Ethanol organosolv lignin from different agricultural residues: Toward basic structural units and antioxidant activity.
The growing interest in the substitution of synthetic food antioxidants by natural ones has fostered research on vegetable sources and the screening of raw materials for identifying new antioxidants. Special attention is focused on their extraction from inexpensive or residual sources from agricultural industries. Herein, the antioxidant activities of lignin obtained from 4 residual sources were investigated. The obtained lignin samples were characterized by different analytical techniques evaluating their chemical structure, phenolic content, thermal behavior and molecular weight. The antioxidant activity of the analyzed lignins was evaluated by the DPPH assay, the radical ABTS assay, and trivalent iron reduction method. It was found t that lignin antioxidants could scavenge free radicals and reduce oxidants. The high correlation between antioxidant capacity and its total phenol content indicated that phenolic hydroxyl groups were the main contributors to these lignins' antioxidant activity.


Cytokine mapping in cerebrospinal fluid and blood in multiple sclerosis patients without oligoclonal bands.
Since there are clinical and genetic differences between MS patients with intrathecal oligoclonal bands (OCB+) in the cerebrospinal fluid (CSF) compared with those without (OCB-), the aim was to find out if OCB- patients showed a different pattern of cytokine immune activation compared with OCB+ patients. The study included 25 MS patients (10 OCB- and 15 OCB+) and 13 controls. A panel of cytokines was measured; IL-1β, IL-6, IL-8/CXCL8, IL-10, TNF and GM-CSF in serum, CSF and in supernatants from polyclonally stimulated blood mononuclear cells, where also levels of IL-12p40, IL-13, IL-15, IL-17 and IFN-γ were measured. The concentrations of soluble (s) VCAM-1 and sCD14 were measured in serum and CSF. In general, there were no extensive differences in cytokine concentrations between the OCB- and OCB+ groups. OCB- MS patients do not seem to constitute a separate entity concerning inflammatory parameters measured as cytokine concentrations in CSF and blood.


Fetal-neonatal and maternal outcomes in women with psoriasis vulgaris: A nationwide population-based registry linkage study in Taiwan.
Interdisciplinary care involving dermatologists and obstetricians is important for pregnant women with psoriasis. However, well-controlled risk estimates and detailed outcome measurements for adverse pregnancy and fetal outcomes are rare and inconsistent. The aim of the present study was to investigate maternal and fetal outcomes of mothers with psoriasis by using a population-based nationwide health registrar database. We identified 2 350 330 singleton pregnancies, of which 4058 singleton pregnancies were psoriatic patients using the Taiwan National Health Insurance database and birth registry from 2001 to 2012. Odds ratios (OR) and 95% confidence intervals (CI) for pregnancy outcomes were calculated using an adjusted generalized estimating equation model. Pregnancies in psoriatic patients were associated with an adjusted OR (95% CI) of 1.57 (1.31-1.89) for pre-eclampsia, 1.5 (1.28-1.75) for pregnancy-related hypertension and 1.57 (1.36-1.82) for severe post-partum hemorrhage. Offspring of women with psoriasis were associated with an adjusted OR (95% CI) of 1.48 (1.11-1.96) for stillbirth, 1.27 (1.14-1.41) for low birthweight of less than 2500 g, 1.13 (1.02-1.25) for preterm labor, 1.12 (1.02-1.23) for small for gestational age and 1.09 (0.96-1.25) for fetal distress. Lower Apgar scores were also observed in babies born to mothers with psoriasis. In conclusion, pregnancies in women with psoriasis have a significantly higher risk of adverse pregnancy outcome compared with unaffected mothers.


A rare case report of infratentorial cisternal angiolipoma with review of literature.
Angiolipomas are slow-growing benign mesenchymal-derived tumors consisting of mature adipocytes and thin-walled blood vessels. While the majority of angiolipomas are found in subcutaneous tissues, rarely there are case reports of intracranial lesions. We present a case of cisternal angiolipoma in a 10-year-old female. She presented with vague symptoms like dizziness without neurological deficits and radiological evaluation confirmed a left-sided infratentorial cisternal partially enhancing mass. She underwent craniotomy and had complete resection of the mass, which was histologically composed of mature adipocytes and blood vessels, consistent with angiolipoma. A review of the literature found only 18 cases of intracranial angiolipoma ever reported with our case representing the first case of infratentorial cisternal region.


The incidence and management of catheter occlusion in patients on home parenteral nutrition.
For patients on Home parenteral nutrition (HPN), catheter-related problems are the major source of morbidity and occlusion of the central venous catheter is one of these. We have managed 17 episodes of catheter occlusion in 10 patients on HPN. The median time from insertion to occlusive episode was 23 months. 10 catheters (59%) were saved by the used of thrombolytics (one by thrombolytics and ethanol) and 7 were replaced. The recent incidence of catheter occlusion in this cohort was one episode per 150 patient-months of HPN (0.08 episodes per year). Patients with Crohns disease appear to be at greater risk of developing catheter occlusion (p = <0.05).


Chondroitin sulfate prevents platelet derived growth factor-mediated phosphorylation of PDGF-Rbeta in normal human fibroblasts severely impairing mitogenic responses.
Platelet-derived growth factor (PDGF) is a major polypeptide mitogen for cells of mesenchymal origin such as fibroblasts. Chondroitin sulfate chains (CS), which are abundant in the extracellular matrix have been shown to physically interact with PDGF-BB modulating its biological function. The aim of the present study was to examine the involvement of CS on PDGF-BB induced proliferative responses and receptor activation in human lung fibroblasts. The addition of exogenous free CS chains caused a significant downregulation of the PDGF-BB mediated mitogenic and chemotactic responses. Similar results were obtained by the increase of endogenous CS biosynthesis after beta-D-xyloside treatment. Furthermore, removal of the membrane-bound CS chains by selective enzymatic treatment significantly increased the proliferative capacity of human fibroblasts. Analysis of PDGF-R phosphorylation in the presence of CS or beta-D-xyloside, revealed a reduction of PDGF-Rbeta phosphorylation in the tyrosine residue 1021. These results demonstrate, for the first time, that CS either soluble or surface bound downregulates the mitogenic responses of PDGF-BB in normal human lung fibroblasts through the reduction of PDGF-Rbeta phosphorylation.


Shaking the tree: mapping complex disease genes with linkage disequilibrium.
Much effort and expense are being spent internationally to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, the technology for detecting and genotyping single nucleotide polymorphisms (SNPs) has undergone rapid development, yielding extensive catalogues of these polymorphisms across the genome. Population-based maps of the correlations amongst SNPs (linkage disequilibrium) are now being developed to accelerate the discovery of genes for complex human diseases. These genomic advances coincide with an increasing recognition of the importance of very large sample sizes for studying genetic effects. Together, these new genetic and epidemiological data hold renewed promise for the identification of susceptibility genes for complex traits. We review the state of knowledge about the structure of the human genome as related to SNPs and linkage disequilibrium, discuss the potential applications of this knowledge to mapping complex disease genes, and consider the issues facing whole genome association scanning using SNPs.


