Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein X (SCPx). Activity measurements in liver and fibroblasts using a newly developed method.
Sterol carrier protein X (SCPx) plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids. To investigate whether patients with an unresolved defect in peroxisomal beta-oxidation are deficient for SCPx, we developed a novel and specific assay to measure the activity of SCPx in both liver and fibroblast homogenates. The substrate used in the assay, 3alpha, 7alpha,12alpha-trihydroxy-24-keto-5beta-cholestanoy l-CoA (24-keto-THC-CoA), is produced by preincubating the enoyl-CoA of the bile acid intermediate THCA with a lysate from the yeast Saccharomyces cerevisiae expressing human D-bifunctional protein. After the preincubation period, liver or fibroblast homogenate is added plus CoASH, and the production of choloyl-CoA is determined by HPLC. The specificity of the assay was demonstrated by the finding of a full deficiency in fibroblasts from an SCPx knock-out mouse. In addition to SCPx activity measurements in fibroblasts from patients with a defect in peroxisomal beta-oxidation of unresolved etiology, we studied the stability and activity of SCPx in fibroblasts from patients with Zellweger syndrome, which lack functional peroxisomes. We found that SCPx is not only stable in the cytosol, but displays a higher activity in fibroblasts from patients with Zellweger syndrome than in control fibroblasts. Furthermore, in all patients studied with a defect in peroxisomal beta-oxidation of unknown origin, SCPx was found to be normally active, indicating that human SCPx deficiency remains to be identified.


[UPLC-Q-TOF-MS/MS analysis on prototypes components and metabolites of effective fractions of Polygonum orientale flower in rat serum and urine].
Ultra performance liquid chromatography coupled with time-of-flight mass spectrometry( UPLC-Q-TOF-MS/MS) method was applied to analyze the prototypes and metabolites of the effective components of Polygonum orientale in SD rat serum and urine. The separation was performed on Agilent Eclipse Plus C_(18) column( 2. 1 mm×100 mm,1. 8 μm),with 0. 1% formic acid solution( A)-acetonitrile( B) as the mobile phase for gradient elution. Mass spectrometry data of biological samples were obtained under positive and negative electrospray ion mode. By comparing chromatogram differences between blank samples and drug treatment samples,prototype components and metabolites of the effective components of P. orientale extract were identified. The results showed that 12 metabolites were detected in serum and 26 metabolites in urine( including cross-components) of rats. The main metabolic pathways included hydrogenation,hydroxylation,glucuronidation,sulfation reaction,and methylation-glucuronidation,etc. The method established in this study was reliable and effective for studying the metabolic characteristics of the effective components of P. orientale in rats,and it can provide a reference for further studies on therapeutic material basis of this herb.


Relationships between HbA1c and continuous glucose monitoring metrics of glycaemic control and glucose variability in a large cohort of children and adolescents with type 1 diabetes.
To evaluate the relationships between HbA1c and Continuous Glucose Monitoring (CGM) metrics in children/adolescents with Type 1 Diabetes (T1D). HbA1c and real-life CGM data of the 12 weeks preceding its measurement were retrospectively collected from 654 children/adolescents with T1D. The relationships between HbA1c and CGM metrics were assessed by Spearman correlation coefficient. Participants were categorized into groups based on HbA1c and CGM metrics values. ANOVA was run across HbA1c and CGM metrics groups in the entire study population and in subjects stratified by CGM type, insulin therapy, age and puberty. HbA1c was positively correlated with mean glucose, SD, %TAR > 180 mg/dL, %TAR > 250 mg/dL, HBGI and negatively with %TIR, %TBR and %time < 54 mg/dL. HbA1c-based groups were significantly associated with these metrics, but for each group their value widely ranged with a substantial overlap between them. HbA1c and HbA1c-based groups were not associated with %CV and LBGI, as well as %CV and LBGI-based groups had not significantly different HbA1c. Comparable results were found analysing subjects according to age, type of CGM, insulin therapy and puberty. The relationships between HbA1c and CGM metrics described in this cohort of paediatric subjects with T1D support the importance of the evaluation of these metrics, in particular %CV and LBGI, independently of HbA1c value.


Total Synthesis of Gramistilbenoids A, B, and C.
Stilbenes are biologically active metabolites of plants that have the potential to attenuate a broad range of human diseases. Gramistilbenoids are a class of natural products with a stilbene skeleton, isolated from the bamboo orchid ( Arundina graminifolia), and with significant cytotoxicity against cancer cell lines (NB4, A549, SHSY5Y, PC3, and MCF7). These are the first identified naturally occurring diphenylethylenes to possess a hydroxyethyl unit. However, some of these compounds are not abundant in nature, and thus, their synthesis is advantageous. This paper reports the first synthesis of gramistilbenoids A (1), B (2), and C (3), with overall yields of 10, 2, and 8% respectively. These natural products were synthesized using key reactions, such as Horner-Wadsworth-Emmons olefination, Stille coupling, and hydroboration-oxidation.


Effect of fluoridated toothpaste on white spot lesions in postorthodontic patients.
This article illustrates a new treatment approach and evaluates the effect of use of fluoridated toothpaste on the remineralization of white spot lesions (WSLs) diagnosed at debonding. Thirty-one orthodontic patients (mean age: 19.6 years), with a minimum of four WSLs on the buccal surfaces of the maxillary and mandibular incisors, canines, premolars and first molars after orthodontic therapy, were enrolled in a double-blind, randomized, longitudinal trial lasting 8 weeks. The subjects were divided into two groups using fluoridated toothpaste (test group, n = 31) and nonfluoridated toothpaste (control group, n = 31). A custom-made mouth tray, covering the maxillary dentition, was used while brushing with the fluoridated toothpaste three times per day. Maxillary dentition acted as control and mandibular as the test. The WSLs were scored by using the International Caries Detection and Assessment System (ICDAS II) index, at baseline and 8 weeks after debonding. The ICDAS II index of the WSLs decreased in the test group in the mandibular dentition but not on the maxillary dentition during the 8-week trial (p < 0.0001). There was also a slight improvement in the control group (not significant). The frequent use of fluoridated toothpaste had a remineralizing effect on WSLs. How to cite this article: Agarwal A, Pandey H, Pandey L, Choudhary G. Effect of Fluoridated Toothpaste on White Spot Lesions in Postorthodontic Patients. Int J Clin Pediatr Dent 2013;6(2):85-88.


Usefulness of laparoscopic radiofrequency ablation of hepatocellular carcinoma.
Our intent was to evaluate whether laparoscopic radiofrequency ablation for patients with unresectable hepatocellular carcinoma and a high degree of liver damage has a role to play in the management of the disease. Laparoscopic and hand-assisted laparoscopic radiofrequency ablations were performed on five patients and the short-range outcome and complications of these patients were evaluated. The evaluation of the primary liver tumor by the radiofrequency ablation was carried out by computed tomography on the seventh day after surgery. Three patients underwent laparoscopic radiofrequency ablation, and the other two patients underwent hand-assisted laparoscopic radiofrequency ablation. The Child-Pugh status of all tumors was B status, and one patient had complications due to postoperative ascites. Laparoscopic and hand-assisted laparoscopic radiofrequency ablation with a cooled-tip electrode needle was found to be a safe and effective local treatment of hepatic focal lesions.


Relationship of dyspnea to respiratory drive and pulmonary function tests in obese patients before and after weight loss.
Dyspnea is a common complaint in obese patients, who also frequently have abnormal pulmonary function test (PFT) results without evidence of lung disease. We studied the relationship between dyspnea, PFT results, and respiratory drive in morbidly obese patients before and after weight loss. Twenty-eight obese patients underwent PFTs including spirometry, lung volume measurements, and ventilatory drive assessment using the carbon dioxide rebreathing technique. The score of the dyspnea portion of the Chronic Respiratory Disease Questionnaire (CRQ) was used to assess dyspnea. CRQ and respiratory drive measurements were repeated in 10 patients after induced weight loss by gastroplasty Mean +/- SD body mass index (BMI) prior to surgery was 47 +/- 6.5 kg/m2. Patients were then classified into two groups: group 1, mild-to-moderate dyspnea (dyspnea score > 4); and group 2, severe dyspnea (dyspnea score < 4). Group 2 had higher respiratory drive parameters and significantly lower lung volumes compared to group 1. After gastroplasty, there were significant reductions in BMI (p = 0.000), dyspnea score (p = 0.000), occlusion pressure 100 ms after the start of inspiration (P100) at end-tidal carbon dioxide (ETCO2) of 60 mmHg (p = 0.011), minute ventilation (Ve) at ETCO2 of 60 mmHg, and Ve slope (0.017). P100 slope was reduced, but it did not reach statistical significance. The degree of dyspnea commonly observed in obese patients can be explained, in part, by increased ventilatory drive and reduced static lung volumes. Gastroplasty results in a significant reduction in BMI and respiratory drive measurements as well as significant improvement in dyspnea.


Cardiac amyloidosis: the heart of the matter.
Amyloidosis comprises a unique group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in organs and tissue including the heart. Cardiac amyloidosis could be primary a part of systemic acquired amyloidosis, or a result of heredofamilial amyloidosis. Although the infiltration of the heart from different types of amyloid results in restrictive cardiomyopathy that manifests with refractory congestive heart failure and conduction abnormalities, unequivocal identification of the deposited amyloidogenic protein is mandatory in order to avoid misdiagnosis and inappropriate treatment. Recent developments in imaging techniques and extracardiac tissue biopsy have minimized the need for invasive endomyocardial biopsy for amyloidosis. Despite advances in treatment, the prognosis of a patient with amyloidosis is still poor and depends upon the underlying disease, and the type and degree of dysfunction of the involved organs. Thus, early diagnosis is mandatory because patients with advanced disease are usually too ill for intensive therapy. This review outlines current approaches to diagnosis, assessment of disease severity, and treatment of cardiac amyloidosis.


