Predictive validation of single-episode uncomplicated depression as a benign subtype of unipolar major depression.
To evaluate the predictive validity of a proposed benign major depressive disorder (MDD) subtype, single-episode 'uncomplicated MDD', defined as MDD that remits within 6 months and lacks severe impairment, psychotic ideation, suicidal ideation, psychomotor retardation, and feeling worthless. Using two-wave National Epidemiologic Survey on Alcohol and Related Conditions data, four groups differing in wave 1 lifetime MDD history (no history [n = 27 609]; single-episode uncomplicated [n = 418]; other single-episode [n = 1943]; multiple episode [n = 2473]) were evaluated for 3-year follow-up rates of major depressive episode (MDE), generalized anxiety disorder (GAD), and suicide attempt. Follow-up rates for no-MDD-history, single-episode uncomplicated MDD, other single-episode MDD, and multiple-episode MDD, respectively, were depressive episode 6.1%, 6.9%, 19.5%, 27.1%; GAD 2.7%, 4.3%, 7.8%, 11.2%; and suicide attempt 0.3%, 0.1%, 0.8%, 1.7%. For all validators, 3-year rates for single-episode uncomplicated cases were not significantly different from no-MDD-history rates, but significantly lower than both single- and multiple-episode other-MDD rates. Mild MDD, defined by having only five or six symptoms, did not yield similarly benign results; logistic regression showed 'uncomplicated' provides incremental validity over 'mild' in explaining validator rates. Validator differences were not explainable by treatment-rate differences. Single-episode uncomplicated MDD is a benign subtype lacking typical MDD negative sequelae. The planned DSM-5.1 revision should reinstitute an extended bereavement exclusion applied to all stressors.


Parent or community: where do 20-month-olds exposed to two accents acquire their representation of words?
The recognition of familiar words was evaluated in 20-month-old children raised in a rhotic accent environment to parents that had either rhotic or non-rhotic accents. Using an Intermodal Preferential Looking task children were presented with familiar objects (e.g. 'bird') named in their rhotic or non-rhotic form. Children were only able to identify familiar words pronounced in a rhotic accent, irrespective of their parents' accent. This suggests that it is the local community rather than parental input that determines accent preference in the early stages of acquisition. Consequences for the architecture of the early lexicon and for models of word learning are discussed.


Trade-offs inDaphnia vertical migration strategies.
Planktonic animals performing diel vertical migration (DVM) experience a tradeoff between reduced mortality and reduced reproductive output due to lower food availability in their refuge. Models of DVM as an evolutionarily stable strategy predict that, under certain conditions, strategies of both migration and non-migration can coexist. Vertical profiles of animal abundances during day and night, however, do not allow any discrimination between the behaviour of individuals or subpopulations. We used length-body protein regressions as a measure of the nutritional state ofDaphnia to distinguish possible sub-populations differing in their migration strategy. An overwhelming part of the population migrated downwards during the day. However, the few daphnids in the epilimnion during the day had significantly higher protein content than the animals in the deep water, indicating that these daphnids did not migrate randomly but remained in the surface food-rich water all day. This shows that migrating animals gain no metabolic advantage over non-migrating ones.


CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia-Romagna region.
We have genotyped the patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency identified from March 1980 to December 1997 through a combined program of neonatal screening and case survey in the Emilia-Romagna Region (Italy). We have also analysed retrospectively the possible advantages of genotypical neonatal classification. A 'phase A' of screening and clinical monitoring (March 1980-September 1983 and March 1991-December 1997) and a 'phase B' of clinical monitoring only (October 1983-February 1991) were taken into account. A total of 61 patients (20 salt wasting, nine simple virilizing and 32 nonclassical forms) were genotyped, HLA typed and hormonally tested to understand better the genotype/phenotype relationship and the epidemiology and geographical distribution of associated mutations. The fully genotyped patients were classified into four mutation groups according to the degree of enzymatic activity ('null' and 'A' to 'C'). The most frequent genotype alterations were deletion (24.1% classical, 3.3% nonclassical forms), large gene conversion (9.2% classical, 1.7% nonclassical forms), In2 splice (27.7% classical, 15.0% nonclassical forms), I172N (5.5% classical, 10.0% nonclassical forms), V281L (3.7% classical, 43.3% nonclassical forms), P453S (5.0% nonclassical forms). A significant difference (chi2 = 5.101; P < 0.025) in the distribution of classical genotypes was found in Romagna (south-east; incidence 1 : 7437 newborns) compared to Emilia (north-west; incidence 1 : 25 090 newborns). Two putative new mutations were found in our population. Little discrepancy was found between genotype and phenotype. The high frequency of genotypes 'null' or 'A' in the 'phase A' vs. 'phase B' of our study confirms the usefulness of neonatal screening in preventing the death of male patients with salt wasting forms. The substantial similarity in the mutational spectrum of classical forms found in our study, based on the detection of all the classical patients of a specific area, leads us to believe that the distribution of mutations is due to the inherent characteristics of the gene locus, and that regional effects play a minor role. Prompt neonatal genotyping can be of valuable diagnostic assistance in neonatal screening for the confirmation of the diagnosis in newborns with moderately elevated 17 hydroxyprogesterone levels.


Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region.
Germ-line alterations of BRCA1 are responsible for about 50% of familial breast cancers. Although its biological function(s) has not yet been fully determined, it has been suggested that it may act as a tumor suppressor gene in breast and ovarian cancers. In sporadic breast cancers alterations of BRCA1 have not been detected and in vitro experiments have indicated that BRCA1 negatively regulates cellular proliferation. The present study was designed to identify and quantify, the BRCA1 mRNA levels, in normal and neoplasic human breast tissue. BRCA1 mRNA molecules were quantified using competitive reverse transcriptase PCR assays. DNA methylation patterns of this gene have been analysed by Southern blot experiments using methylation sensitive restriction enzymes. We found that BRCA1 mRNA levels were significantly lower in sporadic breast cancers (37 cases analysed, 24 cases of invasive ductal carcinomas not otherwise specified (NOS), two lobular carcinomas in situ two medullary carcinomas, four invasive lobular carcinomas, two invasive mucinous carcinomas and three invasive ductal carcinomas with predominantly in situ component) compared with normal breast tissues (P=0.0003). This down-regulation of BRCA1 is observed in all histologic types analysed. In invasive ductal carcinomas NOS, this down-regulation does not correlate with any of the prognostic factors studied (tumor size, node status, histologic grade, hormone receptor status). In the samples analysed, alterations of DNA methylation patterns were not dectected in the vicinity of the major transcription start site. These data suggest the involvement of BRCA1 in the carcinogenesis of these histologic types.


Technical Aspects of Intra-Operative Ultrasound for Spinal Cord Injury and Myelopathy: A Practical Review.
To compile intra-operative techniques, established imaging parameters, available equipment and software, and clinical applications of intraoperative ultrasound imaging (IOUSI) for spinal cord injury (SCI) and myelopathy. PubMed and Google Scholar were searched for relevant articles. The articles were reviewed and selected by 2 independent researchers. After article selection, data were extracted and summarized into research domains. PRISMA systematic review process was followed. Of the 2477 articles screened, 16 articles met the inclusion criteria. In patients with SCI and myelopathy, common quantitative measurements obtained using IOUSI were noted: 1) ultrasound elastography, 2) midsagittal anteroposterior diameter, 3) transverse, 4) transverse diameter, 5) maximum spinal cord compression, and 6) compression ratioTo ensure adequate decompression and to look for residual compression, the lateral and the craniocaudal margins of the laminectomy site were inspected in both axial and sagittal planes. In instances where quantitative assessment was not possible, cord decompression and degree of residual compression were gauged by inspecting the interface between the ventral border of the spinal cord and any potentially compressive elements, and by searching for symmetric and rhythmic cerebrospinal fluid pulsations. Use of contrast-enhanced ultrasoundand molecular imaging are additional advances in objective assessments for SCI and myelopathy. This review outlines the potential of IOUSI in patients presenting with SCI and myelopathy. Moreover, by identifying potential for inter-operator variability in certain subjective measurements, we illustrate the need for further research to quantify and standardize those assessments.


Functional and physical interaction of protein-tyrosine kinases Fyn and Csk in the T-cell signaling system.
The Src-like protein-tyrosine kinase Fyn is associated with T-cell antigen receptor. Transient expression of actively mutated Fyn, having Phe-528 instead of Tyr-528 or Thr-338 instead of Ile-338, in Jurkat T-cells stimulated the serum response element (SRE), 12-O-tetradecanoyl-phorbol-13-acetate response element, cyclic AMP response element, and c-fos promoter. The stimulation of SRE was particularly prominent not only with active Fyn but also with normal (wild-type) Fyn. SRE was also stimulated by both normal and active Lck. Furthermore, normal and active Fyn stimulated transcription from the IL-2 gene promoter when transfected cells were stimulated by concanavalin A plus 12-O-tetradecanoylphorbol-13-acetate. Under the same conditions, Lck did not stimulate IL-2 promoter unless it was activated by mutation. Interestingly, a mutant Fyn, which has deletions within the SH2 region and so is able to transform chicken embryo fibroblasts, did not stimulate either the c-fos or IL-2 promoter, suggesting the importance of this region in T-cell signaling. Csk, which phosphorylates tyrosine residues in the negative regulatory sites of Src family kinases, down-regulated Fyn- and Lck-mediated stimulation of the serum response element and Fyn-mediated enhancement of IL-2 promoter activity. These data suggest that Fyn and Lck, whose activities are regulated by Csk, are involved in different phases of T-cell activation.


Effects of streptozotocin-induced diabetes and diet on nitrogen loss from organs and on the capacity of urea synthesis in rats.
Rats with experimental streptozotocin-induced diabetes (75 mg/kg) were divided into two groups. One group was free fed (n = 8), the other group (n = 7) pair fed to a group of control animals (n = 8). The nitrogen and energy balances of the control rats were positive. In the free-fed diabetic rats the nitrogen balance was neutral and the energy balance higher than in controls. In the pair-fed diabetic rats the nitrogen balance was negative and the energy balance reduced. After 4 weeks the capacity of urea-nitrogen synthesis was: 8.1 +/- 0.6 mumol/(min 100 g body weight) (mean +/- SEM) in controls and 22.2 +/- 2.2 mumol/(min 100 g body weight) in both groups of diabetic rats. Initially, the whole body nitrogen content was 453 +/- 9 mmol. Four weeks later it was 536 +/- 19 mmol in controls, 410 +/- 21 mmol in the free-fed diabetic rats, and 315 +/- 6 mmol in the pair-fed diabetic rats. The largest changes occurred in the muscles, initially containing 278 +/- 6 mmol, 4 weeks later 328 +/- 8 mmol, compared to 234 +/- 19 in the free-fed diabetic rats and 166 +/- 18 mmol in the pair-fed diabetic rats. In conclusion uncontrolled diabetes is characterised by loss of nitrogen from muscles and most other organs. The losses from some organs are preventable by increased food intake. Irrespective of food intake the hepatic dynamics of amino nitrogen conversion is changed in a way that favours protein catabolism.


