amplification, even for single-molecule sequencing methods. Here, electro-optical zero-mode waveguides (eZMWs) are presented, which can load DNA into the confinement of zero-mode waveguides with high efficiency and negligible DNA fragment length bias. Using eZMWs, highly efficient voltage-induced loading of DNA fragments of various sizes from ultralow inputs (nanogram-to-picogram levels) is observed. Rapid DNA fragment identification is demonstrated by burst sequencing of short and long DNA molecules (260 and 20 000 bp) loaded from an equimolar picomolar-level concentration mixture in just a few minutes. The device allows further studies in which low-input DNA capture is essential, for example, in epigenetics, where native DNA is required for obtaining modified base information.


No difference in the failure rates of orthodontic brackets bonded with self-etching primer.
This was a randomised controlled clinical trial (RCT) in a UK district general hospital. The interventions tested were orthodontic brackets bonded with standard light-cured hydrophobic primer [acid etch (AE); Transbond XT, 3M Unitek, Monrovia, California, USA] compared with self-etching primer (SEP; Transbond-Plus, 3M Unitek). Both groups used Transbond XT paste(3M Unitek) and curing light. The primary outcome was first-time bracket failure recorded by date and tooth number. Secondary outcomes were mandibular and maxillary bracket failures and the time taken to bond the bracket. There were no statistical differences in failure rates between SEP (4.8%) and AE (3.5%). Bonding time per bracket with SEP was significantly lower at 75.5 s (95% confidence interval, 72.9-78.5) in the SEP compared with the AE group (97.7 s; 95% confidence interval, 94.3-101.2). There was no difference in the failure rates of brackets bonded with either SEP or conventional AE using Transbond XT paste. Bonding with SEP was significantly faster than using conventional AE.


Prevalence and pathology of equine parvovirus-hepatitis in racehorses from New York racetracks.
Theiler's disease, a.k.a. equine serum hepatitis, is a devastating, highly fatal disease of horses. Equine parvovirus-hepatitis (EqPV-H) has been identified as the likely cause of this disease. While the incidence of Theiler's disease is low, the prevalence of EqPV-H DNA in horses is high, with up to 37% in some regions, suggesting that subclinical or persistent infection is common. To determine the prevalence and pathogenicity of EqPV-H infection at New York racetracks, DNA was extracted from archived formalin-fixed, paraffin-embedded liver tissues from racehorses submitted for necropsy to the Animal Health Diagnostic Center as part of the New York State Gaming Commission-Cornell University postmortem examination program. A total of 191 liver samples from horses between 2 and 13 years old were evaluated. Extracted DNA was tested for EqPV-H using PCR and gel electrophoresis. PCR-positive samples were further assessed for tissue morphology using histology and detection of viral nucleic acid using in situ hybridization. Forty-two samples were PCR positive (22%). Of those, 31 samples had positive viral nucleic acid hybridization in hepatocytes with 11 samples showing positive hybridization in necrotic hepatocytes associated with inflammatory cells, indicating active hepatitis. Both individual hepatocyte necrosis and hepatitis were positively associated with EqPV-H detection (p < 0.0001 and p = 0.0005, respectively). These findings indicate that presence of EqPV-H in the liver and parvoviral-associated hepatitis are prevalent in racehorses from New York racetracks, thus warranting additional studies examining potential associations between EqPV-H infection and racehorse performance.


The aggregate and sectoral time-varying market efficiency during crisis periods in Turkey: a comparative analysis with COVID-19 outbreak and the global financial crisis.
This study aims to examine the time-varying efficiency of the Turkish stock market's major stock index and eight sectoral indices, including the industrial, financial, service, information technology, basic metals, tourism, real estate investment, and chemical petrol plastic, during the COVID-19 outbreak and the global financial crisis (GFC) within the framework of the adaptive market hypothesis. This study employs multifractal detrended fluctuation analysis to illustrate these sectors' multifractality and short- and long-term dependence. The results show that all sectoral returns have greater persistence during the COVID-19 outbreak than during the GFC. Second, the real estate and information technology industries had the lowest levels of efficiency during the GFC and the COVID-19 outbreak. Lastly, the fat-tailed distribution has a greater effect on multifractality in these industries. Our results validate the conclusions of the adaptive market hypothesis, according to which arbitrage opportunities vary over time, and contribute to policy formulation for future outbreak-induced economic crises.


Tuberculosis screening among Bolivian sex workers and their children.
Bolivian sex workers were more likely than other employed women to report tuberculosis screening only if they reported HIV screening. Of all women with household tuberculosis exposure, <40% reported screening for themselves or their children. Coupling tuberculosis screening with sex workers' mandatory HIV screenings may be a cost-efficient disease-control strategy.