Is screening asymptomatic men who have sex with men for urethral gonorrhoea worthwhile?
We determined the prevalence of symptomatic and asymptomatic urethral gonorrhoea among men who have sex with men (MSM) at our Australian sexual health clinic. Asymptomatic MSM are screened using the Roche Amplicor((R)) PCR, whereas culture is used for symptomatic MSM. We analysed data from all MSM tested for urethral gonorrhoea from March 2006 to July 2008. Among the 4453 asymptomatic MSM, there were two (0.04%) diagnoses of urethral gonorrhoea, compared with 38 (3.13%) among 1213 symptomatic MSM. Despite a high prevalence of symptomatic infection, asymptomatic urethral gonococcal infection was extremely uncommon among MSM seen in our sexual health clinic.


Burnout, Social Comparison Orientation and the Responses to Social Comparison among Teachers in The Netherlands.
(1) Background: Teaching is a profession in which burnout constitutes a prevalent issue and provides ample opportunity to compare oneself with one's colleagues, i.e., social comparison. The purpose of this research in the Netherlands was to examine responses to social comparison, in relation to burnout, and to individual differences in social comparison orientation (SCO). (2) Methods: Study 1 employed a retrospective measure to assess responses to social comparison. In Study 2, teachers were confronted with a scenario describing either a well or a poorly functioning colleague. (3) Results: Burnout was associated with more negative responses to well and to poorly functioning colleagues, with a less positive response to well-functioning colleagues. This last effect was fully due to the degree to which one identified or contrasted oneself with this colleague. Especially among high-SCO individuals, identification with a well-functioning colleague was accompanied by a positive affect. High-burnout individuals reported more identification with poorly functioning colleagues, and more contrast and less identification with well-functioning colleagues. Responses to well-functioning colleagues were more strongly related to burnout among those high in SCO. (4) Conclusions: An especially negative affect after comparison with well-functioning colleagues is typical for individuals high in burnout, particularly among individuals with a dispositional tendency to compare themselves with others.


Simple Estimate of the Potential Drop across an Amphiprotic Liquid-Liquid Interface.
Two immiscible liquids in contact with each other can have different internal electrostatic potentials. An associated electric double layer (EDL) therefore exists within each liquid. For amphiprotic liquids, the exchange of protons between the two liquids gives rise to two EDLs, a positively charged EDL in one of the liquids and negatively charged EDL in the other. Using the pKa and pKb of one liquid dissolved in the other and the pH equivalent within each amphiprotic liquid, we can estimate the potential drop, Δφ, between the interior of the two liquids, also known as the Galvani potential or liquid-liquid junction potential. This estimation is independent of surface charge and ionic strength. By using the ionic strength to find the thickness of the EDL, we also estimate the average electric field strength across the interface. For the special case of water (H2O) in contact with an immiscible alcohol (ROH), the potential drop across the interface from the water to the alcohol is Δφ = 2.303VT (pKb + pH - pKw - pH2OR), where VT is the thermal voltage at a given temperature T.


Rare evidence for 'gnawing-like' behavior in a small-bodied theropod dinosaur.
Mammalian carnivores show a higher degree of prey bone utilization relative to non-avian theropod dinosaurs, with this major ecological difference reflected in the frequency and morphology of tooth marks in modern and Cenozoic assemblages relative to Mesozoic ones. As such, prey bone utilization (i.e., gnawing, bone-breaking, osteophagy) may represent a key ecological strategy repeatedly exploited by mammalian carnivores but rarely in theropod dinosaurs. Here we describe an isolated adult-sized hadrosaurid pedal ungual (III-4) from the Dinosaur Park Formation (Campanian) of southern Alberta which shows a unique pattern of bite marks from a small- to medium-sized theropod dinosaur. Thirteen distinct tooth marks occur in a restricted area of the ungual, and the pattern suggests up to six repeated, high-power bites delivered to the bone. The tracemaker cannot be definitively identified, but was likely a dromaeosaurid or very young tyrannosaurid. Tooth marks on at least four other Dinosaur Park Formation hadrosaur pedal unguals are reported, but the overall frequency of occurrence in unguals (< 1%) is much lower than that reported for other bones. The pattern of tooth marks on this specimen deviates from most described theropods tooth marks, and given the low volume of meat associated with the ungual, may represent theropod prey bone utilization as part of late-stage carcass consumption, and a behavior similar to mammalian gnawing.


An Injectable and Instant Self-Healing Medical Adhesive for Wound Sealing.
Designing versatile functional medical adhesives with injectability, self-healing, and strong adhesion is of great significance to achieve desirable therapeutic effects for promoting wound sealing in healthcare. Herein, a self-healing injectable adhesive is fabricated by physical interaction of polyphenol compound tannic acid (TA) and eight-arm poly(ethylene glycol) end-capped with succinimide glutarate active ester (PEG-SG). The hydrogen bonding induced from the structural unit (-CH2-CH2-O-) of PEG and catechol hydroxyl (-OH) of TA, accompanied by ester exchange between N-hydroxysuccinimide (-NHS) and amino (-NH2) of proteins, contributes to self-healing ability and rapid strong adhesion. Notably, the PEG/TA adhesive can repeatedly adhere to rigid porcine tissues, close the coronary artery under a large incision tension, and bear a heavy load of 2 kg. By exhibiting shear-thinning and anti-swelling properties, the PEG/TA adhesive can be easily applied through single-syringe extrusion onto various wounds. The single-channel toothpaste-like feature of the adhesive ensures its storage hermetically for portable usage. Moreover, in vivo operation and histological H&E staining results indicate that the PEG/TA adhesive greatly accelerates wound healing and tissue regeneration in a rat model. With the specialty of injectability, instant self-healing, and long-lasting strong adhesion to facilitate excellent therapeutic effects, the multifunctional PEG/TA adhesive may provide a new alternative for self-rescue and surgical situations.


Toxicity, preparation methods and applications of silver nanoparticles: an update.
Nanoparticles (range under 100 nm) prepared by different technology modes including physical, chemical, biological have many applications. Like in the same way silver nanoparticles are used for different beneficial actions like antimicrobial- antibacterial, antifungal and antiviral, anti-inflammatory, anticancer, water treatment, cosmetics, and in the textiles industry. As silver nanoparticles have shown wide application by different mechanisms against various pathophyisiological conditions. To maintain safety under their use, the study of the toxicity of silver nanoparticles has become more important. Health agencies like WHO, NIOSH, EPA, EFSA & EU have issued guidelines for unrisky exposure limit of silver nanopartricles in drinking water, food and breathing. The main purpose of this article is to summarize genotoxicity, cytotoxicity, neurotoxicity, reproductive toxicity of silver nanoparticles in both in vitro and in vivo studies focused on mechanism and methods of detection. The main mechanism of silver nanoparticles toxicity involves disruption of the mitochondrial respiratory chain, which results in the generation of ROS and the stoppage of ATP synthesis which further leads to a cascade of toxic events. ROS production measured by the technique like flow cytometry using DCFHDA dye and other method includes a confocal microscope, lipid peroxidation, etc. Different assay techniques used for evaluation of different kind of toxicities such as the comet assay, MTT assay, and histological assay, are also discussed.


Fabrication of polymer nanocavities with tailored openings.
A templated fabrication of open nanocavities is reported, where rational control of partial polymer attachment on sacrificial metal cores introduces openings in the polymer shells. This approach provides a facile means to modify the structural features of polymer nanocavities by manipulating the surface chemistry of colloidal nanoparticles. In particular, the anisotropic geometry of gold nanorods is exploited to promote the anisotropic polymer attachment, such that two diametric openings occurred in the polymer shell. After etching the gold nanorods, this approach yields open nanochannels that are tunable in both diameter and length. The synthetic scope of the anisotropic core/shell nanoparticles is expanded, supporting the previously proposed mechanism. We demonstrate that reducing the symmetry of nano-objects could open up new ways to create structural features using simple assembly and etching techniques. The thermostability of the open polymer nanostructures is also investigated.


Bone regeneration using an acellular extracellular matrix and bone marrow mesenchymal stem cells expressing Cbfa1.
To treat bone defects, tissue-engineering methods combine an appropriate scaffold with cells and osteogenic signals to stimulate bone repair. Mesenchymal stem cells (MSCs) derived from adult bone marrow are an ideal source of cells for tissue engineering, in particular for applications in skeletal and hard tissue repair. Core binding factor alpha1 (Cbfa1) is an essential transcription factor for osteoblast differentiation. However, the effects of Cbfa1 on MSCs in vitro and in vivo have not been well characterized. In this study, we found that MSCs modified genetically to express Cbfa1 promoted the healing of segmental defects of the radius in rabbits. First, osteogenic differentiation of MSCs transfected with an adenovirus encoding Cbfa1 was demonstrated. Expression of mRNA from a number of osteoblastic marker genes, including osteocalcin, osteopontin, and type I collagen, was detected. In addition, alkaline phosphatase activity and increased osteocalcin content were observed. The cells expressing the Cbfa1 gene were then combined with acellular bone extracellular matrix in a flow perfusion culture system. Finally, the cell-matrix constructs were implanted into radius defects in the rabbit model. After 12 weeks, radiographic, histological, and biomechanical analyses showed that MSCs modified with the Cbfa1 gene resulted in a significantly higher amount of newly-formed bone and rebuilding of the marrow cavity than control cell-matrix constructs. This study indicates that MSCs modified with the Cbfa1 gene can act as suitable seed cells for the regeneration of bone defects.


Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms.
We have obtained the complete coding sequence of the large aggregating chondroitin sulfate proteoglycan of human cartilage (aggrecan) from a combination of cDNA and genomic exon sequencing. We screened a human costal chondrocyte cDNA library, using rat aggrecan cDNA probes, and obtained three nonoverlapping clones totaling 6.2 kilobases in length. These clones were sequenced, and the sequence of the gaps between clones was obtained from genomic exon fragments and polymerase chain reaction-amplified cDNA. The composite sequence is 7137 nucleotides long, encoding 2316 amino acids. The human and rat aggrecan amino acid sequences are about 75% identical, with domains ranging from 100% to about 60% of conserved amino acids. The human sequence contains two regions of highly conserved repeats not found in rat aggrecan: 11 repeats of a hexameric sequence in the keratan sulfate attachment domain, E-E-P-(S,F)-P-S; and a 19-amino acid sequence reiterated 19 times, in the CS-1 portion of the serine-glycine-containing region. There are at least three forms of aggrecan transcripts, generated by alternative exon usage, and the form reported here is the shortest and also the most prevalent, lacking both the epidermal growth factor-like domain, and the complement regulatory protein-like sequence.