Extended Methodology for DFA and DCCA: Application of Automatic Search Procedure and Correlation Map to the Weierstrass-Mandelbrot Functions.
Detrended fluctuation analysis and detrended cross-correlation analysis are used in this study to identify and characterize correlated data. The objective of these two techniques is to separate different fluctuations from the contributions due to external trends by evaluating the autocorrelation and cross-correlation exponents, in order to determine if scale properties persist with the size of the series. Two new methodologies were extended from cross-correlation coefficients for local analysis, which we call the \textit{automatic search procedure.


Immunochemical characterization of the specificities of two human monoclonal IgM's reacting with chondroitin sulfates.
We have studied the specificities of two human monoclonal, IgM containing sera, s/IgMMAC and s/IgMFIS, from patients with polyneuropathy. s/IgMMAC precipitates only with chondroitin sulfate C and not with A and B whereas s/IgMFIS is precipitated by chondroitins A, B (dermatan sulfate), and C. Inhibition assays using 2-acetamido-2-deoxy-3-O-(4-deoxy-beta-L-threo-hex-4-enopyranosyluroni c acid)-D-galactose and its 6- and 4-sulfate derivatives showed that the disaccharide 6-sulfate was the best inhibitor of precipitation of s/IgMMAC by chondroitin sulfate C, and the disaccharide 4-sulfate the best inhibitor of precipitation of s/IgMFIS by either chondroitin sulfates C or B. The nonsulfated disaccharide was a good inhibitor in each instance. D-Glucose 6-sulfate, Na2SO4, several sugar phosphates, and phosphate buffer also inhibited but to different extents with the s/IgMMAC and s/IgMFIS. All studies were carried out in 0.15M NaCl. The data indicate that both monoclonal proteins are antibodies comparable to the phosphorylcholine-binding myeloma proteins, and that the reactions show specificities above and beyond charge effects. The relation of various cross-reacting macromolecules to the monoclonal antibody was studied by diffusion in gels.


Residue screening and analysis of enrofloxacin and its metabolites in real aquatic products based on ultrahigh-performance liquid chromatography coupled with high resolution mass spectrometry.
The abuse of enrofloxacin (ENR) in aquaculture and the lack of monitoring of other metabolites except ciprofloxacin (CIP) may lead to unknown harmful effects on human health. In this study, ENR metabolites were screened in real fish samples based on ultrahigh-performance liquid chromatography coupled with Q-Orbitrap mass spectrometry combined with Compound Discoverer software, and another metabolite deethylene-ENR besides CIP was detected and identified for the first time. Correspondingly, a method for the determination of ENR and CIP and the semi-quantitative analysis of deethylene-ENR in aquatic products was established. Method validation illustrated that excellent linearity and satisfactory recoveries of analytes were obtained. Limits of detection of ENR and CIP were both 0.1 μg kg-1, and their limits of quantification both 1 μg kg-1. CIP and deethylene-ENR were detected in 12 of 14 ENR-positive fish samples, so deethylene-ENR should be of concern as a possible risk candidate in aquatic products.


Endoscopic membranectomy with a high-frequency-wave snare/cutter for membranous stenosis in the upper gastrointestinal tract.
As endoscopic equipment and instruments have been improved, the indication for endoscopic surgery has been extended. The authors achieved endoscopic membranectomy for congenital membranous stenosis in the upper gastrointestinal tract. Case 1 was a 3-year-old girl with membranous stenosis in the descending duodenum. Case 2 was a 1-year-old boy with esophageal membranous stenosis. In case 1, a flexible endoscope with a banding chamber, the inside of which had a tiny groove for a high-frequency-wave snare, was inserted into the duodenum. The diaphragm was drawn into the chamber by endoscopic suction and tied with the snare around its base, then dissected by electrifying the snare. In case 2, the diaphragm was resected with a high-frequency-wave cutter, assisted by a balloon catheter pulling up the diaphragm from the distal side. In both cases, the stenosis was released adequately without complications, and oral feeding was restarted in a day after the procedure. Endoscopic membranectomy using a high-frequency wave snare/cutter was achieved safely and effectively in 2 children with congenital membranous stenosis in the upper gastrointestinal tract.


Characterization of leukotriene B4 synthesis in canine polymorphonuclear leukocytes.
The synthesis and release of leukotriene B4 (LTB4) from canine polymorphonuclear leukocytes (PMNs) was characterized in terms of incubation time, temperature and effects of calcium ionophore A23187 concentrations. Maximal LTB4 concentrations were determined when canine PMNs were incubated with 10 microM A23187. Increasing LTB4 concentrations were determined through 10 min incubation. The maximal LTB4 concentrations (310 +/- 30 pg LTB4/2.5 x 10(5) cells) determined at 10 min did not change through a 55 min incubation period. Greater LTB4 concentrations were synthesized by canine PMNs at 37 degrees C (268 +/- 12 pg LTB4/2.5 x 10(5) cells) than at 25 degrees C (206 +/- 11 pg LTB4/2.5 x 10(5) cells) or 5 degrees C (59 +/- 3 pg LTB4/2.5 x 10(5) cells). The synthesis of LTB4 in canine PMNs was inhibited by incubation of the cells with either of two known lipoxygenase inhibitors, BWA4C or BW755C. BWA4C inhibited LTB4 synthesis with an approximate IC50 = 0.1 microM, whereas BW755C inhibited LTB4 synthesis with an approximate IC50 = 10 microM. These results indicate canine PMNs have the capability to synthesize large quantities of LTB4 when stimulated with calcium ionophore A23187. Furthermore, the 5-lipoxygenase inhibitors BWA4C, an acetohydroxyamic acid, and BW755C, a phenyl pyrazoline, can readily inhibit LTB4 synthesis in canine PMNs.


Generation of an induced pluripotent stem cell line carrying biallelic deletions (SCTCi019-B) in ALDH7A1 using CRISPR/Cas9.
Biallelic pathogenic variants in ALDH7A1 are associated with pyridoxine-dependent epilepsy (PDE). ALDH7A1 encodes for the third enzyme of the lysine catabolism pathway. In this study a human isogenic ALDH7A1 knock-out iPSC line was created using CRISPR/Cas9 technology. One clone (SCTCi019-B) with biallelic deletions in ALDH7A1 was obtained and fully characterized, showing expression of pluripotency markers, a normal karyotype and no off-targets. Human-based models derived from this iPSC line will contribute to gain insights in the molecular mechanism of disease underlying PDE.


Efficacy and safety of dapagliflozin in Japanese patients with inadequately controlled type 1 diabetes (DEPICT-5): 52-week results from a randomized, open-label, phase III clinical trial.
To investigate the safety and tolerability of 5 and 10 mg dapagliflozin added to insulin therapy over 52 weeks in Japanese patients with inadequately controlled type 1 diabetes mellitus (T1DM). This randomized, open-label, parallel-group, multicentre phase III clinical trial was conducted from October 26, 2015 to June 15, 2017. The primary endpoint was the occurrence of adverse events such as hypoglycaemia and diabetic ketoacidosis. Secondary endpoints included changes in glycaemic parameters, total daily insulin dosage and body weight over time. The efficacy of dapagliflozin in patients stratified by body mass index (BMI) <25.0 and ≥25.0 kg/m2 was evaluated in a subgroup analysis. In total, 151 patients received 5 mg (n = 76) or 10 mg (n = 75) dapagliflozin once daily for 52 weeks. Adverse events were observed in 88.2% and 73.3% of patients in the 5 and 10 mg dapagliflozin groups, respectively. Severe hypoglycaemia was reported in 2.6% (n = 2) and 6.7% (n = 5) of patients, and diabetic ketoacidosis in 2.6% (n = 2) and 1.3% (n = 1) of patients in the 5 and 10 mg dapagliflozin groups, respectively. The adjusted mean (95% confidence interval) changes in glycated haemoglobin at week 52 were -0.33% (-0.50, -0.15) and -0.36% (-0.53, -0.18) in the 5 and 10 mg dapagliflozin groups, respectively. There were no differences in efficacy parameters when stratified by BMI. This study demonstrated the long-term safety and tolerability of dapagliflozin added to insulin therapy in Japanese patients with inadequately controlled T1DM.


The socio-demographic determinants of the outcome of type 1 cartilage tympanoplasty in children: Results from a tertiary-care teaching institute in India.
To explore whether and how the established socio-demographic parameters pertaining to a lower-middle income nation influence the outcome of cartilage tympanoplasty in children with chronic otitis media (COM), inactive mucosal variety. In this prospective cohort study, children aged 5-12 years with COM (dry, large/subtotal perforation) were considered for type 1 cartilage tympanoplasty following definite selection criteria. Relevant socio-demographic parameters were noted for each child. These included parents' education (literate/illiterate), living area (slum/village/others), mothers' occupation (laborer/business/housewife or home-maker), family type (nuclear/joint), and monthly family income. Outcome at 6 months follow-up was interpreted as "success" (favorable; anatomically intact and well-epithelialized neograft and dry ear) and "failure" (unfavorable; residual or recurrent perforation and/or discharging ear). The role of individual socio-demographic factor in determining the outcomes was analyzed with relevant statistical methods. The average age of the 74 children included in the study was 9.30 ± 2.13 years. At six months, 86.5% had a successful outcome, with a statistically significant hearing gain (closure of the air-bone gap) of 17.02 ± 8.96 dB (p = .003). Mothers' education had a significant influence on the success rate (Chi: 4.13; significant at p < .05); children of ∼97% of the literate mothers had a successful outcome. Living area was significantly associated with success (Chi: 13.94; significant at p < .01); ∼90% of children living in the slum areas had success, compared to 50% of those residing in villages. The family type also significantly influenced the surgical outcome (Chi: 3.81; significant at p < .05); ∼97% of the children belonging to the joint families encountered success, compared to ∼81% of those brought up in the nuclear families. The success also depended on the mothers' occupation (Chi: 6.47; significant at p < .05); ∼97% of the housewife mothers had children who were successful, against ∼77% of mothers engaged as laborers. Another factor significantly associated with success was the monthly household income. Nearly 97% of the children belonging to families with a monthly household income of >₹3000 (cut-off limit set by the median value) experienced success, in contrast to 79% of those having a monthly family income of <₹3000 (Chi: 4.83; significant at p < .05). Socio-demographic parameters are valuable determinants of the outcome of surgical management of COM in children. For type 1 cartilage tympanoplasty, mothers' education and occupation, family type, living area, and monthly family income significantly influenced the surgical outcome.