Virtual reconstruction and morphological analysis of the cranium of an ancient Egyptian mummy.
A mummy of an Egyptian priestess dating from the 22nd dynasty (c. 770 BC), completely enclosed in an anthropoid (human shaped) coffin, was scanned on a CT scanner. An accurate reconstruction of the cranium was generated from 115 x 2 mm CT images using AVS/Express on a SGI computer. Linear measurements were obtained from six orthogonal cranial views and used in a morphometric analysis software package (CRANID). The analyses carried out were both linear and nearest neighbour discriminant analysis. The results show that there is a 52.9% probability that the mummy is an Egyptian female, with a 24.5% probability that the mummy is an African female. Thus the technique confirms that the coffin contains an Egyptian female, which is consistent with the inscription on the coffin and the shape of the pelvic bones as revealed by plain X-rays. These results show that this technique has potential for analysing forensic cases where the bones are obscured by soft tissue and clothing. This technique may have an application in virtual autopsies.


Low-Cost Flexible ZnO Microwires Array Ultraviolet Photodetector Embedded in PAVL Substrate.
With the advent of wearable device technology, fabrication of inorganic semiconductor devices on flexible organic substrates is of great interest. In this paper, a fascinating method and a low-cost flexible substrate material polyvinyl alcohol (PVAL) have been utilized to embed ZnO microwire (MW) array to produce ultraviolet (UV) photodetector (PD) with decent photoresponsivity. The flexible PVAL substrate is relatively cheap and has better bendability as compared to polyethylene terephthalate (PET) and other traditional flexible substrate materials, which makes it unique in comparison to traditional devices. The device shows a current photoresponsivity of 29.6 A/W in the UV spectral range (350 to 380 nm) and maintains an excellent detection performance with even a bending angle of 180°. In dark, a low current of 1.4 μA at 5 V bias and response time of 4.27 ms was observed. In addition to the excellent device performance at wide bending angles, the fabricated device also performs well with the bending radii close to 0. Therefore, ZnO MW array PD has a great potential for the real-time monitoring of harmful UV exposure to warn the users for the appropriate arrangement avoidance.


Identification and characterization of episomal forms of integrative genomic islands in the genus Francisella.
Recently, we identified a putative prophage on a genomic island (GI) within the genome sequence of Francisella hispaniensis isolate AS0-814 (Francisella tularensis subsp. novicida-like 3523) by the analysis of the CRISPR-Cas systems of Francisella. Various spacer DNAs within the CRISPR region of different F. tularensis subsp. novicida strains were found to be homologous to the putative prophage (Schunder et al., 2013, Int. J. Med. Microbiol. 303:51-60). Now we identified the GI (FhaGI-1) as a mobile element which is able to form a circular episomal structure. The circular episomal form of FhaGI-1 is generated by F. hispaniensis, and the excision of the island is an integrase-dependent and site-specific process. Furthermore, we could demonstrate that the excision of the island is also possible in other bacterial species (Escherichia coli). In addition, we could show that a genetically generated small variant of the island is also functional and, after its electroporation into strain F. tularensis subsp. holarctica LVS, the GI was stable and site-specifically integrated into the genome of the transformants. The integrase is sufficient for the integration and excision of the small variant into and from the DNA backbone, respectively. Thus, the element may be suitable to be used as a genetic tool in F. tularensis research. Furthermore, we identified the tRNA(Val) gene of Francisella as an integration site for GIs. Genomic island FphGI-1 was identified in Francisella philomiragia ATCC 25016. We were not able to detect the episomal form of this GI, probably due to a mutated attR site. However, we could demonstrate that integrative GIs are present in Francisella and that they may allow horizontal gene transfer between different Francisella species.


Recombinant human follicle-stimulating hormone produces more oocytes with a lower total dose per cycle in assisted reproductive technologies compared with highly purified human menopausal gonadotrophin: a meta-analysis.
Human menopausal gonadotrophins and recombinant human follicle stimulating hormone are the two main gonadotrophin products utilized for controlled ovarian stimulation in assisted reproductive technologies. In this meta-analysis, the number of oocytes was designated as the most relevant endpoint directly resulting from ovarian stimulation, and therefore where the drug effect may be estimated with the best sensitivity. All published randomized controlled trials on ovarian stimulation comparing the two gonadotrophin products were evaluated. Internal validity was determined using Chalmers' validated scale. If trials did not meet the established quality criteria, a sensitivity analysis assessed the stability of the results. The comparison of continuous variables was conducted following the weighted mean difference and the standardized mean difference (Cohen's effect size) with the random model. Given the known relationship of baseline conditions on treatment endpoints, results were adjusted for age, body mass index and type of infertility. Sixteen studies involving 4040 patients were included. Treatment with human menopausal gonadotrophins resulted in fewer oocytes (-1.54; 95% CI: -2.53 to -0.56; P < 0.0001) compared to recombinant human follicle-stimulating hormone. When adjusting for baseline conditions, the mean difference estimate was -2.10 (95% CI: -2.83 to -1.36; P < 0.001). A higher total dose of human menopausal gonadotrophin was necessary (mean difference, 235.46 IU [95% CI: 16.62 to 454.30; P = 0.03]; standardized mean difference, 0.33 [95% CI: 0.08 to 0.58; P = 0.01]). The pregnancy absolute risk difference (RD [hMG-r-hFSH]) for fresh transfers was 3% (P = 0.051), and the relative risk 1.10 (P = 0.06). When adjusted for baseline conditions, the relative risk was 1.04 (P = 0.49) and absolute difference was 0.01 (P = 0.34), respectively. Because baseline conditions are predictive of outcome, meta-analytic results are more sensitive when these variables are considered. Using an endpoint closely associated with the stimulation period, sufficient sensitivity is achieved to compare gonadotrophin treatments. As the largest meta-analysis published to date on this subject, treatment with human menopausal gonadotrophins is characterized by fewer oocytes and a higher total dose. When considering only fresh transfers, pregnancy rates were similar.


Subcallosal striations: early findings of multiple sclerosis on sagittal, thin-section, fast FLAIR MR images.
To determine how sensitive and specific the magnetic resonance (MR) imaging finding of subcallosal striations is for multiple sclerosis (MS). In 18 patients with clinically suspected MS and 32 age-matched patients without MS, sagittal 2-mm fast fluid-attenuated inversion-recovery (FLAIR) imaging was added to the routine MR studies of the brain. The images were reviewed for the presence of subcallosal striations, that is, linear, 1-mm-thick foci of hyperintensity perpendicular to the ependyma, like a stack of coins. The images were masked to exclude the hemispheric white matter and were interpreted without knowledge of patient age or medical history. Seventeen patients with clinical MS had subcallosal striations; one did not. Of the 32 patients without MS, five had subcallosal striations and 27 did not. Subcallosal striations were highly associated (P < .001) with clinical MS. Subcallosal striations are thought to represent perivenular demyelination, that is, the same process that later produces the "ovoid" lesions visible on routine MR images. Subcallosal striations are not seen on routine axial MR images and can be seen only on 2-mm sagittal FLAIR images.