Modeling allele-specific expression at the gene and SNP levels simultaneously by a Bayesian logistic mixed regression model.
High-throughput sequencing experiments, which can determine allele origins, have been used to assess genome-wide allele-specific expression. Despite the amount of data generated from high-throughput experiments, statistical methods are often too simplistic to understand the complexity of gene expression. Specifically, existing methods do not test allele-specific expression (ASE) of a gene as a whole and variation in ASE within a gene across exons separately and simultaneously. We propose a generalized linear mixed model to close these gaps, incorporating variations due to genes, single nucleotide polymorphisms (SNPs), and biological replicates. To improve reliability of statistical inferences, we assign priors on each effect in the model so that information is shared across genes in the entire genome. We utilize Bayesian model selection to test the hypothesis of ASE for each gene and variations across SNPs within a gene. We apply our method to four tissue types in a bovine study to de novo detect ASE genes in the bovine genome, and uncover intriguing predictions of regulatory ASEs across gene exons and across tissue types. We compared our method to competing approaches through simulation studies that mimicked the real datasets. The R package, BLMRM, that implements our proposed algorithm, is publicly available for download at https://github.com/JingXieMIZZOU/BLMRM . We will show that the proposed method exhibits improved control of the false discovery rate and improved power over existing methods when SNP variation and biological variation are present. Besides, our method also maintains low computational requirements that allows for whole genome analysis.


Controlled growth of single-walled carbon nanotubes on patterned substrates.
Single-walled carbon nanotubes (SWCNTs) have attracted great interest in the last two decades because of their unique electrical, optical, thermal, mechanical properties, etc. One major research field of SWCNTs is the controlled growth of them from the patterned catalysts on substrates, since the integration of SWCNTs into nanoelectronics and other devices requires well-organized SWCNT arrays. This tutorial review describes the commonly used lithographic techniques to pattern catalysts used for controlled growth of SWCNTs, specifically confined to the horizontal direction. Advantages and disadvantages of each method will be briefly discussed. Applications of the SWCNT arrays grown from the catalyst patterns will also be introduced.


Clinical Assay for the Early Detection of Colorectal Cancer Using Mass Spectrometric Wheat Germ Agglutinin Multiple Reaction Monitoring.
Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low sensitivity in diagnosis of CRC. Therefore, our purpose is to develop a novel strategy for novel clinical biomarkers for early CRC diagnosis. We used mass spectrometry (MS) methods such as nanoLC-MS/MS, targeted LC-MS/MS, and stable isotope-labeled multiple reaction monitoring (MRM) MS coupled to test machine learning algorithms and logistic regression to analyze plasma samples from patients with early-stage CRC, late-stage CRC, and healthy controls (HCs). On the basis of our methods, 356 peptides were identified, 6 differential expressed peptides were verified, and finally three peptides corresponding wheat germ agglutinin (WGA)-captured proteins were semi-quantitated in 286 plasma samples (80 HCs and 206 CRCs). The novel peptide biomarkers combination of PF454-62, ITIH4429-438, and APOE198-207 achieved sensitivity 84.5%, specificity 97.5% and an AUC of 0.96 in CRC diagnosis. In conclusion, our study demonstrated that WGA-captured plasma PF454-62, ITIH4429-438, and APOE198-207 levels in combination may serve as highly effective early diagnostic biomarkers for patients with CRC.


Mediastinal staging of non-small cell lung carcinoma using computed and positron-emission tomography.
We evaluated the accuracy of computed tomography (CT) and positron-emission tomography (PET) in the mediastinal staging of non-small cell lung cancer. Between May 14, 1999, and November 28, 2000, computerized tomography (CT) and positron-emission tomography (PET) were used to clinically stage 94 consecutive patients with non-small cell carcinoma of the lung (NSCCL). All patients underwent subsequent surgical staging with mediastinoscopy, anterior mediastinotomy, and/or thoracotomy with mediastinal lymphadenectomy. Overall accuracy was the same for both procedures. False-negative results occurred 3 times more often with CT; false-positive results occurred twice as often with PET. Sensitivity and specificity were 64% and 94%, respectively, for CT, versus 88% and 86%, respectively, for PET. Positive and negative predictive values were 80% and 88%, respectively, for CT, versus 71% and 95%, respectively, for PET. In addition to routine use of CT, PET seems to achieve high negative predictive value in the evaluation of mediastinal disease; PET seems particularly helpful in assessing absence of tumor in bulky nodes after neoadjuvant chemotherapy and/or radiotherapy.


Risk factors for development of de novo neoplasia after liver transplantation.
Liver transplant recipients are at greater risk for de novo neoplasia, especially lymphoma and nonmelanoma skin cancer; however, risk factors for this complication have not been well studied. Clinical and pathological records of 137 consecutive liver transplant recipients who had survived for at least 1 year were reviewed to register de novo neoplasia. Ten variables were analyzed for their association with the development of de novo malignancies by means of a log-rank test and stepwise selection in a multivariate analysis using the Cox proportional hazard model. Thirty de novo neoplasias appeared in 22 of 137 transplant recipients between 12 and 104 months after orthotopic liver transplantation (OLT; median follow-up, 69 months): 14 patients had 21 skin cancers, 6 patients had solid-organ cancer, and 3 patients developed a lymphoproliferative disease. Probabilities of de novo neoplasia were 13% at 5 years post-OLT and 26% at 8 years post-OLT. The only associated risk factor for any neoplasia was age. Age and hepatocarcinoma were independent risk factors associated with skin cancer. That hepatocarcinoma in the explanted liver is an independent risk factor for skin cancer suggests there is individual susceptibility to both neoplasias.


MicroRNA-452 suppresses pancreatic cancer migration and invasion by directly targeting B-cell-specific Moloney murine leukemia virus insertion site 1.
Pancreatic cancer, one of the most common cancers globally, is the fourth most common cause of cancer-associated mortality in the USA. The 5-year relative survival rate for patients with pancreatic cancer is ~5% and the median survival time is only 6 months. The poor prognosis is mainly due to early and aggressive local invasion and metastasis, as well as dissemination of the pancreatic cancer cells. The present study demonstrated that microRNA-452 (miR-452) was markedly downregulated in pancreatic cancer tissues, particularly in metastatic tumors and pancreatic cancer cell lines. Overexpression of miR-452 significantly inhibited migration and invasion in pancreatic cancer cells. In addition, the molecular mechanism underlying the inhibitory functions of miR-452 in pancreatic cancer was also investigated. The results indicated that B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) was a direct target gene of miR-452 in pancreatic cancer. Overexpression of miR-452 inhibited the migration and invasion of pancreatic cancer, at least partially by knockdown of BMI1 expression. The results provided novel insight with potential therapeutic applications for the treatment of metastatic pancreatic cancer.


Trends in admission timing and mechanism of injury can be used to improve general surgical trauma training.
The temporal patterns and unit-based distributions of trauma patients requiring surgical intervention are poorly described in the UK. We describe the distribution of trauma patients in the UK and assess whether changes in working patterns could provide greater exposure for operative trauma training. We searched the Trauma Audit and Research Network database to identify all patients between 1 January 2014 to 31 December 2016. Operative cases were defined as all patients who underwent laparotomy, thoracotomy or open vascular intervention. We assessed time of arrival, correlations between mechanism of injury and surgery, and the effect of changing shift patterns on exposure to trauma patients by reference to a standard 10-hour shift assuming a dedicated trauma rotation or fellowship. There were 159,719 patients from 194 hospitals submitted to the Network between 2014 and 2016. The busiest 20 centres accounted for 57,568 (36.0%) of cases in total. Of these 2147/57,568 patients (3.7%) required a general surgical operation; 43% of penetrating admissions (925 cases) and 2.2% of blunt admissions (1222 cases). The number of operations correlated more closely with the number of penetrating rather than blunt admissions (r = 0.89 vs r = 0.51). A diurnal pattern in trauma admissions enabled significant increases in trauma exposure with later start times. Centres with high volume and high penetrating rates are likely to require more general surgical input and should be identified as locations for operative trauma training. It is possible to improve the number of trauma patients seen in a shift by optimising shift start time.


Jumping performance of hylid frogs measured with high-speed cine film.
Jumping performance at 20 degrees C was assessed in five species of hylid frogs using high-speed cine film. Mean takeoff velocities (Vt) varied from 1.5 to 2.4 ms-1 among the species. Peak Vt varied from 1.9 to 2.9 ms-1. Body-mass-specific power output averaged over the entire takeoff period varied from 29 to 91 W kg-1 during the jumps with the highest takeoff velocities. These values are similar to those predicted from jumping distance. As the mass of muscles available to power the jump probably amounts to no more than 17% of the body mass, average muscle-mass-specific power can be over 500 W kg-1. The performance during jumping is even more impressive in view of the fact that the peak power during takeoff is about twice the average power. These frogs must use elastic storage to redistribute power during takeoff to produce the peak power required and may use pre-storage of elastic energy to boost the average power available.


Fluorescence spectra of cells stained with a DNA-specific dye, measured by flow cytometry.
Fluorescence spectra of ethanol-fixed rat thymocytes stained with the DNA-specific dye Hoechst 33258 have been measured in an arc lamp-based flow cytometer including a grating monochromator in front of the fluorescence detector. Spectral resolution was 5-10 nm. Increasing dye concentration was found to yield an increasing shift of the fluorescence spectrum toward longer wavelengths, thus supporting previous work on soluble DNA that indicated several different binding modes of this dye. The results show that similar data may be obtained for all commonly used DNA-specific dyes. It appears that this type of spectral information may be used to probe the structure of cell chromatin.