Electrophysiologic effects of hydralazine on sinoatrial function in patients with sick sinus node syndrome.
The electrophysiologic effects of hydralazine were evaluated in nine hypertensive patients with sinoatrial dysfunction. Intravenous hydralazine, 0.15 mg/kg, caused no significant reduction in arterial blood pressure. Yet this dose of hydralazine increased heart rate from 61.9 +/- 4.1 beats/min (mean +/- standard error of the mean) to 68.6 +/- 4.9 (P less than 0.001). Sinus nodal recovery time upon termination of atrial pacing shortened from 3,207 +/- 1,098 to 2,064 +/- 573 msec (P less than 0.05) and second escape cycles shortened as well (P less than 0.025). Acceleration of heart rate and abbreviation of recovery time did not closely correlate with change in blood pressure (r = 0.41 and 0.18, respectively). Junctional escape beats became more frequent and junctional escape time shortened from 2,525 +/- 692 to 1,705 +/- 382 msec (P less than 0.05). Sinoatrial conduction time tended to shorten, but a significant change was not observed. Atrial tachyarrhythmias did not occur and atrial refractoriness was unchanged. Thus, a minimal blood pressure response to hydralazine was associated with enhanced automaticity. Hydralazine merits clinical trial for treatment of sick sinus syndrome with concomitant hypertension.


Studies on fermented corn flour poisoning in rural areas of China. I. Epidemiology, Clinical Manifestations, and Pathology.
An outbreak of a new type of fatal food poisoning has been reported in different parts of the People's Republic of China. Liver, kidney, heart, and brain were the main target organs, and the overall fatality of intoxicated individuals was 38.2%. Evidence obtained from epidemiological studies and animal tests indicates that the food poisoning was caused by the consumption of homemade fermented corn flour products.


A role for plasmin in platelet aggregation: differential regulation of IGF release from IGF-IGFBP complexes?
To determine if plasmin differentially augments platelet aggregation through variable efficiencies of IGF-IGFBP complex cleavage. We utilized ADP-triggered platelet aggregation assays to test the effects of IGF-I versus IGF-II in complex with IGFBP-2 or IGFBP-3 upon the efficiency of plasmin (a known IGFBP protease) as a pro-aggregatory stimulus. In vitro proteolysis assays were performed as controls. We found that IGF-I complexes augmented platelet-mediated aggregation whereas IGF-II either had no effect (IGFBP-2) or inhibited platelet-mediated aggregation (IGFBP-3). In vitro proteolysis assays of IGFBP-2 and IGFBP-3 using plasmin revealed that three of the four aggregation findings were explained by the disparate efficiencies of IGFBP proteolysis associated with each IGF. Only IGF-II-IGFBP-2 complex resulted in a finding that could not be explained by the concept of differential regulation of plasmin's proteolysis efficiency by the two IGF ligands. Our findings demonstrate that the plasmin can differentially modulate platelet aggregation in response to intrinsic heterogeneities within the IGF axis.


A review on the anesthetic management of obese patients undergoing surgery.
There has been an observed increase in theprevalence of obesity over the past few decades. The prevalence of anesthesiology related complications is also observed more frequently in obese patients as compared to patients that are not obese. Due to the increased complications that accompany obesity, obese patients are now more often requiring surgical interventions. Therefore, it is important that anesthesiologists be aware of this development and is equipped to manage these patients effectively and appropriately. As a result, this review highlights the effective management of obese patients undergoing surgery focusing on the preoperative, perioperative and postoperative care of these patients.


Pulsed Doppler velocity patterns produced by arterial anastomoses.
Centerstream velocity waveforms produced by end-to-end and end-to-side anastomoses constructed in the dog illeofemoral arterial system were studied with a 20 MHz pulsed Doppler velocimeter combined with spectral analysis. Flow disturbance was identified by changes in spectral width during the systolic phase of the cardiac cycle. Measurement of the maximum frequency and the spectral width at peak systole was used to quantify the magnitude of flow disturbance at varying locations proximal and distal to the anastomoses. Disruption of the normal laminar flow pattern observed in the unoperated dog artery was evident distal to both anastomotic configurations. An increase in spectral width reflecting disturbed flow was maximal during the deceleration phase of systole. Flow disturbance was localized to a zone within one diameter distal to the anastomosis and dissipated rapidly downstream. The velocity spectrum changes observed downstream of an anastomosis resemble the flow disturbances produced by low grade, nonpressure reducing arterial stenoses. This study suggests that spectral analysis of pulsed Doppler waveforms is a potentially useful method of anastomosis assessment both to rule out major flow disruption produced by technical error, and to provide insight into the role of turbulence in the development of anastomotic intimal hyperplasia.


Axogenic effect of estrogen in male rat hypothalamic neurons involves Ca(2+), protein kinase C, and extracellular signal-regulated kinase signaling.
17-beta-Estradiol (E2) stimulates the growth of axons in male-derived hypothalamic neurons in vitro. This effect is not exerted through the classical intracellular estrogen receptor (ER) but depends on a membrane mechanism involving TrkB. In the present study, we investigate the intracellular signaling cascade that mediates the axogenic effect of E2. Treatment with an intracellular Ca(2+) chelator, a Ca(2+)-dependent protein kinase C (PKC) inhibitor, or two specific inhibitors of extracellular signal-regulated kinases (ERK) mitogen-activated protein kinases (MAPK) completely inhibited the E2-induced axogenesis. E2 and the membrane-impermeant construct E2BSA rapidly induced phosphorylation of ERK, which was blocked by the specific inhibitor of the ERK pathway UO126 but not by the ER antagonist ICI 182,780. Decrease of intracellular free Ca(2+) or disruption of PKC activation by Ro 32-0432 attenuated ERK activation, indicating the confluence of signals in the MAPK pathway. Subcellular analysis of ERK demonstrated that the phospho-ERK signal is augmented in the nucleus after 15 min of E2 stimulation. We have also shown that E2 increased phosphorylation of CREB via ERK signaling. In summary, this study demonstrates that E2, probably via a membrane-associated receptor, induces axonal growth by activating CREB phosphorylation through ERK signaling by a mechanism involving Ca(2+) and PKC activation.


Burden of kidney disease among patients with peritoneal dialysis versus conventional in-centre haemodialysis: A randomised, non-inferiority trial.
Little is known about the impact of haemodialysis (HD) and peritoneal dialysis (PD) on health-related quality of life (HRQoL). We compared HRQoL between conventional in-centre HD and home-based PD in 1082 newly diagnosed kidney failure patients. This was an open-label, randomised, non-inferiority trial of adult patients with a diagnosis of end-stage kidney disease (estimated glomerular filtration rate ≤ 15 mL/min/1.73 m2) requiring maintenance dialysis from 36 sites in China randomised 1:1 to receive PD or conventional in-centre HD. The primary outcome was the 'Burden of Kidney Disease' assessed using the Kidney Disease Quality of Life-Short Form (KDQoL-SF) survey over 48 weeks and the main secondary outcomes were the remaining scales of KDQoL-SF and all-cause mortality. The effect of PD versus HD on the primary outcome was compared by their geometric mean (GM) ratio, and non-inferiority was defined by the lower bound of a one-sided 95% confidence interval (CI) >0.9. A total of 725 subjects completed the trial per protocol (395 PD and 330 HD, mean age 49.8 (standard deviation (SD) 14.4) years, 41.4% women). For the primary outcome, the mean (SD) change in 'Burden of Kidney Disease' over 48 weeks was 2.61 (1.27) in PD group and 2.58 (1.35) in HD group, and the GM ratio (95% CI) was 1.059 (0.908-1.234), exceeding the limit for non-inferiority. For the secondary outcomes, the PD and HD groups were similar in all scales. There were 17 and 31 deaths in PD and HD groups, respectively. Patients receiving PD had more adverse events, adverse event leading to hospitalisation and serious adverse events compared to those allocated to HD, but adverse events leading to death and discontinuation of the trial were not different between PD and HD. In this trial, PD may be non-inferior to HD on the 'Burden of Kidney Disease' among Chinese kidney failure patients who are of younger age and have lower comorbidity after 48 weeks' follow-up.


The utility of immunohistochemical testing for mismatch repair proteins in fine needle aspiration specimens of pancreatic adenocarcinoma.
Microsatellite instability (MSI) testing is recommended for all colonic and endometrial carcinomas to screen for Lynch syndrome. The role of MSI testing in pancreatic adenocarcinoma has not been well-established. Screening can be done via immunohistochemical (IHC) staining for mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2). We report our experience and the clinical utility of MMR IHC on pancreatic adenocarcinomas in fine-needle aspiration (FNA) specimens. We performed a retrospective review to identify all patients diagnosed with pancreatic adenocarcinoma by FNA at our institution between December 2017 and September 2019. For cases with sufficient tumor cells for testing, the MMR results and morphology were summarized, as well as corresponding clinical information, including age, clinical stage, treatment, and concurrent other cancers. From December 2017 to September 2019, there were a total of 184 pancreatic FNAs with a diagnosis of adenocarcinoma. Of these 184 FNAs, 65 (35%) contained sufficient material in the cell block to perform IHC for MMR. The cell block material was collected in either RPMI or CytoLyt. Poor technical quality precluded interpretation of PMS2 in 4 cases and MSH6 in 2 cases. All other cases showed intact expression of all four proteins. IHC for MMR proteins can be done on specimens collected in RPMI or CytoLyt, but RPMI appears to be more reliable. None of the pancreatic adenocarcinomas in this study showed loss of MMR protein expression. Routine testing of MMR loss may not be indicated in pancreatic adenocarcinomas in the general patient population.


Ventromedial hypothalamic and paraventricular nucleus lesions damage a common system to produce hyperphagia.
We investigated the anatomical basis of paraventricular (PVN) and ventromedial (VMH) hypothalamic hyperphagia. Asymmetrical electrolytic lesions, damaging the VMH and PVN contralaterally, produced significant hyperphagia and weight gains (mean = 257.2 g) almost three times those of controls (89.8 g) during 56 postsurgical days. Weight gain in these rats was not significantly different from that in rats with bilateral lesions of the VMH (277.2 g) or PVN (188.2 g). Combined bilateral destruction of the PVN and VMH produced weight gain (272.8 g) almost identical to that seen after bilateral VMH lesions alone. The lack of additivity of these combined lesions and the effectiveness of the asymmetrical lesions are consistent with the hypothesis that lesions of either of these two regions damage a longitudinally running system to produce elevated food intake and body weight. Cell bodies of this system may lie within the PVN and send efferent projections through the VMH. Hyperinsulinemia developed only in rats with bilateral damage in the VMH. Thus, hypothalamic hyperphagia and hyperinsulinemia appear to be dissociable, reflecting damage to separate neural systems.