Concordant evolution of a symbiont with its host insect species: molecular phylogeny of genus Glossina and its bacteriome-associated endosymbiont, Wigglesworthia glossinidia.
Many arthropods with restricted diets rely on symbiotic associations for full nutrition and fecundity. Tsetse flies (Diptera: Glossinidae) harbor three symbiotic organisms in addition to the parasitic African trypanosomes they transmit. Two of these microorganisms reside in different gut cells, while the third organism is harbored in reproductive tissues and belongs to the genus Wolbachia. The primary symbiont (genus Wigglesworthia glossinidia) lives in differentiated epithelial cells (bacteriocytes) which form an organ (bacteriome) in the anterior gut, while the secondary (S) symbionts are present in midgut cells. Here we have characterized the phylogeny of Wigglesworthia based on their 16S rDNA sequence analysis from eight species representing the three subgenera of Glossina: Austenina (=fusca group), Nemorhina (=palpalis group), and Glossina (=morsitans group). Independently, the ribosomal DNA internal transcribed spacer-2 (ITS-2) regions from these species were analyzed. The analysis of Wigglesworthia indicated that they form a distinct lineage in the gamma subdivision of Proteobacteria and display concordance with their host insect species. The trees generated by parsimony confirmed the monophyletic taxonomic placement of Glossina, where fusca group species formed the deepest branch followed by morsitans and palpalis groups, respectively. The placement of the species Glossina austeni by both the traditional morphological and biochemical criteria has been controversial. Results presented here, based on both the ITS-2 and the symbiont 16S rDNA sequence analysis, suggest that Glossina austeni should be placed into a separate fourth subgenus, Machadomyia, which forms a sister-group relationship with the morsitans group species.


Biological UV-doses and the effect of an ozone layer depletion.
Effective UV-doses were calculated based on the integrated product of the biological action spectrum (the one proposed by IEC, which extends to 400 nm, was adopted) and the spectral irradiance. The calculations include absorption and scattering of UV-radiation in the atmosphere, both for normal ozone conditions as well as for a depleted ozone layer. For Scandinavian latitudes the effective annual UV-dose increases by approximately 4% per degrees of latitude towards the Equator. An ozone depletion of one percent increases the annual UV-dose by approximately 1% at 60 degrees N (increases slightly at lower latitudes). A large depletion of 50% over Scandinavia (60 degrees N) would give these countries an effective UV-dose similar to that obtained, with normal ozone conditions, at a latitude of 40 degrees N (California or the Mediterranean countries). The Antarctic ozone hole increases the annual UV-dose by 20 to 25% which is a similar increase as that attained by moving 5 to 6 degrees of latitude nearer the Equator. The annual UV-dose at higher latitudes is mainly determined by the summer values of ozone. Both the ozone values and the effective UV-doses vary from one year to another (within +/- 4%). No positive or negative trend is observed for Scandinavia from 1978 to 1988.


Pseudo-dense Hair Transplantation: Strategy of "Less Inside, More Outside" and Central Bulking with Curled Chest Hairs as Treatment for Scalp Scars.
Hair transplantation in areas of scalp scars is a clinical challenge. However, by creating the visual illusion of central bulking with the use of peripherally transplanted curled chest hairs, cicatricial alopecia can perhaps be cosmetically improved. In a case of a 34-year-old affected man, this strategic procedure was implemented with positive results, as the transplantation was successful, the scar was far less noticeable, and the patient was satisfied with the results. The "pseudo-dense hair transplantation" method can be applied to similar patients, noting that a more succinct procedure will need to be elucidated for the varying etiologies of cicatricial alopecia.


Usefulness of an immunohistochemical score in advanced pancreatic neuroendocrine tumors treated with CAPTEM or everolimus.
Pancreatic neuroendocrine tumors are rare neoplasms for which few predictive and/or prognostic biomarkers have been validated. Our previous work suggested the potential of the combined expression of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) as prognostic factors for relapse and survival. In this new multicenter study we evaluated immunohistochemistry expression in 76 patients with advanced PanNET who were treated with capecitabine-temozolomide or everolimus. Based on the immunohistochemistry panel, an immunohistochemistry prognostic score (IPS) was developed. In patients treated with capecitabine and temozolomide, low IPS was an independent prognostic factor for progression-free-survival and overall-survival. Similar findings were observed with highest IPS for overall-survival in patients treated with everolimus. From our knowledge, it is the first time that a simple IPS could be useful to predict outcome for patients with metastatic pancreatic neuroendocrine tumors treated with everolimus or capecitabine and temozolomide.


Leadership styles' influence on ICU nurses' quality of professional life: A cross-sectional study.
Intensive Care Units are emotionally intense environments where professional autonomy and interprofessional collaboration are essential. Nurses are at high risk of burnout, and the level of compassion satisfaction has a deep impact on the quality of their professional life. Although leadership styles and burnout have been the subject of an extensive body of research, there is an existing gap regarding the relationship between leadership strategies and intensive care nurses' quality of working life and the impact on their compassion satisfaction. Specifically, there is a lack of literature in southern European countries concerning the influence of organizational and cultural contexts. To evaluate the impact of nurse managers' leadership styles on Intensive Care Unit nurses' job satisfaction and compassion satisfaction. A cross-sectional study. An online set of validated tests was sent to a non-probabilistic sample of nurses, recruited via the Italian association of intensive care and emergency nursing website. The set of tests consisted of the Empowering Leadership Questionnaire, Compassion Satisfaction Scale, and McCloskey Mueller Satisfaction Scale. Nurses actively working in intensive care and critical care settings were included in this study. ICU managers and leaders were excluded. 308 nurses (response rate 63,2%) completed the questionnaires. Statistical analysis showed that the Leadership dimension of "Showing concern towards the team" had a significant effect on Compassion Satisfaction. In addition, this dimension had an effect on nurses' overall job satisfaction on five out of eight subscales. Leaders' authentic listening, communication, and participation capabilities have a positive impact on nurses' job and compassion satisfaction. The interest for team well-being, taking time to discuss team concerns, and working closely with the team affects unpredicted factors like working hours, flexibility in shift scheduling, satisfaction about recognition, and career advancement. Results suggest that nurse managers can draw on/adopt leadership strategies oriented to authentic listening and interaction with the team in order to manage organizational issues, increase nurses' professional quality of life and prevent burnout.