Community-based participatory research in Boston's neighborhoods: A review of asthma case examples.
Three case examples of asthma studies that differ in terms of community and involvement are considered. The Boston Chinatown studies faced limited funding that restricted the level of community involvement, but resulted in some of the first published evidence about asthma in Asian American children. These studies led to an asthma education program grant to a local Asian clinic and elementary school. The public housing study was a well-funded multi-year study of asthma and pest management with city, university and community partners. Residents were trained to collect data and participated throughout the study. Follow up pest management and pesticide buy-back programs headed by the city and community partners have been funded. The Dorchester case had more limited funding, but had the greatest level of involvement of parents of asthmatic children in all phases of the research. This survey led to an interesting novel finding of lower asthma prevalence in foreign born black residents.


CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model.
This study set out to investigate the antitumor effects of a treatment strategy combining the mTOR inhibitor CCI-779 with cisplatin in vitro and in a human melanoma SCID mouse model. In vitro 518A2, Mel-JUSO or 607B cell lines were incubated with CCI-779, cisplatin and CCI-779 plus cisplatin. Based on these results, a 4-group, parallel, controlled experimental study design was initiated in vivo. SCID mice were injected with melanoma cells, and after the development of tumors the mice received daily injections of CCI-779 or solvent. On treatment days 2 and 6 cisplatin or mock solution were administered. In vitro a synergistic antitumor effect was observed for the treatment regimen of CCI-779 plus cisplatin. In SCID mice after 2 weeks of therapy with CCI-779 plus cisplatin 4 of 6 tumors of the 518A2 cell line were completely eradicated. In the two remaining 518A2 xenografts this treatment strategy reduced the tumor weight by 94 +/- 9% compared to solvent. CCI-779 plus cisplatin also exerted a significant antitumor effect in Mel-JUSO and 607B xenografts compared to mock-treated animals. We provide circumstantial evidence that the use of CCI-779 plus cisplatin might qualify as a promising strategy in the treatment of human melanoma.


Attempted and Completed Suicide in Cuban Adolescents, 2011-2014.
Recent decades have seen an uptick in suicide attempts and completed suicides among adolescents and young adults worldwide. In the Americas, including Cuba, suicide is the third leading cause of death in adolescents (ages 10-19 years). Characterize the epidemiology of attempted and completed suicide in Cuban adolescents from 2011 through 2014. A descriptive epidemiological study was carried out. The information was gathered from morbidity records for suicide attempts and mortality records for suicide deaths in adolescents, taken from the Cuban Ministry of Public Health's Medical Records and Health Statistics Division database for January 1, 2011 through December 31, 2014. Variables were sex, age, occupation or employment status, and suicide method. Suicide attempt incidence rates and suicide mortality rates by age group per 100,000 population (crude, adjusted and age/sex specific), mortality sex ratio and attempt/suicide ratio were calculated. Relative change was calculated as a percentage, as were frequencies by variable for attempted suicide and suicide, and by age and sex for method used. A total of 19,541 suicide attempts and 149 suicides were reported. Average annual numbers were 4,885.2 suicide attempts and 37.2 suicides (131:1 ratio). There were 3,966 suicide attempts among boys, for a sex ratio of 0.25:1. Age-adjusted suicide attempt rates decreased from 391.8 per 100,000 population to 304.5 (22.3% reduction over the study period). Boys accounted for 107 of 149 suicide deaths, for a sex ratio of 2.5:1. Age-adjusted suicide mortality rates decreased from 2.8 to 2.3 per 100,000 population (17.9% reduction). The group aged 15-19 years had the highest age-adjusted suicide rate (3.9 per 100,000 population) and contributed the most deaths (114/149, 76.5%), although it did experience a 31.8% reduction over the study period. The group aged 10-14 years recorded a relative increase of 60% over the study period. Hanging was the most common suicide method (116/149, 77.9%). The suicide rate in Cuban adolescents (2.6 per 100,000 population, 3.7 in boys and 1.5 in girls) is less than that reported by the Region of the Americas between 2005 and 2009, 3.7 per 100,000 population (5/100,000 in boys and 2.3/100,000 in girls). Suicide rates in Cuban adolescents are lower than reported elsewhere in the Americas. Suicide attempts and suicide rates decreased modestly between 2011 and 2014. Hanging is the most commonly used method. The highest rates occur in the group aged 15-19 years, but those aged 10-14 years showed a relative increase over the study period. These results update the epidemiology of suicide in Cuban adolescents and demonstrate the extent of the problem. Suicides and suicide attempts show opposite patterns in boys and girls; suicides are more frequent among boys while suicide attempts are more frequent among girls. These results update the epidemiology of suicide in Cuban adolescents and reveal the extent of the problem for one of the main preventable causes of death in this age group.


[Rib tuberculosis: value of imaging. Report of 4 cases].
We report 4 cases of tuberculous osteitis of the ribs in patients aged 25 to 60 years. All patients had thoracic CT scan. Two cases presented as multifocal tuberculosis, involving nodes and lung in one case, a costo-verebral joint and lung in the second case. In two patients, the aspect was a misleading pseudo-tumor form with a primitive malignant bone tumor and infiltration of perivertebral and endocanalar soft tissue in one case of costo-transverse joint tuberculosis with neurologial disorder; in the other case, the rib affection presented as a breast tumor due to the involvement of anterior thoracic wall in a 50-year-old woman. In all cases, the radiological aspect was quite extensive osteolysis of the rib with involvement of endo- and/or extrathoracic soft tissue noted as cystic or tissue density. We underline the value of CT scan for a complete investigation of rib lesions, which enables characterization of soft tissues involvement, guiding biopsies and search for associated vertebral lesions.


Blood transfusion in total hip replacement: is it always necessary?
Routine blood transfusion was prospectively withheld from 10 patients undergoing routine elective total hip arthroplasty who fulfilled specific criteria. A standard anaesthetic regimen was used. The mean perioperative fall in haemoglobin concentration was 1.9 g/dl, and only one patient required a postoperative blood transfusion. There were no postoperative complications. The need for routine peroperative blood transfusion of patients undergoing total hip arthroplasty is questioned.


Drug-induced apoptosis in osteosarcoma cell lines is mediated by caspase activation independent of CD95-receptor/ligand interaction.
Osteosarcoma is one of the most common primary malignant tumors of bone. Treatment of this tumor with systemic chemotherapy dramatically improves the prognosis, although the molecular mechanisms involved in the drug action are poorly understood. In chemosensitive leukaemic T cells and certain solid tumors, cytotoxic drugs mediate the induction of apoptosis by activation of the CD95/APO-1/Fas system. Triggering of the corresponding signaling pathway may involve CD95-receptor/ligand interaction, activation of caspases, or alterations in mitochondrial function. The purpose of our study was to determine if similar mechanisms are involved in the chemosensitivity of osteosarcomas. We found that cytotoxic drugs induce characteristic biochemical and morphological alterations related to apoptosis in osteosarcoma cell lines, including activation of caspases and disturbance of mitochondrial function. However, drug treatment did not result in activation of CD95-receptor or CD95-ligand mRNA. In addition, drug-induced apoptosis was blocked by caspase inhibitors but not by inhibition of CD95-ligand action, indicating a CD95-receptor/ligand-independent mechanism in osteosarcoma cell lines.


Solid pseudopapillary tumors of the pancreas: a case series, comparison of histopathological and clinical data.
Solid pseudopapillary neoplasms (SPNs) are rare pancreatic tumors. They occur most frequently in young females and are often diagnosed accidentally. SPNs are characterized by an excellent clinical outcome. In our case series the clinical course, pathohistological data and clinical outcome of eight patients (7 female patients, 1 male patient) with SPN are described. Histological examination as well as immunohistochemical analysis shows similar results in all eight cases. Although in the literature a few cases of SPNs with bad prognosis have been reported, up to now none of our patients shows any signs of recurrence or metastasis. Moreover, we give in this case series a summary of SPNs in the literature, important clinical and pathological differential diagnosis, and additionally discuss relevant differential diagnosis occurring in daily routine work.


Telephone-based assessment of the fear of falling in older people and factors associated.
This study aimed to validate the telephone-based application of the Falls Efficacy Scale-International (FES-I) for the assessment of the fear of falling in older people, and to investigate, among personal and environmental factors, which ones can explain this fear in this population. Participants answered the FES-I on two randomized occasions, face-to-face and by telephone. Intraclass correlation coefficient (ICC 3,1 ) was used to investigate the levels of agreement between the two occasions. The possible factors associated were sex, age, previous history of falls, family arrangement, practice of physical activity, presence of orthopedic pathologies, use of walking aids, presence of visual impairment, and presence of stairs in the home environment. Linear regression analysis was applied to investigate which of these factors could explain the fear of falling in older people. One hundred twenty-two individuals were included. There was no significant difference in the mean difference obtained between the two applications of the FES-I (1 point; 95% confidence interval, -4 to 6), with a high level of agreement (ICC = 0.88). Sex and presence of orthopedic pathologies explained 14% of the model. The FES-I showed to be a reliable scale to be applied for telephone assessments of fear of falling in older people. In addition, women with orthopedic pathologies are the profile of older people with most afraid of falling.


The flexible loop of Staphylococcus aureus IsdG is required for its degradation in the absence of heme.
Degradation of specific native proteins allows bacteria to rapidly adapt to changing environments when the activity of those proteins is no longer required. Although these processes are vital to bacterial survival, relatively little is known regarding how bacterial proteins are recognized and targeted for degradation. Staphylococcus aureus is an important human pathogen that requires iron for growth and pathogenesis. In the vertebrate host, S. aureus fulfills its iron requirement by obtaining heme iron from host hemoproteins via IsdG- and IsdI-mediated heme degradation. IsdG and IsdI are structurally and mechanistically analogous but are differentially regulated by iron and heme availability. Specifically, IsdG is targeted for degradation in the absence of heme. Therefore, we utilized the differential regulation of IsdG and IsdI to investigate the mechanism of regulated proteolysis. In contrast to canonical protease recognition sequences, we show that IsdG is targeted for degradation by internally coded sequences. Specifically, a flexible loop near the heme-binding pocket is required for IsdG degradation in the absence of heme.