Prominent Josephson tunneling between twisted single copper oxide planes of Bi2Sr2-xLaxCuO6+y.
Josephson tunneling in twisted cuprate junctions provides a litmus test for the pairing symmetry, which is fundamental for understanding the microscopic mechanism of high temperature superconductivity. This issue is rekindled by experimental advances in van der Waals stacking and the proposal of an emergent d+id-wave. So far, all experiments have been carried out on Bi2Sr2CaCu2O8+x (Bi-2212) with double CuO2 planes but show controversial results. Here, we investigate junctions made of Bi2Sr2-xLaxCuO6+y (Bi-2201) with single CuO2 planes. Our on-site cold stacking technique ensures uncompromised crystalline quality and stoichiometry at the interface. Junctions with carefully calibrated twist angles around 45° show strong Josephson tunneling and conventional temperature dependence. Furthermore, we observe standard Fraunhofer diffraction patterns and integer Fiske steps in a junction with a twist angle of 45.0±0.2°. Together, these results pose strong constraints on the d or d+id-wave pairing and suggest an indispensable isotropic pairing component.


Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses.
Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.


Plasma metabolites associated with functional and clinical outcomes in heart failure with reduced ejection fraction with and without type 2 diabetes.
Heart failure with reduced ejection fraction (HFrEF) is increasingly treated with medications for type 2 diabetes mellitus (T2DM). Whether metabolic derangements in HFrEF and T2DM are associated with differential outcomes remains unclear. Therefore, understanding molecular pathways in HFrEF and T2DM and their effects on clinical endpoints is important. The FIGHT trial randomized 300 individuals with HFrEF and a recent HF hospitalization to liraglutide (a GLP-1 receptor agonist) versus placebo to assess effects on mortality, HF rehospitalization, and 6-month change in NT-ProBNP. Although the trial showed no clinical benefit of liraglutide, the trial population was highly enriched for individuals with T2DM. Sixty metabolites were quantified via mass spectrometry in plasma from 254 FIGHT participants (N = 147 (57.9%) with T2DM). Principal components analysis reduced the high number of correlated metabolites into uncorrelated factors. The association of factor levels with 90-day changes in 6-min walk distance (6MWD) and NT-proBNP, and with time to mortality or HF hospitalization were evaluated. There were no changes in metabolite factors according to treatment assignment. However, in analyses stratified by T2DM status, changes in five plasma metabolite factors correlated with changes in functional outcomes beyond adjustment: factor 2 (branched-chain amino acids [BCAA]) correlated with changes in NT-proBNP (ρ = - 0.291, p = 4 × 10-4) and 6MWD (ρ= 0.265, p = 0.011); factor 1 (medium-chain acylcarnitines; ρ = 0.220, p = 0.008), factor 4 (long-chain dicarboxylacylcarnitines; ρ = 0.191, p = 0.019), factor 5 (long-chain acylcarnitines; ρ = 0.198, p = 0.017), and factor 8 (urea cycle metabolites; ρ = - 0.239, p = 4 × 10-3), correlated with change in NT-proBNP. Factor 4 was associated with time-to-event (HR = 1.513 [95% CI 1.208-1.896], p = 3 × 10-4) with a trend towards stronger prognostic effect in T2DM (T2DM: p = 1 × 10-3, non-T2DM: p = 0.1). We identified metabolites of BCAA, urea cycle and fatty acid metabolism as biomarkers of HFrEF outcomes, with observed differences in HFrEF patients with T2DM. Such biomarkers might enable future diagnostic or therapeutic interventions in individuals with HFrEF and T2DM.Trial Registration: Clinicaltrials.gov. Identifier: NCT01800968. First posted: February 28, 2013.


Genetic variants of dipeptidyl peptidase IV are linked to the clinicopathologic development of prostate cancer.
CD26/dipeptidyl peptidase IV (DPP4) is a multifunctional cell-surface glycoprotein widely found in many cell types, and a soluble form is present in body fluids. There is longstanding evidence indicating a tumour-promoting or -suppressive role of DPP4 in different cancer types. However, studies focusing on the impacts of genetic variants of DPP4 on cancers are very rare. Herein, we conducted a case-control study to evaluate whether single-nucleotide polymorphisms (SNPs) of DPP4 were associated with the risk or clinicopathologic development of prostate cancer (PCa). We genotyped four loci of DPP4 SNPs, including rs7608798 (A/G), rs3788979 (C/T), rs2268889 (T/C) and rs6741949 (G/C), using a TaqMan allelic discrimination assay in 704 PCa patients and 704 healthy controls. Our results showed that PCa patients with the DPP4 rs7608798 AG+GG genotype or rs2268889 TC+CC genotype had a higher risk of developing an advanced clinical primary tumour (cT) stage (adjusted odds ratio (AOR): 1.680, 95% confidence interval (CI): 1.062-2.659, p = 0.025; AOR: 1.693, 95% CI: 1.092-2.624, p = 0.018). Additionally, in The Cancer Genome Atlas (TCGA) database, we observed that lower DPP4 expression levels were correlated with higher Gleason scores, advanced cT and pathological stages, tumour metastasis, and shorter progression-free survival rates in PCa patients. Furthermore, overexpression of DPP4 suppressed migration/invasion of metastatic PC3 PCa cells. Our findings suggest that DPP4 levels may affect the progression of PCa, and the DPP4 rs7608798 and rs2268889 SNPs are associated with the clinicopathologic development of PCa in a Taiwanese population.


Association between air pollutants and initiation of biological therapy in patients with ankylosing spondylitis: a nationwide, population-based, nested case-control study.
Outdoor air pollution has been found to trigger systemic inflammatory responses and aggravate the activity of certain rheumatic diseases. However, few studies have explored the influence of air pollution on the activity of ankylosing spondylitis (AS). As patients with active AS in Taiwan can be reimbursed through the National Health Insurance programme for biological therapy, we investigated the association between air pollutants and the initiation of reimbursed biologics for active AS. Since 2011, hourly concentrations of ambient air pollutants, including PM2.5, PM10, NO2, CO, SO2, and O3, have been estimated in Taiwan. Using Taiwanese National Health Insurance Research Database, we identified patients with newly diagnosed AS from 2003 to 2013. We selected 584 patients initiating biologics from 2012 to 2013 and 2336 gender-, age at biologic initiation-, year of AS diagnosis- and disease duration-matched controls. We examined the associations of biologics initiation with air pollutants exposure within 1 year prior to biologic use whilst adjusting for potential confounders, including disease duration, urbanisation level, monthly income, Charlson comorbidity index (CCI), uveitis, psoriasis and the use of medications for AS. Results are shown as adjusted odds ratio (aOR) with 95% confidence intervals (CIs). The initiation of biologics was associated with exposure to CO (per 1 ppm) (aOR, 8.57; 95% CI, 2.02-36.32) and NO2 (per 10 ppb) (aOR, 0.23; 95% CI, 0.11-0.50). Other independent predictors included disease duration (incremental year, aOR, 8.95), CCI (aOR, 1.31), psoriasis (aOR, 25.19), use of non-steroidal anti-inflammatory drugs (aOR, 23.66), methotrexate use (aOR, 4.50; 95% CI, 2.93-7.00), sulfasalazine use (aOR, 12.16; 95% CI, 8.98-15.45) and prednisolone equivalent dosages (mg/day, aOR, 1.12). This nationwide, population-based study revealed the initiation of reimbursed biologics was positively associated with CO levels, but negatively associated with NO2 levels. Major limitations included lack of information on individual smoking status and multicollinearity amongst air pollutants.


Silicone augmentation of the enophthalmic socket. A 14 year review.
We injected Silastic RTV S-5392 to increase the obrital volume in 25 enophthalmic patients with enophthalmus. Once the technique had been perfected, the complication rate was nil. Seven patients examined 12-14 years later had no later complications and uniformly satisfactory results.


Circulating extracellular vesicles from patients with traumatic brain injury induce cerebrovascular endothelial dysfunction.
Endothelial dysfunction is a key proponent of pathophysiological process of traumatic brain injury (TBI). We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. However, the molecular mechanisms of this EV-induced endothelial dysfunction (endotheliopathy) remain unclear. Here, we enriched plasma EVs from TBI patients (TEVs), and detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs and the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models. We found that TEVs induced dysfunction of cultured human umbilical vein endothelial cells and mediated endothelial dysfunction in both normal and TBI mice, which were propagated through the HMGB1-activated receptor for advanced glycation end products (RAGE)/Cathepsin B signaling, and the resultant NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and canonical caspase-1/gasdermin D (GSDMD)-dependent pyroptosis. Finally, von Willebrand factor (VWF) was detected on the surface of 77.01 ± 7.51% of HMGB1+TEVs. The TEV-mediated endotheliopathy was reversed by a polyclonal VWF antibody, indicating that VWF might serve a coupling factor that tethered TEVs to ECs, thus facilitating HMGB1-induced endotheliopathy. These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction and contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for the development of potential therapeutic targets and diagnostic biomarkers for TBI.


Transforaminal endoscopic lumbar discectomy with targeted puncture and foraminotomy for very highly migrated disc herniation: A technique note with case series.
Transforaminal endoscopic lumbar discectomy (TELD) has been widely used for lumbar disc herniation. However, in some challenging cases such as very highly migrated disc herniation (VHMDH), traditional TELD is difficult to access the pathology. From January 2016 to December 2019, 63 patients with single-level VHMDH underwent TELD using targeted puncture and foraminotomy techniques were included. All patients were followed up for 26.5 months on average (range, 24-48 months). Operative time, length of hospital stay, visual analog scale (VAS) score, Oswestry Disability Index (ODI), modified MacNab criteria and surgical complications were evaluated. The operative time was 40-120 min (56.8 on average). The length of hospitalization was 2.5 days (range, 2-4 d). VAS score decreased significantly from 5.5 ± 1.3 preoperatively to 1.9 ± 1.30 (p < 0.001) 1 day postoperatively, and to 0.9 ± 0.8 (p < 0.001) at the final follow-up. ODI score improved significantly from 23.5 ± 3.2 preoperatively to 13.4 ± 3.0 (p < 0.001) 1 day postoperatively; and 3.1 ± 1.2 (p < 0.001) at the final follow-up. According to the modified MacNab criteria, 40 patients (63.5%) showed excellent results, 20 patients (31.7%) were rated as good, 2 patients (3.2%) were rated as fine, and 1 patient (1.6%) was rated as bad at the final follow-up. No residual fragments, nerve root or cauda equina injury was shown in this series. One recurrent case was resolved by open surgery. With modified targeted puncture and foraminotomy techniques, VHMDH can be accessed safely and effectively, and satisfactory clinical outcomes can be obtained for these patients.