Purification of a GalNAc-cluster-conjugated oligonucleotide by reversed-phase twin-column continuous chromatography.
Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) is a continuous chromatography technique used to maximize purification yields compared to traditional batch purification methods. Here we apply MCSGP for the reversed phase purification of a N-acetylgalactosamine (GalNAc)-cluster-conjugated DNA-LNA gapmer oligonucleotide therapeutic using a twin-column chromatography system. Based on a batch process as a starting point, MCSGP was designed, optimized and compared with the batch process regarding process performance and scale-up requirements. Product yields increased from 52.7% using batch chromatography to 91.5% using MCSGP, with purity, productivity, and buffer consumption otherwise comparable. In a manufacturing scenario, use of MCSGP would allow the downscaling of oligonucleotide synthesis by 42.5%, which would result in a significant cost reduction and increased throughput. Moreover, the equipment, chemicals and methodology used in MCSGP are analogous to a standard reversed phase purification allowing for a "like for like" transition to the upgraded MCSGP process.


[Ion mobility spectrometer (IMS): a novel online monitor of trace volatile organic compounds].
The principle, character and developments of the instrument of ion mobility spectrometry are introduced, the applications of IMS to chemical warfare agents, explosives, drugs, environments monitoring and on-site industrial sensing are discussed, and some work on IMS in ISAS is represented.


A comparative trial of pivmecillinam and ampicillin in bacteriuria of pregnancy.
A comparative trial of pivmecillinam and ampicillin was performed on 100 women with bacteriuria of pregnancy. They received either 400 mg pivmecillinam four times daily or 500 mg ampicillin four times daily for seven days. Cure rates at two weeks were 88% in the pivmecillinam group and 85% in the ampicillin group. At six weeks the respective rates were 76% and 64%. Failure of therapy was not associated with the appearance of bacterial resistance in either treatment group. Side-effects, particularly vomiting and premature cessation of therapy, were significantly more frequent in the pivmecillinam group. No significant effects on liver function were found. In subsequent patients treated in a non-comparative manner with 200 mg pivmecillinam three times daily, the incidence of side effects was markedly reduced with no loss of efficacy.


[Childhood dermatosis in a dermatology clinic of a general university hospital in Spain].
Pediatric dermatology is a relatively new subspecialty for which few epidemiological studies are available. We aimed to determine the work load associated with this subspecialty and the most common presenting complaints among pediatric patients in the general dermatology clinic of our hospital. A descriptive study was performed based on hospital records to analyze patients aged 16 years or under seen in our department in 2005 and their diagnoses. Pediatric dermatology accounts for 12.1 % of the work load in our department (1,329/10,998 patients were <or= 16 years old). By disease groups, tumors and infections were the most common diagnoses and accounted for 55.4 % of all cases. A long way behind was eczema (15.0 %) and diseases affecting hair follicles, nails, and sweat and sebaceous glands (8.8 %). The most common individual diagnosis was melanocytic nevus (19.8 %), followed by viral warts (12.1 %), atopic dermatitis (8.9 %), molluscum contagiosum (8.4 %), and acne (7.0 %). In most developed countries, atopic dermatitis is the most common dermatologic disease in children. In our study, however, melanocytic nevus was the most common presenting complaint, reflecting perhaps that there are more children in Spain with multiple nevi due to overexposure to sunlight or because of concern about melanoma among the population. Another possibility is that Spain has fewer cases of atopic dermatitis than more industrialized countries in northern Europe. Measures to avoid exposure to sunlight and use of sunscreen should be promoted during infancy. This could help slow the increase of melanoma in the adult population.


Total hepatectomy and liver transplantation as a two-stage procedure for toxic liver: case reports.
Total hepatectomy with temporary portocaval shunt was employed as a bridging procedure before liver transplantation, in the setting of fulminant hepatic failure with "toxic liver syndrome"; acute, severe, and extensive liver necrosis associated with cardiovascular shock and acute renal failure with or without respiratory failure. This procedure sought to improve metabolic acidosis and hemodynamic instability related to advanced liver necrosis. The aim of this study was to report our experience with three patients who underwent total hepatectomy and protocaval shunt, followed by liver transplantation (two-stage procedure).


An automated structured education intervention based on a smartphone app in Chinese patients with type 1 diabetes: a protocol for a single-blinded randomized controlled trial.
Although evidence had demonstrated the effectiveness of smartphone apps in diabetes care, the majority of apps had been developed for type 2 diabetes mellitus (T2DM) patients and targeted at populations outside of China. The effects of applying a smartphone app with structured education on glycemic control in type 1 diabetes mellitus (T1DM) are unclear. A digital, culturally tailored structured education program was developed in a smartphone app (Yi tang yun qiao) to provide an automated, individualized education program aimed at improving self-management skills in patients with T1DM in China. This trial aims to investigate the effectiveness of this smartphone app among Chinese T1DM patients. This single-blinded, 24-week, parallel-group randomized controlled trial of a smartphone app versus routine care will be conducted in Changsha, China. We plan to recruit 138 patients with T1DM who will be randomly allocated into the intervention group (automated, individualized education through an app) or routine care group. The intervention will last for 24 weeks. The primary outcome will be the change in glycated hemoglobin (HbA1c) from baseline to week 24. The secondary outcomes will include time in range, fasting blood glucose, levels of serum triglycerides and cholesterol, blood pressure, body mass index, quality of life, diabetes self-care activities, diabetes self-efficacy, depression, anxiety, and patient satisfaction. Adverse events will be formally documented. Data analysis will be conducted using the intention-to-treat principle with appropriate univariate and multivariate methods. Missing data will be imputed with a multiple imputation method under the "missing at random" assumption. This trial will investigate the effectiveness of an app-based automated structured education intervention for Chinese patients with T1DM. If the intervention is effective, this study will provide a strategy that satisfies the need for effective lifelong diabetes care to reduce the disease burden and related complications resulting from T1DM. ClinicalTrials.gov NCT04016987 . Registered on 29 October 2019.


Categorical variables, interactions and generalized additive models. Applications in computer-aided diagnosis systems.
Recently, the generalized additive models (GAMs) have been presented as a novel statistical approach to distinguish lesion/non-lesion in computer-aided diagnosis (CAD) systems. In this paper, we present an extension of the GAM that allows for the introduction of factors and their interactions with continuous variables, for reducing false positives in a CAD system for detecting clustered microcalcifications in digital mammograms. The results obtained have shown an increase in the sensitivity from 83.12% to 85.71%, while the false positive rate was drastically reduced from 1.46 to 0.74 false detections per image.


Highly Selective CO2 Electroreduction to CH4 by In Situ Generated Cu2 O Single-Type Sites on a Conductive MOF: Stabilizing Key Intermediates with Hydrogen Bonding.
It is still a great challenge to achieve high selectivity of CH4 in CO2 electroreduction reactions (CO2 RR) because of the similar reduction potentials of possible products and the sluggish kinetics for CO2 activation. Stabilizing key reaction intermediates by single type of active sites supported on porous conductive material is crucial to achieve high selectivity for single product such as CH4 . Here, Cu2 O(111) quantum dots with an average size of 3.5 nm are in situ synthesized on a porous conductive copper-based metal-organic framework (CuHHTP), exhibiting high selectivity of 73 % towards CH4 with partial current density of 10.8 mA cm-2 at -1.4 V vs. RHE (reversible hydrogen electrode) in CO2 RR. Operando infrared spectroscopy and DFT calculations reveal that the key intermediates (such as *CH2 O and *OCH3 ) involved in the pathway of CH4 formation are stabilized by the single active Cu2 O(111) and hydrogen bonding, thus generating CH4 instead of CO.