Evaluation of primary and secondary responses to a T-cell-dependent antigen, keyhole limpet hemocyanin, in rats.
To develop a rat T-cell-dependent antibody response (TDAR) model evaluating both primary and secondary antibody responses, keyhole limpet hemocyanin (KLH) was used to immunize rats twice during a 14-day course of study, a pattern closely linked to that of a short-term general toxicity study. Female rats of four representative strains (e.g., Sprague-Dawley, Wistar, Fischer, and Lewis) were immunized twice with intravenous administrations of KLH (300 µg/rat) on Days 5 and 9 during a 14-day treatment regimen with cyclophosphamide (CPA) at 1, 3, or 6 mg/kg/day. The primary and secondary immunizations of KLH markedly elevated serum anti-KLH IgM and IgG levels in all strains on Days 9 and 15. Remarkable higher levels of anti-KLH IgG (≈ 1000 µg/ml) were noted in all strains, which were more than 4-times compared with those of anti-KLH IgM levels at Day 9, indicating that predominant IgG reactions were induced by the dual immunizations. A large inter-individual variability in KLH-specific IgM and IgG production was observed in all strains. However, levels of the KLH-specific antibodies were considered sufficient for the evaluation, even in Sprague-Dawley and Wistar rats reported as strains with a wide range of variability since immunosuppression of CPA on responses in both anti-KLH IgM and IgG were observed in all strains to the same extent. In addition, the sensitivity of the KLH-ELISA assay system detecting the immunosuppressive effects of CPA was comparable to other assay systems with PFC assay or ELISA using SRBC. The results here demonstrated that these experimental designs could provide valuable information about the influence on both the primary and secondary humoral immune responses in rats when exposed to potential immunomodulatory drugs. Furthermore, the design of the presented TDAR study would support comprehensive evaluation together with the outcome of the conventional general toxicity study.


Effects of lowering the alcohol minimum purchasing age on weekend hospitalised assaults of young Māori in New Zealand.
We examine the association between reducing the alcohol minimum purchasing age from 20 to 18 years in December 1999 and rates of weekend assault hospitalisation among young Māori in the following 12 years. Our previous work showed deleterious effects for young people overall. In keeping with Treaty of Waitangi principles, we sought to determine whether the policy was similarly detrimental for Māori. We used Poisson regression to examine data from 1995 to 2011 on Māori hospitalised on Friday-Sunday following assault, separately by gender among 15- to 17-year-olds and 18- to 19-year-olds, versus 20- to 21-year-olds as a control for changes in economic and environmental factors. There was no evidence to suggest weekend assault hospitalisations increased significantly more among 15- to 17-year-old or 18- to 19-year-old Māori males in the post-change periods (incidence rate ratios varied between 0.83 and 1.13; P values >0.25) compared with increases observed in 20- to 21-year-old Māori males. For Māori females, estimates were more variable, but overall, there was no evidence of the hypothesised effect (incidence rate ratios between 0.60 and 1.09; P values >0.07). Overall, we find no evidence that lowering the minimum alcohol purchasing age increased weekend hospitalised assaults among young Māori. Inferences are compromised by lack of statistical power which underlines the importance of planning for evaluation of important policies well before they are implemented, particularly with a view to meeting obligations to Māori arising from the Treaty of Waitangi.


HIV type 1 mutational patterns in HIV type 1 subtype C-infected long-term survivors in Karonga District Malawi: further analysis and correction.
Here we present new sequence data from HIV-1 subtype C-infected long-term survivors (LTS) from Karonga District, Malawi. Gag and env sequence data were produced from nine individuals each of whom has been HIV-1 positive for more than 20 years. We show that the three amino acid deletion in gag p17 previously described from these LTS is not real and was a result of an alignment error. We find that the use of dried blood spots for DNA-based studies is limited after storage for 20 years. We also show some unlikely amino acid changes in env C2-V3 in LTS over time and different patterns of genetic divergence among LTS. Although no clear association between mutations and survival could be shown, amino acid changes that are present in more than one LTS may, in the future, be shown to be important.


Heminephrectomy--ureterectomy as the sole procedure in ectopic ureterocele in children.
During the years 1976-1981, 12 children with duplex kidneys and ectopic ureterocele were operated upon with heminephrectomy and ureterectomy only. This simple procedure led to cure in 10 out of 12 patients. In two of the patients it later had to be supplemented by resection of the ureterocele and reimplantation of the orthotopic ureter. Such a two-stage procedure does not seem to jeopardize the final result.


Changing antibiotic sensitivity patterns at a university hospital, 1992 through 1999.
The emergence of antibiotic-resistant organisms is of great concern in the medical community. Antibiotic sensitivity patterns were studied at a large university hospital. From 1992 through 1999, susceptibility testing was done and results recorded for all isolates of Streptococcus pneumoniae, Enterococcus sp, Staphylococcus aureus, coagulase-negative Staphylococcus, Eshcherichia coli, Haemophilus influenzae, and Pseudomonas aeruginosa. Microbiologic and sensitivity data were reviewed and compiled. Over the 8-year period, several common bacterial pathogens declined in susceptibility to various antimicrobial agents. Most notable were the decreased sensitivities of S pneumoniae to penicillin (96% to 63%), coagulase-negative Staphylococcus to oxacillin (50% to 38%), and P aeruginosa to aminoglycosides [(gentamicin (85% to 64%), tobramycin (96% to 83%), amikacin (92% to 74%)] and ciprofloxacin (85% to 69%). These decreased antibiotic sensitivities reflect increased bacterial selection pressure as a result of widespread antibiotic use. A combined approach involving infection-control specialists, infectious disease physicians, and hospital administrators is necessary to address this increasingly difficult problem.


Clinical and imaging features of suspected prodromal fracture of the proximal phalanx in three Thoroughbred racehorses.
Sagittal fracture of the proximal phalanx (P1) is an important musculoskeletal injury of the performance horse. Although widely considered to be monotonic in nature, there is emerging evidence that some P1 fractures may have stress-injury aetiology. Three cases are described in which imaging features found were suggestive of prodromal bone injury. All cases returned to full performance use after a period of rest. The authors conclude that it is possible that some P1 fractures in the Thoroughbred racehorse may develop through stress/fatigue injury pathways. It is proposed that intervention prior to overt fracture may be possible in some cases.


Tracking of cardiometabolic risk factor clustering from childhood to adulthood.
Cardiometabolic risk factor clustering is predictive of future cardiovascular disease. If clustering of risk factors is a stable characteristic from childhood to adulthood, then intervention in high-risk children may provide an early opportunity to decrease the progression to overt cardiovascular disease outcomes. Thus, the purpose of this paper was to review the evidence for risk factor clustering being a stable characteristic from childhood to adulthood. Seven articles were identified that met the inclusion criteria. Despite varying definitions of risk factor clustering and different methodologies for assessing tracking, the results generally showed stability of risk factor clustering from childhood into adulthood. Inter-age correlations of risk factor cluster scores ranged from 0.42 to 0.67, and the proportions of individuals remaining in the upper quantiles of risk over time were significantly greater than predicted by chance alone. Future studies are needed to elucidate the effects of gender, ethnicity, and lifestyle behaviors on the tracking of risk factor clustering.


Unusual clinical manifestation and challenging serological interpretation of syphilis: insights from a case report.
The clinical manifestations of recent syphilis can be variable, with typical and atypical patterns. Several conditions may cause atypical clinical aspects, including human immunodeficiency virus (HIV) co-infection. Besides the clinical features, co-infections may completely alter syphilis serological tests, causing interpretative difficulties and diagnostic delays. Aim of the work is to describe the difficulties encountered during the diagnostic evaluation of atypical skin manifestations and of the serology for syphilis of an HIV-infected patient who had contracted it several times. In 2020, a 52-year old HIV-positive bisexual male patient was admitted to our department with a 4-month history of moderately itchy cutaneous lesions localized at his neck, trunk and arms. In 2013, the patient presented with a classic syphilitic roseola of the trunk and a secondary syphilis was diagnosed, with increased levels of rapid plasma reagin (RPR), Treponema pallidum hemagglutination assay (TPHA), anti-Treponema pallidum IgM and IgG Index. A second episode occurred in 2018, as a primary syphilis with multiple ulcerative lesions of the penis, and increased levels of RPR, IgG and IgM. In 2019, a further episode of secondary syphilis was treated with Doxycycline. In 2020, erythematous and papular lesions with vesicular components and urticarial erythema multiforme (EM)-like lesions were present at the neck, trunk and arms. Serological tests and Nucleic Acid Amplification Test (NAAT) for Treponema Pallidum were performed, as well as a cutaneous biopsy with histological and immunohistochemical evaluation of one lesion. NAAT was negative for T. pallidum. Serological test results were discordant with a new syphilis infection, showing only increased levels of RPR and anti-Treponema IgG. The cutaneous biopsy revealed a non specific histological pattern, while the immunohistochemical evaluation with anti-spirochetal antibodies was mandatory for the diagnosis of recent syphilis, showing clusters of rod-shaped elements, some of which with spiral form, focally present at the epidermis and adnexal structures. Nowadays, syphilis may present with atypical clinical and serological features. Physicians should be aware of these possible alterations and consider syphilis even in case of uncommon clinical aspect and unclear serological tests. Cutaneous biopsy and immunohistochemical exam may be mandatory for the diagnosis.


An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations.
The seven-spanning calcium-sensing receptor (CaSR) activates multiple G proteins including Gq and Gi, and thereby activates a variety of second messengers and inhibits parathyroid hormone (PTH) secretion. However, the exact signaling mechanisms underlying the functional activity of CaSR are not yet fully understood. The heterozygous inactivation of CaSR or its inhibition by antibody blocking results in either familial hypocalciuric hypercalcemia or acquired hypocalciuric hypercalcemia (AHH), respectively. Here, we report the identification of a unique CaSR autoantibody in an AHH patient. Paradoxically, we find that this autoantibody potentiates the Ca(2+)/Gq-dependent accumulation of inositol phosphates by slightly shifting the dose dependence curve of the Ca(2+) mediated activation of phosphatidylinositol turnover to the left, whereas it inhibits the Ca(2+)/Gi-dependent phosphorylation of ERK1/2 in HEK293 cells stably expressing human CaSR. Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca(2+), increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects. Our observations thus indicate that a calcium-stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi. Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion. This is the first report of a disease-related autoantibody that functions as an allosteric modulator and maintains G protein-coupled receptors (GPCRs) in a unique active conformation with its agonist. We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.