Gene cloning of cold-adapted isocitrate lyase from a psychrophilic bacterium, Colwellia psychrerythraea, and analysis of amino acid residues involved in cold adaptation of this enzyme.
The gene (icl) encoding cold-adapted isocitrate lyase (ICL) of a psychrophilic bacterium, Colwellia psychrerythraea, was cloned and sequenced. Open reading frame of the gene was 1,587 bp in length and corresponded to a polypeptide composed of 528 amino acids. The deduced amino acid sequence showed high homology with that of cold-adapted ICL from other psychrophilic bacterium, C. maris (88% identity), but the sequential homology with that of the Escherichia coli ICL was low (28% identity). Primer extension analysis revealed that transcriptional start site for the C. psychrerythraea icl gene was guanine, located at 87 bases upstream of translational initiation codon. The expression of this gene in the cells of an E. coli mutant defective in ICL was induced by not only low temperature but also acetate. However, cis-acting elements for cold-inducible expression known in the several other bacterial genes were absent in the promoter region of the C. psychrerythraea icl gene. The substitution of Ala214 for Ser in the C. psychrerythraea ICL introduced by point mutation resulted in the increased thermostability and lowering of the specific activity at low temperature, indicating that Ala214 is important for psychrophilic properties of this enzyme.


Vertebral artery surgery.
Vertebral artery revascularization is indicated for symptomatic vertebral artery disease. Safe and effective revascularization can be offered to such patients with good long-term outcomes. Percutaneous transluminal angioplasty, with and without stents, may eventually develop a role. However, prospective trials to compare angioplasty with the safety and long-term efficacy of surgical revascularization are needed before any benefit can be assumed.


Kruppel-like factor 1-GATA1 fusion protein improves the sickle cell disease phenotype in mice both in vitro and in vivo.
Sickle cell disease (SCD) and β-thalassemia are among the most common genetic disorders worldwide, affecting global health and mortality. Hemoglobin A2 (HbA2, α2δ2) is expressed at a low level in adult blood due to the lack of the Kruppel-like factor 1 (KLF1) binding motif in the δ-globin promoter region. However, HbA2 is fully functional as an oxygen transporter, and could be a valid antisickling agent in SCD, as well as a substitute for hemoglobin A in β-thalassemia. We have previously demonstrated that KLF1-GATA1 fusion protein could interact with the δ-globin promoter and increase δ-globin expression in human primary CD34+ cells. We report the effects of 2 KLF1-GATA1 fusion proteins on hemoglobin expression, as well as SCD phenotypic correction in vitro and in vivo. Forced expression of KLF1-GATA1 fusion protein enhanced δ-globin gene and HbA2 expression, as well as reduced hypoxia-related sickling, in erythroid cells cultured from both human sickle CD34+ cells and SCD mouse hematopoietic stem cells (HSCs). The fusion proteins had no impact on erythroid cell differentiation, proliferation, and enucleation. Transplantation of highly purified SCD mouse HSCs expressing KLF1-GATA1 fusion protein into SCD mice lessened the severity of the anemia, reduced the sickling of red blood cells, improved SCD-related pathological alterations in spleen, kidney, and liver, and restored urine-concentrating ability in recipient mice. Taken together, these results indicate that the use of KLF1-GATA1 fusion constructs may represent a new gene therapy approach for hemoglobinopathies.


[Incomplete aortic ring (arcus aortae circumflexus); compression of oesophagus and trachea (author's transl)].
A baby of 5 months had an incomplete aortic ring (arcus aortae circumflexus) in combination with a ligamentum arteriosum. Even in infancy specific symptoms may occur. Carefull angiographic investigation can avoid misjudging the symptoms (stridor, dysphagia) and can contribute to an exact diagnosis thus preventing unnecessary operation.


New C3H KitN824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance.
Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.


Enhancement of polyoma virus middle T antigen tyrosine phosphorylation by epidermal growth factor.
Polyoma virus codes for three proteins involved in host cell transformation: the large, middle and small T antigens. Middle T antigen is a major transforming protein which is responsible for the induction of the phenotype of transformed cells and, without it, transformation does not occur (reviewed in refs 1-4). Middle T antigen alone can transform established cell lines, although large, and possibly small, T antigens are also required for the full expression of the phenotype of transformed cells in media with a low concentration of serum. A subfraction of middle T antigen is associated with a protein kinase activity which phosphorylates middle T antigen in vitro on tyrosine. There is a strong correlation between the level of this kinase activity and the degree of expression of the phenotype of transformed cells. We report here that epidermal growth factor (EGF) stimulates tyrosine phosphorylation of middle T antigen, suggesting the possibility that mitogenic growth factor(s) regulates this phosphorylation activity.


Noncontraceptive health benefits of intrauterine devices: a systematic review.
Most women and their clinicians are unaware that IUDs confer important noncontraceptive health benefits. This review summarizes the evidence from published articles on this topic. We conducted a series of systematic literature searches to identify articles on the noncontraceptive health benefits of IUD use. We reviewed the potentially pertinent ones for content, grouped them according to type of IUD, and evaluated them using the U.S. Preventive Services Task Force rating system. Over 500 titles were identified and several hundred abstracts were reviewed. Use of nonhormonal IUDs (plastic and copper) was associated with a decrease in endometrial cancer. The levonorgestrel intrauterine system can treat a variety of gynecological disorders, including menorrhagia and anemia. The levonorgestrel system has also been used successfully as part of hormone replacement therapy, as adjuvant therapy with tamoxifen, and as an alternative to hysterectomy for women with bleeding problems. Like oral contraceptives, intrauterine contraceptives confer important noncontraceptive health benefits.