Femtosecond laser astigmatic keratotomy for postkeratoplasty astigmatism.
Two eyes of 2 patients with high astigmatism following penetrating keratoplasty were treated with femtosecond laser-assisted paired arcuate keratotomies in the donor cornea. Outcome measures included best-corrected visual acuity, refraction, keratometry, and topographic findings. The preoperative cylinder was 8.5 diopters (D) in the first case and 7.0 D in the second case. Respectively, the postoperative cylinder improved to 4.9 D after a follow-up of 8 months and to 4.3 D after a follow-up of 7 months. Best-corrected visual acuity improved from 20/100 to 20/30 in the first case and from 20/200 to 20/60 in the second case. No complications were encountered; no microperforations were observed, and neither graft rejection nor failure occurred. The results of astigmatic keratotomy performed with femtosecond laser were reliable and predictable. Femtosecond astigmatic keratotomy may prove to be a safe procedure with satisfactory results.


Amyoplasia congenita-like condition and maternal malathion exposure.
This report concerns an amyoplasia-like condition in a case with maternal exposure to malathion during the 11th to 12th week of pregnancy. Malathion is an agent acting on the neuromuscular system. The possibility of a causal association is discussed.


System identification of human triceps surae stretch reflex dynamics.
The interpretation of stretch-evoked reflex responses is complicated by the fact that the pattern of response will depend upon both the underlying reflex mechanisms and the time course of the stretch used to evoke the response. The objective of the present study was to use engineering systems analysis techniques to identify the dynamics of the human triceps surae (TS) stretch reflex in terms of its impulse response by deconvolving the position input from the observed response. Five normal subjects were instructed to maintain a tonic contraction of (TS) while subjected to repeated, computer-generated, stochastic perturbations of ankle position. Position, torque and smoothed, rectified surface EMGs were recorded and ensemble averaged over 25 stimulus presentations. Linear impulse response functions describing the dynamic relation between ankle velocity and TS EMG were found to account for a significant amount of the observed EMG variance (mean 60%). However, the impulse responses were noisy and the predicted EMG was systematically smaller than the observed EMG during the dorsiflexing phases of displacement. These findings suggested that a direction dependent nonlinearity might be present. Consequently, impulse responses relating half-wave rectified velocity to TS EMG were computed and found to be less noisy and to account for significantly more variance (mean 74%) than the purely linear model. The undirectional, velocity-sensitive impulse response functions were dominated by a large peak at about 40 ms followed by a smaller period of reduced activity. This is consistent with its mediation by primary spindle afferents. Although the shape of the impulse response remained unchanged, its amplitude, which provides a measure of relative gain, varied systematically with the level of contraction and the displacement amplitude. Multiple regression analysis demonstrated that most of the variation in the impulse response amplitude could be attributed to proportional increases with level of contraction (measured by average EMG) and proportional decreases with displacement amplitude.


Forgetting rates in neuropsychiatric disorders.
Previous studies have attributed accelerated forgetting rates on recognition memory tasks to temporal lobe pathology, but findings in some patient groups may have been attributable to metabolic disruption. Findings in psychiatric disorders such as schizophrenia are conflicting. The purpose of the present study was to compare forgetting rates in patients with confusional states (post-electroconvulsive therapy (post-ECT), delirium), with those obtained in schizophrenic patients (with putative temporal lobe pathology), non-ECT depressed patients, and healthy controls. The findings could also be compared with previous reports in patients with head injury, focal structural lesions, and Alzheimer's dementia. Two studies employed a picture recognition task to examine forgetting rates, the first between delays of 1 minute, 15 minutes, and 30 minutes, and the second between delays of 10 minutes, 2 hours, and 24 hours. There were no significant differences in forgetting rates between 1 minute and 30 minutes, but the ECT group showed accelerated forgetting between 10 minutes and 2 hours compared with healthy controls, associated with a rapid decline in "hit rate". This was not attributable to differential changes in either depression or severity of memory impairment. There were no differences in forgetting rates across the other subject groups. Post-ECT confusional state patients (similarly to "within post-traumatic amnesia" patients with head injury) show accelerated forgetting on a recognition memory task and, in this, they contrast with patients who have focal structural lesions or widespread cortical atrophy. Accelerated forgetting may reflect the effect of disrupted cerebral metabolism on either "consolidation" or memory "binding" processes.


Effect of selenium and vitamin E supplementation on lipid abnormalities in plasma, aorta, and adipose tissue of Zucker rats.
Twenty-nine obese female Zucker rats (fa/fa) were fed with a laboratory chow supplemented or not with a selenium-rich yeast (Selenion), or Selenion + vitamin E, or vitamin E alone. Twelve lean female Zucker rats (Fa/Fa) of the same littermates fed with the same diet were used as control. After 32 wk of diet, obesity induced a large increase in plasma insulin and lipid levels. A significant decrease in the plasma vitamin E/triglycerides ratio (p<0.005) and an increase in plasma thiobarbituric reactive substances (TBARS) (p<0.005) were also observed. Plasma selenium and vitamin E increased in all supplemented rats. The plasma insulin level was decreased by selenion supplementation and the vitamin E/triglycerides ratio was completely corrected by double supplementation with Selenion + vitamin E. TBARS were also efficiently decreased in two obese groups receiving vitamin E. In plasma, adipose tissue and aorta, obesity induced an increase in palmitic acid (C16:0), a very large increase in monounsaturated fatty acids (palmitoleic acid C16:1, stearic acid C18:1) associated with a decrease in polyunsaturated n-6 fatty acids (linoleic acid C18:2 n-6, arachidonic C20:4 n-6). These alterations in fatty acid distribution were only partly modulated by Se and vitamin E supplements. However, in the aorta, antioxidant treatment in obese rats significantly reduced the increase in C16:0 and C16:1 (p<0.05 and p<0.01, respectively) and the decrease in arachidonic acid (p<0.05). These changes could be beneficial in the reduction of insulin resistance and help to protect the vascular endothelium.


Effect of Statin Therapy on Age-Associated Changes in Physical Function Among Men With and Without HIV in the Multicenter AIDS Cohort Study.
The longer-term risks of statins on physical function among people with HIV are unclear. Longitudinal analysis of Multicenter AIDS Cohort Study men between 40 and 75 years of age with ≥2 measures of gait speed or grip strength. Generalized estimating equations with interaction terms between (1) statin use and age and (2) HIV serostatus, age, and statin use were considered to evaluate associations between statin use and physical function. Models were adjusted for demographics and cardiovascular risk factors. Among 2021 men (1048 with HIV), baseline median age was 52 (interquartile range 46-58) years; 636 were consistent, 398 intermittent, and 987 never statin users. There was a significant interaction between age, statin, and HIV serostatus for gait speed. Among people with HIV, for every 5-year age increase, gait speed (m/s) decline was marginally greater among consistent versus never statin users {-0.008 [95% confidence interval (CI) -0.017 to -0.00007]; P = 0.048}, with more notable differences between intermittent and never users [-0.017 (95% CI -0.027 to -0.008); P < 0.001]. Similar results were observed among men without HIV. Significant differences in grip strength (kg) decline were seen between intermittent and never users [-0.53 (95% CI -0.98 to -0.07); P = 0.024] and differences between consistent and never users [-0.28 (95% CI -0.63 to 0.06); P = 0.11] were not statistically significant. Among men with and without HIV, intermittent statin users had more pronounced declines in physical function compared with consistent and never users. Consistent statin use does not seem to have a major impact on physical function in men with or without HIV.