Real-world clinical data identifies gender-related profiles in chronic obstructive pulmonary disease.
This study aims to compare diagnostic and clinical outcomes of Chronic Obstructive Pulmonary Disease (COPD) from the gender perspective using retrospective health care data and patient reported outcomes in a real-world setting. An electronic database was constructed from complete medical records of 844 COPD patients who were recruited in Helsinki and Turku University Central Hospitals during the years 2005-07. The patients were identified from the hospital discharge registries by ICD10 code J44.8 in the age group of 18-75 years of age. The medical history was obtained from all healthcare providers who had treated these patients during the previous 5-10 years; the study intends to continue their follow-up annually for the next 10 years. Thirty-six percent (N = 266) of the participants were women. The COPD diagnosis had been made at the same age for both genders. Women, however, reported significantly less pack-years than men. Compared to the men, the women displayed less advanced airway obstruction, but more severe gas transfer impairment. Parenchymal damage when evaluated by diffusion capacity correlated significantly stronger with FEV(1) (% of predicted) in women than men. The BMI index of the women was lower than that of the men. Cardiovascular diseases, diabetes and alcoholism were significantly more common in men, but women suffered more psychiatric conditions, especially depression. This cohort showed several significant gender dependent differences in the clinical presentation that need to taken under consideration in the assessment of COPD progression and the disease management.


Cyclic nucleotide-gated channels contribute to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons.
Plateau potentials are prolonged membrane depolarizations that are observed in hippocampal pyramidal neurons when spiking and Ca(2+) entry occur in combination with muscarinic receptor activation. In this study, we used whole-cell voltage clamping to study the current underlying the plateau potential and to determine the cellular signaling pathways contributing to this current. When combined with muscarinic stimulation, depolarizing command potentials that evoked Ca(2+) influx elicited a prolonged tail current (I(tail)) that had an extrapolated reversal potential of -20 mV. I(tail) was not observed when intracellular Ca(2+) levels were chelated with 10 mm intracellular BAPTA, and I(tail) was reversibly depressed in low external sodium. When I(tail) was evoked at intervals >3 min, current amplitudes were stable for up to 1 hr. However, at shorter intervals, I(tail) was refractory, with a time constant of recovery of 43.5 sec. The inhibitors of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and 6-anilino-5,8-quinolinequinone depressed I(tail) and zaprinast, which blocks cGMP-specific phosphodiesterase, enhanced I(tail), suggesting that a component of I(tail) was activated by cGMP. The inhibitors of cyclic nucleotide-gated (CNG) channels l-cis-diltiazem and 2',4'-dichlorobenzamil reversibly depressed I(tail). However, protein kinase G inhibition had no effect. Therefore, these results indicate that a component of I(tail) is attributable to activation of CNG channels. We conclude that Ca(2+) influx when combined with muscarinic receptor activation activates soluble guanylate cyclase and increases cGMP levels. The increased cGMP activates CNG channels and leads to prolonged depolarization. The cation conductance of the CNG channel contributes to the prolonged depolarization of the plateau potential.


Effect of worksite health promotion programs on employee absenteeism. A comparative analysis.
Employee absenteeism is an important economic variable that needs to be examined by occupational health nurses when evaluating worksite health promotion programs. Two of the three Blue Cross and Blue Shield Plan studies suggested that their programs acted to contain absenteeism among program participants. The worksite programs that met with success tended to be comprehensive and to have strong management support. Strengths of the three studies included the use of comparison groups and pretest measures of absenteeism in the analyses. Limitations included selection bias, subject dropout over time, limited monitoring of the program process, and the use of an analysis method that did not consider the statistical characteristics of the absenteeism variable.


Effect of kappa-casein polymorphism on milk composition in the Orobica goat.
The aim of this work was to study the effects of isoelectrofocusing (IEF) milk protein variants on milk composition in the Italian Orobica goat breed, which is characterized by a rather high frequency of the kappa-casein (CSN3) B(IEF) allele. Significant associations were found between the IEF phenotype and protein and casein percentages. A favorable effect of the CSN3 B(IEF) variant was found for both protein and casein percentages, with a codominance trend for the 3 phenotypes: BB > AB > AA. Depending on the selection purpose, emphasis could be given to different kappa-casein variants in breeding. The high frequency of B(IEF) could be exploited in breeding strategies to improve the protein and casein percentages when cheese making is a selection objective.


FIV diversity: FIV Ple subtype composition may influence disease outcome in African lions.
Feline immunodeficiency virus (FIV) infects domestic cats and at least 20 additional species of non-domestic felids throughout the world. Strains specific to domestic cat (FIV(Fca)) produce AIDS-like disease progression, sequelae and pathology providing an informative model for HIV infection in humans. Less is known about the immunological and pathological influence of FIV in other felid species although multiple distinct strains of FIV circulate in natural populations. As in HIV-1 and HIV-2, multiple diverse cross-species infections may have occurred. In the Serengeti National Park, Tanzania, three divergent subtypes of lion FIV (FIV(Ple)) are endemic, whereby 100% of adult lions are infected with one or more of these strains. Herein, the relative distribution of these subtypes in the population are surveyed and, combined with observed differences in lion mortality due to secondary infections based on FIV(Ple) subtypes, the data suggest that FIV(Ple) subtypes may have different patterns of pathogenicity and transmissibility among wild lion populations.


Identification of NLRP3PYD Homo-Oligomerization Inhibitors with Anti-Inflammatory Activity.
Inflammasomes are multiprotein complexes that represent critical elements of the inflammatory response. The dysregulation of the best-characterized complex, the NLRP3 inflammasome, has been linked to the pathogenesis of diseases such as multiple sclerosis, type 2 diabetes mellitus, Alzheimer's disease, and cancer. While there exist molecular inhibitors specific for the various components of inflammasome complexes, no currently reported inhibitors specifically target NLRP3PYD homo-oligomerization. In the present study, we describe the identification of QM380 and QM381 as NLRP3PYD homo-oligomerization inhibitors after screening small molecules from the MyriaScreen library using a split-luciferase complementation assay. Our results demonstrate that these NLRP3PYD inhibitors interfere with ASC speck formation, inhibit pro-inflammatory cytokine IL1-β release, and decrease pyroptotic cell death. We employed spectroscopic techniques and computational docking analyses with QM380 and QM381 and the PYD domain to confirm the experimental results and predict possible mechanisms underlying the inhibition of NLRP3PYD homo-interactions.


[Functionalized exosome-loaded ginsenoside Rg1 for the treatment of ischemic stroke].
The aim of this study was to investigate the therapeutic effects and potential mechanism of c(RGDyK) peptide modified mesenchymal stem cell exosomes loaded with ginsenoside Rg1 (G-Rg1) on ischemic stroke. Thread-tying method was used to establish SD rats transient middle cerebral occlusion model (tMCAO). The model rats were randomly divided into tMCAO group, Exo group, free G-Rg1 group, Exo-Rg1 group and cRGD-Exo-Rg1 group, and sham group was used as control. The infarct volume was measured by 2, 3, 5-triphenyltetrachloride (TTC) staining, the changes of neuron and endothelium were observed by immunofluorescence, and the expression of related proteins was detected by Western blotting. The results showed that cRGD-Exo-Rg1 up-regulated the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIF-1α) by activating PI3K/AKT pathway, thus promoting angiogenesis and neurogenesis, effectively reducing the volume of cerebral infarction and improving neural function. In addition, the delivery of cRGD-Exo-Rg1 to ischemic brain tissue up-regulated the expression of occludin and claudin-5, and reduced the injury of blood-brain barrier. Taken together, cRGD-Exo-Rg1 was effective in the treatment of ischemic stroke by promoting angiogenesis and neurogenesis, which provided experimental evidence for the potential clinical benefits of other neuroprotective therapies.


Three-dimensional kinematics of the proximal interphalangeal joint: effects of raising the heels or the toe.
The proximal interphalangeal joint (PIPJ) has always been considered as a low-motion joint with an almost constant angle during loading of the limb. Until very recently, its motion was not taken into account in kinematic studies in vivo. Recent in vivo studies yielded surprisingly high ranges of motion in this joint. The aim of this study was to measure, in terms of the 3 possible rotations (flexion/extension, collateromotion and axial rotation), the movements of the PIPJ in vitro during limb loading in a neutral position (500-6000 N) and after the addition of heel and toe wedges (6 degrees and 12 degrees). The joint coordinate system, as it was recently described for use in the horse, was used to compute the 3 components of rotation. With the hoof in neutral position, low-amplitude flexion movements (7.9 degrees) were observed. They were not associated with collateromotion or axial rotation. The flexion of the joint increased exponentially with load suggesting that, during the midstance phase, heavy loads are necessary to evoke substantial flexion. Raising the heels induced an early flexion of the joint with an increase of its total amplitude. Raising the toe produced an extension at 500 N, beyond which the amount of flexion was reduced. These results show that PIPJ flexion/extension during in vitro loading remains substantially smaller than suggested by in vivo studies based on skin markers. Raising the toe or heel directly affects the behaviour of this joint, but does not induce motion outside the sagittal plane. Hoof wedges are commonly used in clinical practice for purposes other than affecting PIPJ motion. In these cases, their biomechanical effects on this joint should be taken into account.


An enteral elemental diet for infants and children with surgical disorders.
Sixty-nine infants and children with surgical disorders were fed an enteral elemental diet consisting of synthetic L-amino acids, dextroglucose, soybean oil, electrolytes and vitamins. Satisfactory clinical results were achieved in 55 patients, whose average positive nitrogen balance was approximately 578 mg/day in neonates, 1,518 mg/day in infants and 2,452 mg/day in children; average weight gain was approximately 16 g/day in neonates, 23 g/day in infants, and 21 g/day in children during total enteral nutrition with the diet. Elevation of serum transaminase values was noted in 5 patients receiving total enteral nutrition with the diet. Liver toxicity may have been caused by the composition of amino acids of the diet, solely free amino acids as protein component. However, the diet provided a valuable therapeutic alternative to total parenteral nutrition in selected infants and children requiring surgery.