Cell volume homeostasis: ionic and nonionic mechanisms. The sodium pump in the emergence of animal cells.
Plant cells and bacterial cells are surrounded by a massive polysaccharide wall, which constrains their high internal osmotic pressure (tens of atmospheres). Animal cells, in contrast, are in osmotic equilibrium with their environment, have no restraining surround, and can take on a variety of shapes and can change these from moment to moment. This osmotic balance is achieved, in the first place, by the action of the energy-consuming sodium pump, one of the P-type ATPase transport protein family, members of which are found also in bacteria. The pump's action brings about a transmembranal electrochemical gradient of sodium ions, harnessed in a range of transport systems which couple the dissipation of this gradient to establishing a gradient of the coupled substrate. These transport systems include many which are responsible for short-term regulation of the cell's volume in response to acute changes of their osmotic balance. Thus, the primary role of the sodium pump as a regulator of cell volume has been built upon to provide the basis for an enormous variety of physiological functions.


Possible contribution of C-reactive protein within coronary plaque to increasing its own plasma levels across coronary circulation.
C-reactive protein (CRP) mRNA was detected in coronary plaque. Plasma CRP levels across the coronary circulation were increased much more in patients with unstable angina pectoris and somewhat more in those with stable angina pectoris compared with controls whose coronary arteries were angiographically normal. Thus, CRP within coronary plaque might contribute to increased plasma CRP levels across coronary circulation, particularly among patients with unstable angina pectoris.


Schizophrenia, Bipolar Disorder, and Alzheimer's Disease are not Causal Factors of Bone Mineral Density: A Mendelian Randomization Analysis.
Until recently, it remains unclear whether schizophrenia, bipolar disorder (BD), and Alzheimer's disease (AD) is associated with bone mineral density (BMD). We aimed to investigate the causal effects of schizophrenia, BD and AD on BMD with Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms (SNPs) strongly associated with these three neuropsychiatric diseases as instrumental variables were selected from genome-wide association studies in the MR Base database. We analyzed the effects of these SNPs on the femoral neck BMD (FN-BMD), lumbar spine BMD (LS-BMD) and forearm BMD (FA-BMD), and evaluated the heterogeneities and pleiotropy of these genetic variants. We also evaluated the potential confounding factors in the association between these three neuropsychiatric diseases and the BMD level. It was found that none of these genetic variants were significantly associated with BMD or confounding factors. Using these genetic variants, we did not find statistically significant causal effects of per unit increase in the log-odds of having schizophrenia, BD or AD with FN-BMD, LS-BMD and FA-BMD changes (e.g. schizophrenia and FN-BMD, MR-Egger OR 0.9673, 95% CI 0.8382 to 1.1163, p = 0.6519). The MR results also revealed that directional pleiotropy was unlikely to bias the causality (e.g., schizophrenia and FN-BMD, intercept = 0.0023, p = 0.6887), and no evidence of heterogeneity was found between the genetic variants (e.g., schizophrenia and FN-BMD, MR-Egger Q = 46.1502, I2 = 0.0899, p = 0.3047). Our MR study did not support causal effects of increased risk of schizophrenia, BD and AD status with BMD level.


Exosomal circ_DLGAP4 promotes diabetic kidney disease progression by sponging miR-143 and targeting ERBB3/NF-κB/MMP-2 axis.
Diabetic kidney disease (DKD) is closely associated with the high risk of cardiovascular disease and mortality. Exosomal circRNAs can exert significant roles in the pathology of various diseases. Nevertheless, the role of exosomal circRNAs in DKD progression remains barely known. Circular RNA DLGAP4 has been reported to be in involved in acute ischemic stroke. In our study, we found exosomal circ_DLGAP4 was increased in the exosomes isolated from HG-treated mesangial cells (MCs), DKD patients, and DKD rat models compared with the corresponding normal subjects. Then, we observed that exo-circ_DLGAP4 significantly promoted proliferation and fibrosis of MCs cells. Moreover, to study the underlying mechanism of circ_DLGAP4 in regulating DKD, bioinformatics method was consulted and miR-143 was predicted as its target. The direct correlation between miR-143 and circ_DLGAP4 was validated in MCs. MCs proliferation and fibrosis were increased by circ_DLGAP4, which could be decreased by mimic-miR-143. Next, elevated expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) is involved in various diseases. However, the function of ERBB3 in DKD development remains poorly known. Next, ERBB3 was predicted as the downstream target for miR-143. It was displayed that circ_DLGAP4 promoted proliferation and fibrosis of MCs by sponging miR-143 and regulating ERBB3/NF-κB/MMP-2 axis. Meanwhile, the loss of exo-circ_DLGAP4 induced miR-143 and repressed ERBB3/NF-κB/MMP-2 expression in MCs. Subsequently, in vivo assays were performed and it was proved that overexpression of circ_DLGAP4 markedly promoted DKD progression in vivo via modulating miR-143/ERBB3/NF-κB/MMP-2. In conclusion, we indicated that exosomal circ_DLGAP4 could prove a novel insight for DKD development.


Ingestible sensors correlate closely with peripheral temperature measurements in febrile patients.
Reliable non-invasive methods for measuring body temperature are essential for the diagnosis and monitoring of infectious disease. This study used Intraclass Correlation Coefficients (ICC) and the Bland- Altman plot to analyse the agreement between temperature measurements using an ingestible capsule sensor, a skin sensor and two non-invasive peripheral temperature measurements (axillary and infrared non-contact), collected from a population of febrile patient admitted for infectious disease. Of the 77 febrile patients screened, 26 patients were enrolled. The ICC between axillary temperature measurements (Taxi) vs. non-contact measurements (Tno-c) were 0.34 [-0.18; 0.63], 0.87 [0.55; 0.94] between Taxi vs. ingestible capsule measurements (Tcap) and 0.12 [-0.09; 0.37] between Taxi vs. Tetac. The mean difference between Taxi vs Tno-c was -1.18 °C with limits of agreement (LoA) from -2.96 to 0.58 °C. The mean difference between Taxi vs Tcap was 0.48 °C, with LoA from -0.60 to 1.56 °C. The mean difference between Taxi vs Tetac was -4.23 °C with LoA from -7.22 to -1.23 °C. Ingestible capsule measurements are reliable enough to adequately estimate the core body temperature in clinical practice. Its non-invasiveness, and the real-time remote control offer new opportunities for future research into fever during infectious diseases.


Liquid chromatographic methods coupled to chemometrics: a short review to present the key workflow for the investigation of wine phenolic composition as it is affected by environmental factors.
The guarantee of wine authenticity arises great concern because of its nutritional and economic importance. Phenolic fingerprints have been used as a source of chemical information for various authentication issues, including botanical and geographical origin, as well as vintage age. The local environment affects wine production and especially its phenolic metabolites. Integrated analytical methodologies combined with chemometrics can be applied in wine fingerprinting studies for the determination and establishment of phenolic markers that contain comprehensive and standardized information about the wine profile and how it can be affected by various environmental factors. This review summarizes all the recent trends in the generation of chemometric models that have been developed for treating chromatographic data and have been used for the investigation of critical wine authenticity issues, revealing phenolic markers responsible for the botanical, geographical, and vintage age classification of wines. Overall, the current review suggests that chromatographic methodologies are promising and powerful techniques that can be used for the accurate determination of phenolic compounds in difficult matrices like wine, highlighting the advantages of the applications of supervised chemometric tools over unsupervised for the construction of prediction models that have been successfully used for the classification based on their territorial and botanical origin.


Validity of self-reported sunscreen use by parents, children, and lifeguards.
Verbal self-report is the method most often used to assess sunscreen use, but the data may be confounded by recall error and social desirability. Sunscreen swabbing is a non-invasive procedure to objectively assess the presence of sunscreen on the skin. This study examined the agreement between verbal reports of sunscreen use from survey and diary measures and objectively measured sunscreen use. Participants were 564 parents, children aged 5-10 years, and lifeguards at 16 swimming pools in four regions of the U.S. Participants completed self-reported measures, including baseline and final surveys, as well as a 4-day diary and objective swabbing measures of sunscreen presence on 2 separate days. Data were collected in 2006 and analyzed in 2006-2007. Levels of sunscreen use were relatively high based on surveys (65.7%); diary data (40.3%); and swabbing measures (59.1%). Agreement between swabbing and diary measures of sunscreen use was fair to good, with kappa statistics for children at 0.40, followed by lifeguards at 0.34 and parents at 0.27. Validity coefficients across measures of sunscreen use were higher for lifeguards and parents than for children, and diary measures were higher than surveys. No systematic errors were found across groups or by gender, latitude, study arm, or risk category. These findings are comparable to those in other validation studies, including studies of the validity of dietary assessments. Self-reported estimates of sunscreen use by diaries or surveys appear to be as good as objective measures.


Mechanistic targets for the ablation of atrial fibrillation.
The mechanisms responsible for sustaining atrial fibrillation are a key debate in cardiovascular pathophysiology, and directly influence the approach to therapy including ablation Clinical and basic studies have split AF mechanisms into two basic camps: 'spatially distributed disorganization' and 'localized sources'. Recent data suggest that these mechanisms can also be separated by the method for mapping - with nearly all traditional electrogram analyses showing spatially distributed disorganization and nearly all optical mapping studies showing localized sources We will review this dichotomy in light of these recently identified differences in mapping, and in the context of recent clinical studies in which localized ablation has been shown to impact AF, also lending support to the localized source hypothesis. We will conclude with other concepts on mechanism-based ablation and areas of ongoing research that must be addressed to continue improving our knowledge and treatment of AF.


Self-perceived health space and geographic areas in Switzerland.
Self-perceived health is an important characteristic for the investigation of public health questions. Based on health characteristics from the 1997 Swiss Health Survey, the relationship between health perception and geographic areas in Switzerland was analysed. Using an explorative data analysis, categorical principal component analysis, a two-dimensional 'health space' was created, using 16 items of self-reported health. The first dimension of this health space represents 'general health', the second dimension contrasts 'mental and physical symptoms'. Into this health space, five different Swiss area typologies were projected. The area types showed distinct 'localities' within the health space, which vary with regard to the magnitude of age and gender differentiation. This type of visualising or 'mapping' of area types within health space has not previously been conducted.