Exploring HPV vaccine hesitant parents' perspectives on decision-making and motivators for vaccination.
The human papillomavirus (HPV) vaccine is highly effective at preventing HPV-associated cancers in both males and females, yet vaccination rates remain sub-optimal in part due to vaccine hesitancy. This study sought to assess which strategies vaccine-hesitant parents perceive as most likely to motivate them to vaccinate their children against HPV. In 2021, we recruited parents with children ages 10-17 years old who were not vaccinated against HPV and who felt unsure or hesitant about their decision to vaccinate their child. Participants were recruited through an online patient portal within a single institution. A screening survey assessed for vaccine hesitancy. Semi-structured interviews focused on HPV vaccine decision-making, motivators, and potential strategies to improve vaccination rates in hesitant parents. Audio recordings were transcribed and analyzed via a combination of deductive and inductive codes. A total of twenty-two vaccine-hesitant parents were interviewed. The major themes identified were a lack of confidence in vaccine decision-making, a desire for more information, and dissatisfaction with provider encounters. Parents reported that their hesitancy was driven by concerns about safety and necessity, often based on negative anecdotal reports. Although pediatricians were the most often cited source of vaccine information, many parents were dissatisfied with the encounters they had regarding the vaccine. Parents expressed a desire for detailed information on both the benefits and risks of the vaccine, and resources that allowed them to actively participate in vaccine discussions with providers. Suggested modes of delivery for this information included in-depth pediatrician discussions, written materials provided by pediatricians, and facilitation tools, such as a list of questions to help parents prepare for pediatrician visits. Thus, strategies that empower parents to feel informed and confident in their decision to vaccinate their children could be useful in motivating vaccine-hesitant parents to vaccinate their children against HPV.


Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome.
To review our experience treating patients with the Hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. Retrospective interventional case series. We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the Hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; sex; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months, respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, nor the patient with T3bN1M0 disease, had required orbital exenteration. Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients.


Retroperitoneal soft-tissue sarcomas: Radiotherapy experience from a tertiary cancer center and review of current evidence.
Surgery remains to be the main therapeutic approach for retroperitoneal sarcomas (RPS) although evidence supports that complementary radiotherapy increases local-control and survival. We present a multidisciplinary management and experience of a tertiary cancer center in the treatment of RPS and analyze current evidence of radiotherapy efficacy. We retrospectively reviewed 19 patients with primary or relapsed RPS treated between November 2009 and October 2018. Multidisciplinary approach comprised complete resection in 15 patients (79%) achieving resection R0 in 11 patients (58%), R1 in 4 patients (21%) and R2 in 2 patients (10%). Seven patients (37%) underwent a preoperative radiation (PRORT), 10 patients (53%), post-operative radiation (PORT) and 2 patients (10%), received radiotherapy exclusively. Ten patients (53%) received adjuvant chemotherapy. With a median follow-up of 24 months (2-114 months), actuarial rates of loco-regional relapse free survival (LRFS) at 1, 2 and 3 years were 77%, 77% and 67%, respectively. Actuarial rates of distant-metastases-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) at 1, 2 and 3 years were 100%, 100% and 80% for DMFS; 94%, 77% and 67% for DFS and 100%, 91% and 91% for OS, respectively. Only surgical margins (negative vs. positive) showed significance for 3y-LRFS: 100% vs. 34.3%, p = 0.018. Treatment tolerance was acceptable with no acute or late toxicity higher than grade 2. Complementary radiotherapy appears to be useful and well tolerated for the multidisciplinary management of RPS. Presence of positive surgical margins seems to be the most relevant prognostic factor through the follow-up.


The treatment of idiopathic and secondary hydrarthrosis of the knee by intra-articular Rifamycin SV.
Fifty-three patients, 28 females and 25 males, aged from 21 to 68 years, affected with mono- and bilateral intermittent hydrarthrosis of the knee and of a non-inflammatory nature, were included in an open study. All of the knees involved were treated with intra-articular infiltrations with Rifamycin SV. The weekly dosage of Rifamycin SV was 500 mg; the average duration of treatment was 6 weeks. Follow-up 1 year after the end of treatment showed a decrease or regression in joint effusion in all of the knees treated.


Isolation methods of large and small extracellular vesicles derived from cardiovascular progenitors: A comparative study.
Since the discovery of the beneficial therapeutical effects of extracellular vesicles (EVs), these agents have been attracting great interest as next-generation therapies. EVs are nanosized membrane bodies secreted by all types of cells that mediate cell-cell communication. Although the classification of different subpopulations of EVs can be complex, they are broadly divided into microvesicles and exosomes based on their biogenesis and in large and small EVs based on their size. As this is an emerging field, current investigations are focused on basic aspects such as the more convenient method for EV isolation. In the present paper, we used cardiac progenitor cells (CPCs) to study and compare different cell culture conditions for EV isolation as well as two of the most commonly employed purification methods: ultracentrifugation (UC) and size-exclusion chromatography (SEC). Large and small EVs were separately analysed. We found that serum starvation of cells during the EV collecting period led to a dramatic decrease in EV secretion and major cell death. Regarding the isolation method, our findings suggest that UC and SEC gave similar EV recovery rates. Separation of large and small EV-enriched subpopulations was efficiently achieved with both purification protocols although certain difference in sample heterogeneity was observed. Noteworthy, while calnexin was abundant in large EVs, ALIX and CD63 were mainly found in small EVs. Finally, when the functionality of EVs was assessed on primary culture of adult murine cardiac fibroblasts, we found that EVs were taken up by these cells, which resulted in a pronounced reduction in the proliferative and migratory capacity of the cells. Specifically, a tendency towards a larger effect of SEC-related EVs was observed. No differences could be found between large and small EVs. Altogether, these results contribute to establish the basis for the use of EVs as therapeutic platforms, in particular in regenerative fields.