Variations in the Physical Performance of Olympic Boxers over a Four-Day National Qualifying Tournament.
The aim of this study was to examine changes in body mass (BM) and power-related measures in Olympic boxers during an official qualifying boxing tournament. Fourteen elite amateur boxers from the Brazilian National Team (eight men and six women) participated in this study. Athletes performed three fights in four days against the same opponent of the same weight-category. Before and immediately after every fight, BM, countermovement jump (CMJ) height, and power production in the bench-press and half-squat exercises were assessed in the same order and on the same time of the day. A two-way repeated-measures ANOVA with the Bonferroni post-hoc analysis was used to determine the variations between pre- and post-measures. The statistical significance was set as p < 0.05. The athletes were able to maintain their baseline weight and physical performance throughout the experimental period, as shown by the lack of significant changes in BM, CMJ height, and upper- and lower-limb power output. Throughout a four-day qualifying tournament, the BM and power-related performance of Olympic boxers were not affected either by match execution or by successive matches. As scoring actions are highly dependent on muscle power, it is likely that these combat athletes are able to maintain optimal levels of performance across consecutive matches.


Maternal exposure to genistein during pregnancy and oxidative DNA damage in testes of male mouse offspring.
Genistein is a dietary supplement with phyto-estrogenic properties. Therefore, high intake of genistein during pregnancy may have adverse effects on the genetic integrity of testes and germ cells of male offspring. In this study, we examined whether maternal exposure to genistein during pregnancy induced oxidative DNA damage in the male germline at adolescence. Atm-ΔSRI mice have lower glucose-6-phosphate dehydrogenase (G6PDH) activity, which is important for maintaining levels of reduced glutathione and therefore these mice have an increased susceptibility to oxidative stress. Parental heterozygous Atm-ΔSRI mice received a genistein-rich or control diet, after which they were mated to obtain offspring. During pregnancy, mothers remained on the respective diets and after delivery all animals received control diets. Redox status and oxidative DNA damage were assessed in testes and sperm of 12 weeks old male offspring. Gene expression of Cyp1b1, Comt, and Nqo1 was assessed in testes, and DNA methylation as possible mechanism for transmission of effects to later life. Intake of genistein during pregnancy increased oxidative DNA damage in testes of offspring, especially in heterozygous Atm-ΔSRI mice. These increased DNA damage levels coincided with decreased expression of Comt and Nqo1. Heterozygous Atm-ΔSRI mice had higher levels of DNA strand breaks in sperm compared to wild type littermates, and DNA damage was further enhanced by a genistein-rich maternal diet. G6PDH activity was higher in mice with high maternal intake of genistein compared to control diets, suggesting compensation against oxidative stress. A positive correlation was observed between the levels of DNA methylation and oxidative DNA damage in testes. These data indicate that prenatal exposure to genistein altered gene expression and increased DNA damage in testes and sperm of adolescent male offspring. These effects of genistein on DNA damage in later life coincided with alterations in DNA methylation.


A pilot study of brief heart rate variability biofeedback to reduce craving in young adult men receiving inpatient treatment for substance use disorders.
The present pilot study investigated the implementation feasibility, and efficacy for reducing alcohol and drug craving, of a brief, 3-session heart rate variability biofeedback (HRV BFB) intervention added to a traditional 28-day substance abuse disorder inpatient treatment program. Forty-eight young adult men received either treatment as usual (TAU) plus three sessions of HRV BFB training over 3 weeks, or TAU only. Participants receiving HRV BFB training were instructed to practice daily using a hand-held HRV BFB device. HRV BFB training was well tolerated by participants and supported by treatment staff. Men receiving TAU + HRV BFB demonstrated a greater, medium effect size reduction in alcohol and drug craving compared to those receiving TAU only, although this difference did not reach statistical significance. In addition, an interaction effect was observed in analyses that accounted for baseline craving levels, wherein heart rate variability (HRV) levels at treatment entry were predictive of changes in craving in the TAU group only. Low baseline levels of HRV were associated with increases in craving, whereas higher baseline HRV levels were associated with greater decreases in craving from start to end of treatment. In the TAU + HRV BFB group, however, there was no such association. That is, HRV BFB appeared to dissociate individual differences in baseline HRV levels from changes in craving. Given that alcohol and drug craving often precipitates relapse, HRV BFB merits further study as an adjunct treatment to ameliorate craving experienced by persons with substance use disorders.


[Indicator set to measure accessibility and performance of inpatient psychiatric services].
In our country, the lack of necessary information to assess health - assistance systems, programs, and services highlights the need to develop and implement a set of indicators that provides relevant, reliable and in - time information. The present paper proposes a basic set of indicators for inpatient - psychiatric services (CIB - IP), which helps assess their accessibility and performance. Each of the proposed indicators is described, together with its convenience and limitations. The assessment of specific - policy impact, program monitoring, epidemiologic surveillance, accessibility improvement, resource planning, program - coverage design, and quotation can be supported by this set of indicators. As relevant characteristics we highlight its reliability, timing convenience, feasibility, and low - cost operation. Its implementation can provide relevant information in a relatively short term. Thus, we recommend the immediate implementation of this indicator set.


Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.
In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC. Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.


Risk Factors in Early Implant Failure: A Meta-Analysis.
Clinicians should be able to weigh the role of the main risk factors associated with early implant failure. The aim of this meta-analysis was to assess the influence of different patient-related and implant-related risk factors on the occurrence of early implant failure. In July, 2014 the main electronic databases were searched for studies reporting on early failures. Relevant papers were selected by 2 independent authors using predefined selection criteria. Three authors independently scored the included studies for quality assessment. The estimated odds ratios of the main risk factors from the selected papers were subjected to meta-analysis. Nine studies were included. A total of 18,171 implants were meta-analyzed, of which 10,921 were analyzed for smoking, 15,260 for implant diameter, 16,075 for implant length, and 16,711 for implant location (maxilla vs mandible). The main significant risk factors for early implant failures were the smoking habit (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.3, 2.3), implants shorter than 10 mm (OR, 1.6; 95% CI, 1.2, 2.2) and implants placed in the maxilla (OR, 1.3; 95% CI, 1.0, 1.6). Clinicians should be aware of the increased risk of early failure in the presence of smokers, implants with reduced length, and implant-supported maxillary rehabilitation.


C-terminal deletions of the Escherichia coli RecA protein. Characterization of in vivo and in vitro effects.
A set of C-terminal deletion mutants of the RecA protein of Escherichia coli, progressively removing 6, 13, 17, and 25 amino acid residues, has been generated, expressed, and purified. In vivo, the deletion of 13 to 17 C-terminal residues results in increased sensitivity to mitomycin C. In vitro, the deletions enhance binding to duplex DNA as previously observed. We demonstrate that much of this enhancement involves the deletion of residues between positions 339 and 346. In addition, the C-terminal deletions cause a substantial upward shift in the pH-reaction profile of DNA strand exchange reactions. The C-terminal deletions of more than 13 amino acid residues result in strong inhibition of DNA strand exchange below pH 7, where the wild-type protein promotes a proficient reaction. However, at the same time, the deletion of 13-17 C-terminal residues eliminates the reduction in DNA strand exchange seen with the wild-type protein at pH values between 7.5 and 9. The results suggest the existence of extensive interactions, possibly involving multiple salt bridges, between the C terminus and other parts of the protein. These interactions affect the pK(a) of key groups involved in DNA strand exchange as well as the direct binding of RecA protein to duplex DNA.


Synovial Haemangioma of the Elbow: A rare paediatric case and imaging dilemma.
Synovial haemangiomas are rare benign vascular proliferations arising in synovium-lined surfaces. While the knee is by far the joint most commonly involved, this condition can also occur in the elbow. We report an eight-year-old boy who presented to the National University of Malaysia Medical Centre, Kuala Lumpur, Malaysia, in 2016 with a left elbow swelling of one year's duration. Magnetic resonance imaging showed a lobulated intra-articular mass with intermediate signal intensity on T1-weighted imaging and low signal punctate and linear structures within the hyperintense mass on T2-weighted imaging. In addition, there was heterogeneous yet avid contrast enhancement on post-gadolinium contrast images. The mass had juxta-articular extension and bony erosion to the coronoid process and the head of the radius. Synovial haemangiomas present a diagnostic dilemma. This report highlights certain imaging characteristics to distinguish this entity from other differential diagnoses.


The effect of corpus callosum lesions on unilateral neglect in monkeys.
The cerebral hemispheres may be mutually inhibitory. An injured hemisphere may continue to be inhibited while the uninjured hemisphere is released from inhibition, inducing attentional bias. Patients with neglect might therefore benefit from transection of the corpus callosum. To test this hypothesis, we ablated the frontal arcuate gyrus alone or several months after corpus callosum transection in monkeys. Neglect was significantly worse in animals with a corpus callosum transection. Therefore, the hemispheres may be mutually excitatory or compensatory, and a callosal transection would not be therapeutic. Because the rate of recovery in the two groups was not different, recovery seemed to be an intrahemispheric phenomenon.


Total implantation of a remotely controlled insulin minipump in a human insulin-dependent diabetic.
This study reports our first total implantation of an insulin minipump in a severely unstable 23-year-old female insulin-dependent diabetic. The implantable unit includes a stepping motor, a percutaneously refillable insulin reservoir (10 ml, U 100 special insulin), a battery with a life span of one year, and a method for prevention of overdosage. Variable continuous basal and superimposed 1-hour high rates are programmed and checked via an external remote controller. The pump was inserted in the lateral muscles of the abdomen and the insulin delivery catheter terminated in the peritoneal cavity. Excellent glycemic control was reached rapidly and has continued seven months after implantation (mean blood glucose is 123 +/- 62 mg/dl; glycosylated hemoglobin is 7.0 +/- 1.2%), with the unit providing the only source of insulin. The only negative aspects were a chronic lymphorrhea in the first two months, and a need for frequent and laborious insulin refills (every 20 days). Only slight local discomfort was experienced. Thus, although further miniaturization and autonomy are expected, these preliminary results show that with careful instruction and followup, implanted pumps could represent a reliable and safe alternative to conventional insulin therapy for selected diabetics.