C-terminal deletion mutant p21(WAF1/CIP1) enhances E2F-1-mediated apoptosis in colon adenocarcinoma cells.
The present study was designed to investigate the efficacy of combination gene therapy using adenoviral vectors expressing gene products shown to possess apoptotic activity: E2F-1 (Ad-E2F-1) and a C-terminal deletion mutant of p21(WAF1/cIP1) (Ad-p21(-PCNA)), on growth inhibition and apoptosis of human colon cancer cells in vitro and in vivo. Marked E2F-1 and p21(-PCNA) overexpression in response to adenovirus infection was evident by Western blot analysis. IC(25) concentrations of each virus were used for each treatment in vitro to detect cooperative effects on cell death. Coexpression of E2F-1 and p21(-PCNA) resulted in an additive effect on cell death compared to infection with either virus alone. Cell cycle analysis, poly(ADP-ribose) polymerase (PARP) cleavage and analysis of cell morphology also revealed that coinfection with both Ad-E2F-1 and Ad-p21(-PCNA) enhanced cellular apoptosis compared to either virus alone. Interestingly, E2F-1 protein expression was markedly enhanced in the E2F-1/p21(-PCNA) adenovirus combination compared to Ad-E2F-1 infection alone. However, these same effects were not evident in cells coinfected with Ad-E2F-1 and an adenovirus expressing wild-type human p21(WAF1/CIP1) (Ad-p21(WT)). The increase in E2F-1 expression with coexpression of E2F-1 and p21(-PCNA) was not a result of increased E2F-1 protein stability, but was related to increased transcriptional activity from the CMV promoter. Cell cycle analysis revealed G1 arrest 72 hours following single-gene therapy with either the wild-type or mutant p21, whereas increased accumulation of cells in G2/M phase was demonstrated in the E2F-1-overexpressing cells. In the combined therapies, E2F-1/p21(-PCNA) treatment still resulted in G1 arrest, but E2F-1 was able to counteract the G1 arrest when coinfected with p21(WT). These results provide further evidence of the importance of the p21:PCNA-binding domain in mediating the complex cell cycle interaction between E2F-1 and p21. Simultaneous intratumoral injection of Ad-E2F-1 and Ad-p21(-PCNA) dramatically reduced tumor burden of SW620 xenografts compared to either treatment alone in our in vivo model but not in HT-29 colon cancer xenografts. When combined with Ad-p21(-PCNA), E2F-1 adenovirus therapy resulted in approximately 95% decrease in tumor volume of SW620 tumor xenografts compared with controls (P<.05). In conclusion, although simultaneous delivery of E2F-1 and p21(-PCNA) transgenes results in increased E2F-1 expression and enhanced apoptosis of both SW620 and HT-29 colon cancer cells in vitro, this combination was only effective in the treatment of SW620 metastatic colon cancer in vivo. This may represent a potentially useful combination gene therapy strategy for metastatic colon cancer.


Association between high-risk human papillomavirus DNA load and precursor lesions of cervical cancer in Mexican women.
Our objective was to determine the association between viral load of high risk human papilloma virus (HPV) using the Hybrid Capture II (HC II) system and cervical intraepithelial neoplasia (CIN) lesion stage. A total of 182 consecutive women with confirmed diagnoses of CIN 1-3 and 182 healthy women with negative Pap were included. All subjects underwent structured interviews focused on socioeconomic and reproductive factors. HC II testing was used to detect human papilloma virus (HPV) DNA. Viral load was measured by light measurements expressed as relative lights unit (RLU) ratio (specimens/control). Log(10)RLU ratios were categorized for analysis into four groups: negative (</=0); low viral load (0.01-1.0), middle viral load (1.01-2.0), and high viral load (2.0-3.6). Frequencies and association measurement odds ratio (OR) adjusted by unconditional multinomial regression (UMR) were used in analysis. A total of 75 of 80 (93.7%) patients with CIN 2-3, 82 of 101 (79.4%) with CIN 1, and 36 of 182 (19.8%) controls were positive for HPV DNA. The higher the viral load of HPV DNA infection observed, the higher the probability of being associated with stage of CIN (P <0.001). Association between low viral load HPV and CIN 1 was 16.8 (7.2-39) compared with the highest association observed with high viral load and CIN 2-3 (OR(a) = 365.8, 94.7-1412). Both control and cases in the oldest women presented the highest viral load. We found high frequencies of HPV DNA in CIN 1 and in CIN 2-3 patients. A clear association between viral load of HPV DNA was determined by HC II assay and CIN stage.


Recognition of animal faces is impaired in developmental prosopagnosia.
An on-going debate in psychology and neuroscience concerns the way faces and objects are represented. Domain-specific theories suggest that faces are processed via a specialised mechanism, separate from objects. Developmental prosopagnosia (DP) is a neurodevelopmental disorder in which there is a deficit in the ability to recognize conspecific (human) faces. It is unclear, however, whether prosopagnosia also affects recognition of heterospecific (animal) faces. To address this question, we compared recognition performance with human and animal faces in neurotypical controls and participants with DP. We found that DPs showed deficits in the recognition of both human and animal faces compared to neurotypical controls. In contrast to, we found no group-level deficit in the recognition of animate or inanimate non-face objects in DPs. Using an individual-level approach, we demonstrate that in 60% of cases in which face recognition is impaired, there is a concurrent deficit with animal faces. Together, these results show that DPs have a general deficit in the recognition of faces that encompass a range of configural and morphological structures.


Clinical and prognostic characteristics of 158 cases of relapsing polychondritis in China and review of the literature.
This work is aimed to study the clinical and prognostic features of relapsing polychondritis (RP) in China. A total of 158 RP cases from 1985 to 2013 in China were included and compared with international case series in terms of clinical features, systemic involvement, differential diagnosis and prognosis. (1) The average age at the onset was 45.3 years old, the average age for initial symptoms was 14.4 months, female/male ratio was 0.7:1 and misdiagnosis rate was 47 %. (2) The incidence of arthritis was lower than that in Caucasians. The incidences of auricular chondritis (68 %: 84-95 %), ocular inflammation (44 %: 49-65 %) and renal involvement (3 %: 7-26 %) were lower, and laryngotracheal symptoms (69 %: 31-67 %), skin (46 %: 4-38 %) and neurological involvement (12 %: 2-8 %) were higher during the follow-up period. The proportion of associated autoimmune disease and systemic vasculitis were 5 and 3 %, respectively, similar to that in Japanese (4 and 2 %), but less than that in Caucasians (12-31 and 8-18 %) except the Francès's study (7 and 3 %). The primary death cause is respiratory failure due to RP, followed by lung infections and cardiovascular events. (3) Juvenile RP (onset ≤18 years) was more severe than adults, similar to results from the Caucasians. However, Chinese juvenile RP had more severe ocular inflammation (57 %: 40-47 %), arthritis (100 %: 71-90 %), cardiovascular (14 %: 3-10 %) and skin involvement (20 %: 10-11 %) than Caucasian juvenile RP. Although sharing most of the clinical features with case series in previous literature, Chinese patients with RP have its unique characteristics.


Cytological analysis and sorting of a human supernumerary minichromosome.
In a newborn female, an abnormal karyotype, 46,XX/47,XX,+mar/47,XX,+9, was found associated with several malformations. The marker chromosome was present in 70% of peripheral blood lymphocytes, and its size appeared to be less than half of the smallest chromosomes. Several differential staining methods provided no indication as to its origin.Chromosomes isolated from EBV-immortalized lymphocytes of the patient were fractionated on a FACS-440. The marker was resolved as a sharp peak in the region close to the chromosomal debris: its DNA content seemed to be close to 40% of chromosomes 21 and 22.About 580000 minichromosomes were sorted. In order to optimize cloning conditions, a pilot cloning experiment was performed on a pool of sorted chromosomes 9, 10, 11 and 12.


Physical mapping of ribosomal DNA sites in Festuca arundinacea and related species by in situ hybridization.
The positions of the 18S-5.8S-26S and 5S rRNA genes have been physically mapped on the chromosomes of diploid, tetraploid, and hexaploid Festuca species by in situ hybridization. The number and position of the rDNA sites in the species were compared. The results confirm some of the earlier phylogenetic studies of these species but suggest that some structural rearrangements have occurred and that sites have been lost during polyploidization. Festuca, in situ hybridization, phylogeny, physical mapping, rDNA.


[Use of fibrin glue in microsurgery of the ear. An analysis of operations at the Pisa ENT Clinic].
The authors report the indications for and methods of application of fibrin glue in reconstructive microsurgery of the middle ear. On the basis of 180 interventions, they describe in detail the use of fibrin glue in myringo- and tympanoplasty for correct fixing of grafts. Furthermore, they illustrate the particular use of fibrin glue in reconstruction of the incudostapedial joint, in covering eroded areas of the lateral semicircular canal and in one case of perilymph gusher.


The cost of waiting and the death toll in Italy during the first wave of the covid-19 pandemic.
This paper documents how a prompter implementation of stricter policy measures in Italy would have reduced by about one-fourth of total COVID-19-related deaths during the first wave of the pandemic. The empirical evidence suggests that rigid but timely restrictions would have been a more effective policy tool than implementing progressively stricter measures over an extended period.


Comparison of different hepatocyte cell lines for use in a hybrid artificial liver model.
Selection of a cell line suitable for a hybrid artificial liver model employing cellulose porous beads (CPBs) was investigated. Hep G2 cells grown in a culture dish exhibited appreciably higher ureogenesis and gluconeogenesis activities than those grown in CPBs. SEM observation of CPBs revealed marked difference in the distribution of attached cells from one bead to another, and showed that almost all the cell-bearing micropores were completely packed with cells.With the aim of selecting a cell line not prone to excessive aggregation and which grows moderately so as not to fill up the micropores, cells of 6 cell lines, HLE, HLF, Hep 3B, PLC/PRF/5, Huh 7 and Hep G2, were cultivated in dishes. Hep G2, HLE, and HLF increased to 5 × 10(5) cells/cm(2), whereas PLC/PRF/5 grew only to 5 × 10(4), and Hep 3B and Huh 7 up to 2 × 10(4) cells/cm(2). The specific activities of ureogenesis and gluconeogenesis of Huh 7 were the highest among the lines tested - 42- and 7-fold those of Hep G2, respectively. When the 6 cell lines were grown in a submerged culture with 0.6 g/l of CPBs, Huh 7 had the lowest cell concentration of 0.54 × 10(6) cells/ml, and the highest activities of ammonia consumption and urea and glucose production (1.38 μ mol NH(3), 99 nmol urea, and 14.5 nmol glucose/10(6)cells/h). Consequently, Huh 7 is considered to be a suitable cell line for use in the development of an artificial liver model employing porous beads.


A collaborative model of integrative care: Synergy between Anthroposophic music therapy, acupuncture, and spiritual care in two patients with breast cancer.
Complementary/integrative medicine (CIM) has been shown to play an important role in supportive cancer care, relieving symptoms and improving quality of life among oncology patients. Communication between CIM practitioners and oncology healthcare professionals has been researched in depth, while little attention has been paid to the interaction between CIM practitioners from different disciplines who work together in the integrative oncology setting. The present paper explores the interaction between an Anthroposophic music therapist and a spiritual care provider who co-treated two female patients with breast cancer undergoing chemotherapy. The joint CIM treatments took place in an Integrative Oncology service in northern Israel, and the collaboration between the two practitioners resulted in a synergistic therapeutic process, promoting the patients' wellbeing and facilitating spiritual growth. There is a need to further explore therapeutic interactions between CIM therapists from different disciplines, who often work together in the integrative oncology setting. Collaboration between different CIM disciplines can lead to a synergy which goes beyond an additive effect of the individual therapies.