Exploring factors influencing patient mortality and loss to follow-up in two paediatric hospital wards in Zamfara, North-West Nigeria, 2016-2018.
Child mortality has been linked to infectious diseases, malnutrition and lack of access to essential health services. We investigated possible predictors for death and patients lost to follow up (LTFU) for paediatric patients at the inpatient department (IPD) and inpatient therapeutic feeding centre (ITFC) of the Anka General Hospital (AGH), Zamfara State, Nigeria, to inform best practices at the hospital. We conducted a retrospective cohort review study using routinely collected data of all patient admissions to the IPD and ITFC with known hospital exit status between 2016 and 2018. Unadjusted and adjusted rate ratios (aRR) and respective 95% confidence intervals (95% CI) were calculated using Poisson regression to estimate the association between the exposure variables and mortality as well as LTFU. The mortality rate in IPD was 22% lower in 2018 compared to 2016 (aRR 0.78; 95% CI 0.66-0.93) and 70% lower for patients coming from lead-affected villages compared to patients from other villages (aRR 0.30; 95% CI 0.19-0.48). The mortality rate for ITFC patients was 41% higher during rainy season (aRR 1.41; 95% CI 1.2-1.6). LTFU rates in ITFC increased in 2017 and 2018 when compared to 2016 (aRR 1.6; 95% CI 1.2-2.0 and aRR 1.4; 95% CI 1.1-1.8) and patients in ITFC had 2.5 times higher LTFU rates when coming from a lead-affected village. Our data contributes clearer understanding of the situation in the paediatric wards in AGH in Nigeria, but identifying specific predictors for the multifaceted nature of mortality and LTFU is challenging. Mortality in paediatric patients in IPD of AGH improved during the study period, which is likely linked to better awareness of the hospital, but still remains high. Access to healthcare due to seasonal restrictions contributes to mortalities due to late presentation. Increased awareness of and easier access to healthcare, such as for patients living in lead-affected villages, which are still benefiting from an MSF lead poisoning intervention, decreases mortalities, but increases LTFU. We recommend targeted case audits and qualitative studies to better understand the role of health-seeking behaviour, and social and traditional factors in the use of formal healthcare in this part of Nigeria and potentially similar settings in other countries.


Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance.
Drug resistance is a major obstacle to successful cancer chemotherapy. P-glycoprotein, which transports certain antitumor agents out of resistant tumor cells, is known to be a major factor in some types of multidrug resistance. Studies have shown that verapamil and the immunosuppressors cyclosporine and FK-506 can reverse multidrug resistance in vitro and in vivo and that the P-glycoprotein monoclonal antibody MRK-16 increases drug toxicity in multidrug-resistant tumors. The purpose of this in vitro study was to establish effective treatment modalities for overcoming multidrug resistance. We assessed the synergistic effects of verapamil, cyclosporine, or FK-506 in combination with MRK-16 and antitumor agents. Human myelogenous leukemia K562 cells and multidrug-resistant K562/ADM cells were treated with vincristine or doxorubicin combined with MRK-16 and cyclosporine alone or together; MRK-16 and verapamil alone or together; or MRK-16 and FK-506. The effects of MRK-16 and cyclosporine or verapamil on the accumulation of vincristine and doxorubicin were examined in K562/ADM cells, and the mechanisms of action were analyzed. MRK-16 and cyclosporine synergistically enhanced the antitumor effects of vincristine and of doxorubicin in K562/ADM cells. However, the combined use of MRK-16 with verapamil or FK-506 did not show such synergistic effects in these cells. Studies of the effect of MRK-16 on cellular accumulation of cyclosporine and verapamil revealed that MRK-16 substantially increased accumulation of cyclosporine in K562/ADM cells, but did not increase accumulation of verapamil. MRK-16 and cyclosporine synergistically enhanced the antitumor effects of vincristine and doxorubicin because MRK-16 increased cellular accumulation of cyclosporine. These results, together with our previous finding that intravenous administration of MRK-16 induced regression of multidrug-resistant subcutaneous tumors in athymic mice, support the hypothesis that the combined use of MRK-16 and cyclosporine might increase the efficacy of antitumor agents against multidrug-resistant tumors expressing P-glycoprotein. Clinical phase I trials of MRK-16 in the treatment of multidrug-resistant tumors are under consideration.


The subsequent interruptive effects of pain on attention.
Pain is known to interrupt attentional performance selectively. In a previous study, we showed that the interruptive effect of thermal pain on attention could persist up to 1500 ms after painful stimulus offset, but whether the pain modality affects this subsequent interruptive effect remains unclear. The present study was conducted to determine the time course of the interruptive effect of electrically induced pain on orienting and executive attention using various intervals between electric stimulation and attentional tasks (0, 250, 500, 750, 1000, 1250 and 1500 ms) and three study groups (pain, non-pain and control). We performed two separate experiments in which participants performed a spatial cue task (Experiment 1) and the Stroop task (Experiment 2). Participants in the pain and non-pain groups received brief electric somatosensory stimulation, and those in the control group received no physical stimulus. We compared the performance of the three groups under the interstimulus interval (ISI) conditions. The impairment of orienting attention prevailed under the first six ISI conditions in the pain and non-pain groups (F2, 63 = 5.72, p < 0.01); executive attention was not affected (F1,66 = 1.64, p = 0.20), confirming the persistence of the interruptive effect after stimulus offset. This study demonstrated the interruptive effect of somatic stimulation on subsequent orienting attention performance, with no effect on executive attention. These findings suggest that pain has differential effects on the components of attention, depending on its modality and salience. This study confirmed that pain had a selective subsequent interruptive effect on attention and found that the time course of the interruption depended on the modality of pain and the component of attention.


Effects of confinement on models of intracellular macromolecular dynamics.
The motions of particles in a viscous fluid confined within a spherical cell have been simulated using Brownian and Stokesian dynamics simulations. High volume fractions mimicking the crowded interior of biological cells were used. Importantly, although confinement yields an overall slowdown in motion, the qualitative effects of motion in the interior of the cell can be effectively modeled as if the system were an infinite periodic system. However, we observe layering of particles at the cell wall due to steric interactions in the confined space. Motions of nearby particles are also strongly correlated at the cell wall, and these correlations increase when hydrodynamic interactions are modeled. Further, particles near the cell wall have a tendency to remain near the cell wall. A consequence of these effects is that the mean contact time between particles is longer at the cell wall than in the interior of the cell. These findings identify a specific way that confinement affects the interactions between particles and points to a previously unidentified mechanism that may play a role in signal transduction and other processes near the membrane of biological cells.


[Transfusion requirements in chronic kidney disease].
Population-based study suggests that chronic kidney disease is frequent. Almost one third of people older than 70 years of age would have a significant decrease in renal function. Anemia appears when glomerular filtration rate falls under 40mL per minute per 1.73m(2). Concurrently with supplementary iron, erythropoiesis-stimulating agents (ESA) allow a strict control of hemoglobin. However, incomplete responses to ESA are possible. The following conditions - inflammatory disorders, chronic blood loss, hyperparathyroidism, surgical process, chronic diseases, adverse effects of immunosuppressive agents - may cause apparent resistance to ESA therapy. All these conditions may request transfusion.