The Effect of Dietary Fibre on Gut Microbiota, Lipid Profile, and Inflammatory Markers in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.
A disequilibrium of the gut microbial community has been closely associated with systemic inflammation and metabolic syndromes including type 2 diabetes. While low fibre and high fat diets may lead to dysbiosis of the gut microbiome as a result of the loss of useful microbes, it has been reported that a high fibre diet may prevent the fermentation of protein and may promote eubiosis of gut microbiota. This review aims to evaluate the effect of dietary fibre (DF) on gut microbiota, lipid profile, and inflammatory markers in patients with type 2 diabetes. The PRISMA framework was relied on to conduct this systematic review and meta-analysis. Searches were carried out using electronic databases and reference list of articles. Eleven studies were included in the systematic review, while ten studies were included in the meta-analysis. The findings revealed five distinct areas including the effects of DF on (a) gut microbiota (122 participants); (b) lipopolysaccharides (LPS, 79 participants) and lipopolysaccharides binding protein (LBP, 81 participants); (c) lipid profile; (d) inflammatory markers; and (e) body mass index (BMI, 319 participants). The relative abundance of Bifidobacterium increased by 0.73 (95% CI: 0.57, 0.89) in the DF group in contrast to the control (p < 0.05). With respect to LPS, the level was lower in the DF group than the control and the difference was significant (p < 0.05). The standardised mean difference for LPS was -0.45 (95% CI: -0.90, -0.01) although the difference between the two groups in relation to LBP was not significant (p = 0.08) and the mean difference was 0.92 (95% CI: -0.12, 1.95). While there was a decrease of -1.05 (95% CI: -2.07, -0.02) with respect to total cholesterol (356 participants) in the DF group as compared with the control (p < 0.05), both groups were not significantly different (p > 0.05) in the other lipid parameters. The difference between the groups was significant (p < 0.05) in relation to C-reactive protein, and the mean difference was 0.43 (95% CI: 0.02, 0.84). This could be due to the short duration of the included studies and differences in participants' diets including the amount of dietary fibre supplements. However, the groups were not significantly different (p > 0.05) with respect to the other inflammatory markers. The meta-analysis of the BMI showed that the DF group decreased by -0.57 (95% CI: -1.02, -0.12) as compared with the control and this was significant (p < 0.01). DF significantly (p < 0.05) increased the relative abundance of Bifidobacterium and significantly decreased (p < 0.05) LPS, total cholesterol, and BMI as compared with the control. However, DF did not seem to have an effect that was significant on LBP, triglyceride, HDL cholesterol, LDL cholesterol, IL-6, TNF-α, adiponectin, and leptin. These findings have implications for public health in relation to the use of dietary fibre in nutritional interventions and as strategies for managing type 2 diabetes.


Requirement of E6AP and the features of human papillomavirus E6 necessary to support degradation of p53.
E6 oncoproteins from human papillomavirus type 16 (16E6) and Bovine Papillomavirus type 1 (BE6) bind to leucine rich peptides (called charged leucine, LXXLL, or signature peptides) found on target cellular proteins. BE6 and 16E6 both bind the product of the UBE3A gene called E6AP on a charged leucine peptide, LQELL. E6AP is an E3 ubiquitin ligase that together with 16E6 interacts with p53 to target p53 degradation. Although both BE6 and 16E6 bind the LQELL peptide of E6AP, only 16E6 acts as an adapter to then bring p53 to E6AP. In order to determine how E6 proteins function as adapters, 16E6, p53, and E6AP were expressed in yeast, and were shown to form a tri-molecular complex. 16E6 mutants were selected that retained interactions with E6AP yet were defective for interaction with p53. Such 16E6 mutations were typically within the amino-terminus of 16E6. Through the use of E6AP null cells, transfected E6AP was shown to be necessary and sufficient for the degradation of p53 in the presence of 16E6. However, the interaction of 16E6 with E6AP was complex. While BE6 interacts only with the LQELL motif of E6AP, an intact LQELL motif is not necessary either for interaction of 16E6 with E6AP or for p53 degradation. In addition, 16E6 mutants that fail to bind the LQELL motif of E6AP can support p53 degradation. These results indicate that 16E6 may have multiple modes of interaction with E6AP and that assembly of p53 containing complexes for targeted degradation by E6AP may occur in more than one way. These results have implications for potential targeting of the interaction of 16E6 and E6AP in the therapy of HPV-induced cancer.


Correlation of anxiety-depression and sleep quality in mothers of children with cystic fibrosis and asthma.
Cystic fibrosis and asthma are considered among the chronic respiratory diseases. Taking care of the sick child by the mother-which is usually the main care taker- can be associated with high loads of stress and result in behavioral problems like anxiety, depression and change in sleep quality. This study aimed at evaluating the correlation between depression-anxiety and sleep quality in mothers of children suffering from cystic fibrosis and asthma hospitalized in Masih Daneshvari Hospital. This was an analytical descriptive cross-sectional study conducted on 148 subjects (mothers of children with cystic fibrosis and asthma hospitalized in Masih Daneshvari Hospital) during 2008-2010. Data were collected using a questionnaire for demographic characteristics, sleep quality and Hospital Anxiety and Depression Scale (HADS). Pittsburgh sleep quality index questionnaire (PQSI) was developed by Dr. Buysse and colleagues at the University of Pittsburgh's Western Psychiatric Institute and Clinic in the late 1980s. The PSQI was created after observing that most patients with psychiatric disorders had sleep disorders as well. Also, required data regarding the pulmonary function of patients was extracted from their medical records. In this study, high levels of anxiety and depression and poor sleep quality requiring clinical intervention were seen in 37.2%, 29.1% and 39% of mothers, respectively. A significant association was detected between sleep quality and depression-anxiety (P-value < 0.005). Also, depression-anxiety was significantly correlated with number of children and smoking (P-value < 0.005). A total of 20% of mothers suffering from depression and 14.3% of mothers with anxiety disorder had a history of cigarette smoking (P-value < 0.005). No significant association was found between substance abuse and occupation with depression-anxiety. Susceptibility was only correlated with anxiety (P-value < 0.005). Our study showed a significant association between sleep quality and depression-anxiety in mothers of children suffering from cystic fibrosis and asthma. Greater attention should be paid to prevent development and aggravation of these conditions in susceptible mothers who are the main care taker of their sick child with chronic diseases.


Behavior disorders and mental retardation: the family system perspective.
The aim of this study was to investigate feelings of stress among parents of mentally retarded children who demonstrate behavior disorders. The interrelations of the children's pathology and family climate variables with the levels of parental stress were studied. The sample consisted of 39 families with moderately mentally retarded children divided into two groups: Children demonstrating disruptive behavior (n = 17), and children who did not demonstrate behavior disorders (n = 22). The instruments included the Child Behavior Checklist, the Classroom Behavior Inventory, the Family Environment Scale, and the Questionnaire on Resources and Stress. Significant differences between the children's levels of pathology validated the two groups' division. The children with disruptive behavior were described by their parents as more hyperactive and aggressive, and were described by their teachers as more distractable and dependent on adults. No significant differences were found between the profiles of family climate among the two groups of parents. However, levels of children's pathology and aspects of family climate predicted the parental stress, pinpointing different patterns of variables for fathers and mothers. Further studies should be addressed to the interrelations between children's pathology, family climate, and parental feelings of stress.


The nature of electromagnetic interference.
This report provides a brief tutorial on the underlying physical forces that lead to interference with hearing aids and assistive listening devices, as well as measurement issues and possible solutions to the problem.


Clinical features of gastroenteritis during a large waterborne Campylobacter outbreak in Askøy, Norway.
Outbreaks of Campylobacter infection are common, but studies exploring the clinical features of acute illness in the outbreak setting are scarce in existing literature. The main purpose of the present study was to investigate the clinical features of self-reported acute illness in gastroenteritis cases during a large waterborne Campylobacter outbreak in Askøy municipality, Norway, in 2019. A web-based self-administered questionnaire, and invitation to participate was sent by the municipality of Askøy as text message to mobile phones using the municipality's warning system to the inhabitants during the ongoing outbreak. Out of 3624 participants, 749 (20.7%) were defined as cases, of which 177 (23.6%) reported severe gastroenteritis. The most common symptoms were loose stools (90.7%), abdominal pain (89.3%) and diarrhea (88.9%), whereas 63.8% reported fever, 50.2% joint pain and 14.2% bloody stools. Tiredness, a symptom non-specific to gastroenteritis, was the overall most common symptom (91.2%). About one in four of the cases reported symptoms consistent with severe gastroenteritis. We found more joint pain and less bloody stools than reported in published studies of laboratory confirmed campylobacteriosis cases. Tiredness was common in the current study, although rarely described in previous literature of acute illness in the outbreak setting.


Liberation of desmosine and isodesmosine as amino acids from insoluble elastin by elastolytic proteases.
The development of atherosclerotic lesions and abdominal aortic aneurysms involves degradation and loss of extracellular matrix components, such as collagen and elastin. Releases of the elastin cross-links desmosine (DES) and isodesmosine (IDE) may reflect elastin degradation in cardiovascular diseases. This study investigated the production of soluble elastin cross-linking structures by proteinases implicated in arterial diseases. Recombinant MMP-12 and neutrophil elastase liberated DES and IDE as amino acids from insoluble elastin. DES and IDE were also released from insoluble elastin exposed to monocyte/macrophage cell lines or human primary macrophages derived from peripheral blood monocytes. Elastin oxidized by reactive oxygen species (ROS) liberated more unconjugated DES and IDE than did non-oxidized elastin when incubated with MMP-12 or neutrophil elastase. These results support the exploration of free DES and IDE as biomarkers of elastin degradation.