Generation of reactive oxygen metabolites by the haemocytes of the mussel Mytilus edulis.
Generation of superoxide anion by stimulated haemocytes of Mytilus edulis was demonstrated using dihydrorhodamine 123 and quantified using reduction of nitroblue tetrazolium (NBT). In the presence of zymosan or phorbol myristate acetate, there was an increased reduction of NBT to formazan. The addition of superoxide dismutase (SOD) and iodoacetamide to the incubation medium resulted in a significant reduction in deposition of reduced formazan. Incubation of haemocytes with the SOD inhibitor diethyldithiocarbamate (DDC) gave rise to a small but significant increase in NBT reduction. The production of hydrogen peroxide by haemocytes was quantified using horseradish peroxidase-dependent oxidation of phenol red. The presence of SOD in the incubation medium together with zymosan resulted in a significant increase in H2O2 production. Haemocytes incubated with DDC prior to the assay or with sodium nitroprusside during the assay showed a decrease in H2O2 production with increasing concentration of the inhibitor.


Sagittal craniostenosis, congenital heart disease, mental deficiency and various dysmorphies in two sibs--a "new" syndrome?
This is a report on two mentally retarded sibs with similar anomalies (sagittal craniosynostosis, complex cardiovascular malformations, mandibular ankylosis) and various dysmorphic features. They could represent a "new" probably monogenic syndrome.


A functional and biochemical analysis of bovine class II MHC antigens using monoclonal antibodies.
Monoclonal antibodies (MAbs) reacting with bovine (2) ovine (3), murine (1) or human (1) Class II MHC antigens were examined for reactivity with bovine peripheral blood leucocytes (PBL) and lymph node cells (LNC) by immunofluorescence, immunoprecipitation and the capacity to inhibit mixed lymphocyte responses (MLR), lectin- and antigen-induced blastogenesis. The 6 MAbs identified comparable percentages of Class II positive lymphocytes in PBL (40.8 to 54.2%) and LNC (6 to 11.5%) regardless of BoLA-A phenotype. Immunohistological staining of Class II MAb was localized principally to the lymphoid follicles in lymph nodes and to isolated epithelial reticular cells in the thymus. The anti-Class II MAb immunoprecipitated alpha- and beta- chains of 26-29K and 32-34K, respectively. These MAb inhibited proliferative responses in the MLR by between 25 and 74%, and diminished blastogenesis induced by specific antigens (purified protein derivative + PPD and ovalbumin) and B-lymphocyte mitogens (PPD, lipopolysaccharide and dextran sulphate) by between 45 and 75%, regardless of BoLA-A phenotype. In contrast, proliferation in response to concanavalin A and phytohaemagglutinin were unaffected by the anti- Class II MAb. Similarly these MAb did not affect lysis by cytotoxic T-lymphocytes, the activity of which was depressed by anti-Class I MAbs and monospecific alloantisera.


Investigation on abnormal gene loci of a Chinese pedigree with hereditary combined deficiency of blood coagulation factor XI, XII, and protein S.
In order to clarify the interaction mechanism, the phenotype and abnormal gene loci of FXI, FXII, and PS were investigated in this study. Chinese pedigree with hereditary combined deficiency of coagulation factor (F) XI, FXII, and PS was enrolled in our study. Activated partial thromboplastin time (APTT), partial thromboplastin time (PT), FXI:C, FXII:C, and protein S (PS):C were determined using the one-stage coagulation method. FXI:antigen (Ag), FXII:Ag, and PS:Ag were detected using enzyme-linked immunosorbent assay (ELISA). Exons and introns of the FXI, FXII, and PS genes were amplified by polymerase chain reaction (PCR), and gene sequencing results were analyzed using Chromas software. A deletion of two bases located in introns A-149 and-150 within the FXI gene of the proband, his father, wife, and both sons. A missense variant in exon 14 (GGT → AGT, Gly542Ser) within FXII of the proband, his parents, and both sons. Four variants in exon 4 within the PS gene of all members of the pedigree: GTT → GTG (Val46Val), CGC → CTC (Arg49Leu), CGT → CAT (Arg60His), and CAG → TAG (Gln61stop). None of the pedigree members showed a tendency for bleeding or thrombosis. Therefore, we speculated that the lack of coagulation factors counteracted the lack of PS, restoring the balance between the coagulation and anticoagulation systems. Another possible explanation is that these defects individually have only partial penetrance.


Effects of a phorbol ester on cell proliferation, cytoskeleton and chromosomes in 3T3 T proadipocytes.
Tumour-promoting 12-0-tetradecanoylphorbol-13-acetate (TPA) showed a biphasic effect on cell proliferation of BALB/3T3 T proadipocytes. TPA (100 ng/ml) inhibited cell proliferation after 6-18 h of treatment but stimulated it during the next 3 d. Cultures treated with TPA for 24 d showed a 3.3 times higher saturation density compared with those without TPA treatment. TPA-induced morphological alterations were studied by immunofluorescence and scanning electronmicroscopy. In addition, detergent-extracted whole mount cell observations were carried out with or without immuno-electronmicroscopy. The results showed that TPA induced a rapid and reversible assembly of actin filaments and redistribution of microtubules which commenced as early as 15-20 min, but did not influence the frequency of sister chromatid exchange.


Expression of VDR and CYP24A1 mRNA in human tumors.
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogues have been shown to inhibit proliferation of human cancer cells mediated by vitamin D receptor (VDR). The over-expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), an enzyme involved in the metabolism of 1,25(OH)2D3 and its analogues, is associated with poor prognosis of some human cancers. In this study, we employed real-time reverse transcription PCR to examine the expression of VDR and CYP24A1 mRNA in a cohort of human breast, lung, colon and ovary tumor samples. We found that CYP24A1 mRNA was significantly up-regulated in colon, ovary and lung tumors, but down-regulated in breast tumor relative to the analogous normal tissues. As a comparison, VDR mRNA was modestly down-regulated in colon, breast and lung tumors, but highly up-regulated in ovarian tumors. Treatment of two breast cancer cell lines, SW-620 and MCF-7, and one colon cancer cell line, HT-29, by 1,25(OH)2D3 for 48 h profoundly stimulated CYP24A1 mRNA expression (EC50=0.6, 0.8 and 29.5 nM in SW-620, HT-29 and MCF-7, respectively), but did not significantly affect VDR mRNA expression. Growth as assessed by DNA synthesis was modestly arrested by 1,25(OH)2D3 after 72 h of incubation, but was not altered after a 5-day incubation period. These data suggest that the VDR signaling pathway may be compromised via the modulation of CYP24A1 and VDR in human tumors.


Peroxisome proliferator-activated receptor gamma expression correlates with the differentiation level of normal, premalignant, and malignant laryngeal squamous cells.
Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been implicated in the differentiation of several cell types, such as adipocytes, monocytes, and epidermal keratinocytes. This study concentrated on PPAR gamma's potential role in the maturation process of laryngeal squamous epithelium, both normal and premalignant, as well as in the differentiation grade of squamous cell carcinomas (SCCs) of the larynx. A retrospective study. A basic research anatomy laboratory, operating within a tertiary care institution. Clinical specimens from 89 subjects with normal laryngeal epithelium and hyperplastic, dysplastic, or malignant lesions. Paraffin-section immunohistochemistry. Strength and extent of PPAR gamma presence, specified by stain intensity and ratio of stained cells, respectively. All stratified histologic categories, that is, normal mucosa, hyperplasia, and dysplasia, displayed a significant increase in PPAR gamma expression in suprabasal differentiated layers compared with basal undifferentiated ones (rho < .01). Hyperplasia and dysplasia manifested lower and higher levels of PPAR gamma, respectively, in comparison with normal epithelium. Whereas grade Pi and III SCCs were characterized by equal expression, well-differentiated tumours possessed considerably raised receptor content. Fluctuations of expression among various histologic categories lacked statistical significance, however. Our results suggest PPAR gamma induction throughout squamous cell differentiation in normal, premalignant, and malignant epithelia.


Gene Discovery for Complex Traits: Lessons from Africa.
The genetics of African populations reveals an otherwise "missing layer" of human variation that arose between 100,000 and 5 million years ago. Both the vast number of these ancient variants and the selective pressures they survived yield insights into genes responsible for complex traits in all populations.


Neurological manifestations of Behçet's disease in a Caribbean population: clinical and imaging findings.
Behçet's disease (BD) is a chronic relapsing multisystem disorder. While most frequently occurring around the Mediterranean and in Japan, isolated cases of BD have been reported in Africa south of the Sahara and in the Caribbean. The aim of this study was to describe our experience of BD in Guadeloupe (French West Indies) where the presence of the disease has not been reported previously. We analysed retrospectively the charts, and clinical and imaging features of patients native to Guadeloupe who were diagnosed with neurological manifestations of BD between 1989 and 1999. In our series of 13 cases, seven had neurological involvement. Neurological manifestations included meningoencephalitis or meningoencephalomyelitis in four cases, cerebral venous thrombosis in one case and peripheral neuropathy in two cases associated with myositis in one. Patients received treatment with colchicine (n=7), corticosteroids (n=6), immunosuppressive therapy (azathioprine and/or cyclophosphamide; n=4), acetylsalicylic acid (n=2) and oral anticoagulation for venous thrombosis (n=1). Long-term sequelae occurred only in patients with recurrent neurological disease. This study suggests that the frequency of BD in this Afro-Caribbean population is higher than this reported in Caucasian populations. Meningoencephalitis is associated with a poor prognosis while other patients achieved recovery.


Photoredox-based late-stage functionalization in SAR study for in vivo potent glucosylceramide synthase inhibitor.
Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson's Disease (PD) and lysosomal storage disorders, such as Gaucher's Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel GCS inhibitors. To further improve activity of this chemical series, SAR was investigated on the fused pyridyl ring core of 2a by employing a photoredox reaction that significantly reduced synthetic demand. Herein, we successfully applied the decarboxylation C-H alkylation photoredox reaction to introduce a wide variety of substituents at the 6-position of the fused pyridine core scaffold. This quick SAR acquisition facilitated the swift identification of the potent GCS inhibitors 2b (IC50 = 5.9 nM) and 2g (IC50 = 3.6 nM). Moreover, 2b exhibited superior in vivo potency to that of our previously reported lead compound, T-036.


Low-sample-consumption and ultrasensitive detection of procalcitonin by boronate affinity recognition-enhanced dynamic light scattering biosensor.
Accurate determination of procalcitonin (PCT) is highly crucial in bacterial infection diagnosis. Many biosensors previously developed suffer from large sample consumption or lengthy waiting time, which raise difficulties for more vulnerable patients, such as infants, old people, and other critically ill patients. To address this dilemma, we present an innovative boronate affinity recognition (BAR)-enhanced dynamic light scattering (DLS) biosensor to achieve ultrasensitive PCT detection. In this biosensing system, monoclonal antibody-modified magnetic nanoparticles (MNP@mAb) are designed as probes to capture PCT from serum samples and generate DLS signal transduction. Polyvalent phenylboronic acid-labeled bovine serum albumin (BSA@PBA) is used as scaffold to aggregate MNP@mAb and PCT (MNP@mAb-PCT) complex because of the specific interaction of cis-diol-containing PCT with boronic acid ligands on the surface of BSA@PBA. The BAR-enhanced DLS biosensor shows ultrahigh sensitivity to PCT determination due to high binding affinity, with the limit of detection of 0.03 pg/mL. The total detection time of PCT in whole blood or serum is less than 15 min with small sample consumption (about 1 μL) due to the rapid magnetic separation and aggregation of MNP@mAb-PCT triggered by BSA@PBA. In addition, the proposed DLS biosensor exhibits a high specificity for PCT quantitative detection. Therefore, this work provides a promising and versatile strategy for extending DLS biosensor to rapid and ultrasensitive detection of trace PCT for broader patients and more urgent cases.


[Sulfonyl-bis-(bromo-methyl-ene)]di-benzene.
The title compound, C14H12Br2O2S, crystallizes as the meso isomer of a diastereoisomeric pair. This structure determination was key to determining that the 1,3 elimination of bromine by tri-phenyl-phosphine occurs with inversion of the configuration at each of the two chiral carbon atoms. In the crystal, the molecules are linked by weak C-H⋯O and C-H⋯Br hydrogen bonds.


Urban vs. rural factors that affect adult asthma.
In this review, our aim was to examine the influence of geographic variations on asthma prevalence and morbidity among adults, which is important for improving our understanding, identifying the burden, and for developing and implementing interventions aimed at reducing asthma morbidity. Asthma is a complex inflammatory disease of multifactorial origin, and is influenced by both environmental and genetic factors. The disparities in asthma prevalence and morbidity among the world's geographic locations are more likely to be associated with environmental exposures than genetic differences. In writing this article, we found that the indoor factors most consistently associated with asthma and asthma-related symptoms in adults included fuel combustion, mold growth, and environmental tobacco smoke in both urban and rural areas. Asthma and asthma-related symptoms occurred more frequently in urban than in rural areas, and that difference correlated with environmental risk exposures, SES, and healthcare access. Environmental risk factors to which urban adults were more frequently exposed than rural adults were dust mites,high levels of vehicle emissions, and a westernized lifestyle.Exposure to indoor biological contaminants in the urban environment is common.The main risk factors for developing asthma in urban areas are atopy and allergy to house dust mites, followed by allergens from animal dander. House dust mite exposure may potentially explain differences in diagnosis of asthma prevalence and morbidity among adults in urban vs. rural areas. In addition, the prevalence of asthma morbidity increases with urbanization. High levels of vehicle emissions,Western lifestyles and degree of urbanization itself, may affect outdoor and thereby indoor air quality. In urban areas, biomass fuels have been widely replaced by cleaner energy sources at home, such as gas and electricity, but in most developing countries, coal is still a major source of fuel for cooking and heating, particularly in winter. Moreover, exposure to ETS is common at home or at work in urban areas.There is evidence that asthma prevalence and morbidity is less common in rural than in urban areas. The possible reasons are that rural residents are exposed early in life to stables and to farm milk production, and such exposures are protective against developing asthma morbidity. Even so, asthma morbidity is disproportionately high among poor inner-city residents and in rural populations. A higher proportion of adult residents of nonmetropolitan areas were characterized as follows:aged 55 years or older, no previous college admission, low household income, no health insurance coverage, and could not see a doctor due to healthcare service availability, etc. In rural areas, biomass fuels meet more than 70% of the rural energy needs. Progress in adopting modern energy sources in rural areas has been slow. The most direct health impact comes from household energy use among the poor, who depend almost entirely on burning biomass fuels in simple cooking devices that are placed in inadequately ventilated spaces. Prospective studies are needed to assess the long-term effects of biomass smoke on lung health among adults in rural areas.Geographic differences in asthma susceptibility exist around the world. The reason for the differences in asthma prevalence in rural and urban areas may be due to the fact that populations have different lifestyles and cultures, as well as different environmental exposures and different genetic backgrounds. Identifying geographic disparities in asthma hospitalizations is critical to implementing prevention strategies,reducing morbidity, and improving healthcare financing for clinical asthma treatment. Although evidence shows that differences in the prevalence of asthma do exist between urban and rural dwellers in many parts of the world, including in developed countries, data are inadequate to evaluate the extent to which different pollutant exposures contribute to asthma morbidity and severity of asthma between urban and rural areas.


Retracted: microRNA-495 alleviates endothelial cell inflammatory injury in coronary heart disease via blockade of the NF-κB pathway by targeting RALB.
Retraction: 'microRNA-495 alleviates endothelial cell inflammatory injury in coronary heart disease via blockade of the NF-?B pathway by targeting RALB', by Feng-Feng Lv, Zheng Lian, Li-Qiu Yan, Gang Wang, Zhe Li, J Cell Physiol.: The above article, published online on 18 August 2020 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.29679), has been retracted by agreement between the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies between results presented and experimental methods described were found. Thus, the editors consider the conclusions of this article to be invalid.


Variation of small bowel sparing with small bowel displacement system according to the physiological status of the bladder during radiotherapy for cervical cancer.
To evaluate the reproducibility of small bowel displacement system (SBDS) volumetrically using weekly CT throughout a regimen of radiotherapy for the treatment of cervical cancer. From October 2004 to January 2005, 10 consecutive patients who received pelvic radiation therapy for uterine cervical carcinoma with the SBDS were included in this study. With the patient laid prone on the conventional simulator table, the Styrofoam compression device is placed under the lower abdomen of the patient. Next, CT scan images, first two sets of without and with the SBDS, followed by with SBDS once a week for 3 weeks consecutively after the beginning of radiotherapy, were taken. Radiation planning was performed using standard pelvic box fields in 3-dimensional radiation treatment planning system. In each CT sets, we measured the identified organ volumes and the volume of small bowel irradiated in treatment portals. We used the regression analysis to know the correlation of the volume of small bowel irradiated according to the volume variation of bladder during radiotherapy. The mean small bowel volume with SBDS of 10 patients during radiotherapy was reduced by 60.5% (from 32.5% to 78.2%), comparing to the small bowel volume without SBDS. The variation of small bowel volume reduction in each patient was ranged from 7.3% to 38.5% (mean: 20.5%). In spite of using the SBDS, the volume reduction of small bowel irradiated was affected significantly by the volume of bladder during radiotherapy. The variation of small bowel irradiated for five patients who had more than 10% small bowel volume variation was significantly correlated with the volume of bladder, but not for five patients less than 10% small bowel volume variation. We confirm that in spite of the variation of bladder volume during radiotherapy, the SBDS is an effective method that can be used to displace the small bowel continuously away from the irradiated field for cervical cancer.


Higher colon cancer tumor proliferative index and lower tumor cell death rate in mice undergoing laparotomy versus insufflation.
Our laboratory has previously shown that tumors are established more easily and grow larger after laparotomy than after laparoscopy. To characterize these differences in tumor growth further, the tumor cell death rates and tumor proliferation rates were compared in vivo after full sham laparotomy versus carbon dioxide (CO2) insufflation. Female Balb/C mice (n = 36) were inoculated intradermally in the dorsal skin with 106 C-26 colon adenocarcinoma cells in 0.1 ml of culture media no more than 1 h before interventions. The mice then were randomized to one of three groups: anesthesia control, CO2 insufflation, or sham laparotomy. The anesthesia control group underwent no procedure. The insufflation group underwent CO2 pneumoperitoneum (4-6 mmHg) for 20 min via a 20-gauge angiocatheter. The laparotomy group underwent a midline incision from xiphoid to pubis, which was closed after 20 min. Tumors were excised from half the mice in each group on postoperative day 7, and from the remaining mice on postoperative day 14. Sections of tumors were made then stained separately for free 3? hydroxyl ends of genomic deoxyribonucleic acid (DNA) using fluorescein-deoxyunidine triphosphate (dUTP), and immunohistochemically for proliferating cell nuclear antigen (PCNA). Apoptosis was measured by quantitating DNA strand breaks in individual cells using fluorescence microscopy. Fluorescein-positive cells in five random high-power fields (x200) were counted in a blinded fashion. The proliferative index of each tumor was determined by averaging PCNA positive cells in five high-power fields (x450) counted in a blinded fashion with the aid of an optical grid. On postoperative day 7, there was no significant difference in the proliferative index or apoptotic rates among the three groups. On postoperative day 14, the proliferative index in the laparotomy group was significantly higher than in either the insufflation or control group (p < 0.001). The proliferative index in the insufflation group also was significantly higher than in the control group (p < 0.05). Inverse differences in apoptotic rates were found. The apoptotic rate in the laparotomy group was significantly lower than in either the insufflation (p < 0.05) or control group (p < 0.001). The apoptotic rate in the insufflation group was significantly lower than in the control group (p < 0.001). We have demonstrated that there is a significantly higher rate of tumor cell proliferation and a significantly lower rate of tumor cell death with the C-26 colon adenocarcinoma tumor line after laparotomy than after insufflation or anesthesia alone on post-operative day 14. The mechanisms of these phenomena are unclear. It appears that certain factors postoperatively stimulate tumors to proliferate at a higher rate, causing tumor cells to die at a lower rate in the laparotomy group than in the insufflation group.


Effects of different enzyme extraction methods on the properties and prebiotic activity of soybean hull polysaccharides.
In this study, five different processes, including hot water (HW-ASP), single enzyme (cellulase, pectinase and papain; C-ASP, PE-ASP, and P-ASP), and compound-enzyme (cellulose: pectinase: papain = 3:3:1; CE-ASP) for the extraction of soybean hull polysaccharides (ASPs) were employed, and the characterization and prebiotics activity of five polysaccharides were analyzed. These polysaccharides possessed different primary structural characteristics, including molecular weight distribution, monosaccharide composition, chemical composition, surface morphology, potential particle size, etc., while similar functional groups. In vitro digestibility assay indicated that C-ASP had strong resistance to gastric juice hydrolysis and α-amylase as compared with HW-ASP. Furthermore, C-ASP elevated the acidifying activity and promoted the growth of probiotics (Lactobacillus paracasei, Lactobacillus rhamnosus, and Lactobacillus acidophilus) during the fermentation (p < 0.05). C-ASP improved the levels of total short-chain fatty acids (SCFAs) and had better prebiotic activity than HW-ASP (p < 0.05). These findings denote that enzyme-assisted polysaccharides extracted from soybean hulls have the potential to be served as novel probiotics.