Up-regulated expression of E2F2 is necessary for p16INK4a-induced cartilage injury.
Cartilage degradation would result in osteoarthritis (OA). p16INK4awas found in some age-related diseases. In this study, we aimed to determine the role of p16INK4a during OA and to investigate the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA) was performed to test the activity of senescence-associated secretory phenotype (SASP). Real-time PCR (RT-PCR) and Western blot were used to determine the expressions of target genes. The increased expressions of p16INK4a and E2F2 were accompanied with cartilage degradation induced by IL-1β. Over-expression of p16INK4a enhanced the secretion of SASP markers (TGFβ, IL-6, IL-8, IL-1α, MMP3 and MMP13), reduced the expression of type II procollagen (COL2A1).Thus, the over-expression of p16INK4a lead to cartilage injury. Moreover, we found that the expression of E2F2 was enhanced in p16INK4a over-expression group, and that cartilage injury caused by p16INK4a was alleviated by depleting E2F2. p16INK4a was up-regulated during the cartilage injury in OA. p16INK4a promoted cartilage injury by increasing the expression of E2F2. Thus, this study extends the molecular regulation network for understanding pathological progression of OA, and provides potential therapeutic target for OA.


High tibial osteotomy in medial compartment osteoarthritis of knee: functional outcome of medial open wedge and lateral closing wedge osteotomies-How does the outliers fare in the medium term?
Our study aimed to compare the functional outcome of HTO performed via lateral closing wedge osteotomy and medial open wedge osteotomy followed up for a mean period of 6 years using Lysholm knee score. Secondary objective was to find out whether an achievement of 2°-6° of mechanical axis had a significant impact in the outcome and how the outliers of 2°-6° (177°-182° (straight knees) and greater than 186° (overcorrection) performed in the medium term and how patients who lost correction to more than - 3° (persistent varus) performed in the medium term. This is a prospective observational study. Sixty-two consecutive patients who had undergone HTO by a single surgeon from 2012 to 2015 were followed up. The final follow-up visit was from August 2019 to December 2019. Nine were lost to follow-up, and 53 presented for the follow-up visit. Case records were noted for the preoperative LKS scores, preoperative mechanical axis, ROM, and preoperative tibiofemoral angle. Post-operative mechanical axis in full-length weight bearing at 4 months was also noted. During the latest visit, patients underwent LKS scoring, full-length weight-bearing X-rays to assess mechanical axis, and assessment of tibiofemoral angle. The results were grouped into excellent, good, fair, and poor outcomes based on LKS scale. The mechanical axes attained at surgery and at the follow-up were grouped into less than 177° as varus, 177°-182° as straight 182°-186° as required correction, and more than 186° as overcorrection. Lysholm knee score was dichotomised using LKS 84 as the cut-off (LKS ≥ 84 high LKS; LKS 84 low LKS). A total of 53 patients with a median age of 56 years (SD 4.23) were included in this study. There were 8 (15.1%) males and 45 (84.9%) females. The mean ± SD of BMI of patients was 28.10 ± 2.66 kg/m2. Medial opening wedge osteotomy was performed in 27 (50.9%) cases, and lateral closing wedge osteotomy was performed in 26 (49.1%). Median duration between the time of surgery and the follow-up was 72 months (IQR 32.5). Preoperatively, the mean LKS score of the patients was 50.25 ± 12.43 (88.68% had poor score and 11.32% had fair score), and the mean mechanical axis of the knee was 172.54 ± 3.78 (all had varus deformity). The mean (SD) preoperative LKS score of the 53 participants before the surgery was 50.25 (12.43). Poor score was reported by 47 (88.68%) and fair score by 6 (11.32%) patients, respectively. At the time of final follow-up, the mean (SD) LKS score of 53 patients was 77.81(17.11). At the time of final follow-up (when compared with the score before surgery), 41(77.36%) patients had improvement in the LKS score, 10 (18.87%) patients had no improvement in the score, and 2 (3.77%) patients worsened from fair to poor. The difference between the LKS score before surgery and at the final follow-up was significantly greater for patients who underwent medial opening wedge osteotomy [median (IQR)35 (26-38)] than for the patients who underwent lateral closing wedge osteotomy [median (IQR) 30 (23-34)], U226.5, p 0.026. Knees with desired valgus angle within 2°-6° and knees which remained straight at the final follow-up showed a good or excellent outcome at the final follow-up (23 out of 53 knees). Those knees with had varus HKA axis had a poor or fair outcome at the final follow-up (23 out of 53 knees). Those knees that were overcorrected also had poor outcomes. Our study shows that both medial open wedge osteotomy and lateral closing wedge osteotomy are capable of improving knee function in medial compartment osteoarthritis of knee. Medial open wedge with locking plates is a biomechanically more stable construct compared with lateral closing wedge osteotomy. Irrespective of the two techniques chosen, the aim of the osteotomy should be to achieve an overcorrection of 2°-6° of valgus or at least to keep the knee straight (normal mechanical axis). This will give a satisfactory medium-term result. However, varus alignment and valgus alignment of more than 6° can result in a deterioration of function of knee. The results of the osteotomy are found to deteriorate with obesity, severe varus in preop mechanical axis and longer duration of follow-up.


Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin.
We previously reported that autoantibodies against carbonic anhydrase II and lactoferrin are frequently identified in patients with autoimmune-related pancreatitis. To clarify the role of carbonic anhydrase II and lactoferrin, we created animal models of autoimmune pancreatitis by immunizing neonatally thymectomized mice with carbonic anhydrase II and lactoferrin and also by transferring immunized spleen cells to nude mice. Neonatally thymectomized BALB/c mice were immunized with carbonic anhydrase II or lactoferrin followed by three booster injections (n = 10 in each group). We transferred whole, CD4+, or CD8+ spleen cells prepared from immunized neonatally thymectomized mice to nude mice (n = 5 in each group). Gene expression of IFN-gamma and IL-4 was investigated using semiquantitative reverse transcription-polymerase chain reaction. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining was used to examine apoptosis. In immunized neonatally thymectomized mice, the prevalence of inflammation was significantly higher in the pancreas. Inflammation was present in all mice receiving whole or CD4+ cells. There was no change in any of the mice receiving CD8+ cells or nonimmunized spleen cells. Carbonic anhydrase II or lactoferrin-immunized mice had apoptotic duct cells or acinar cells, respectively. Expression of the IFN-gamma gene was up-regulated in each group. Similar findings were observed in the salivary glands and liver. An immunologic mechanism against carbonic anhydrase II or lactoferrin is involved in the pathogenesis of these pancreatitis models, in which the effector cells are Th1-type CD4+ T cells.


MRI findings in children with congenital cytomegalovirus infection retrospectively diagnosed with dried umbilical cord.
Brain MRI provides important information about suspected congenital CMV infection in neonatally underdiagnosed children. This study aimed to describe MRI findings in children in whom congenital CMV infection was not suspected during the neonatal period and was proven retrospectively. We enrolled 31 children referred to the pediatric neurology clinic with neurological symptoms who were proven to have congenital CMV infection based on dried umbilical cord samples. Upon diagnosis, MR and CT images were assessed using the van der Knaap scoring system integrated with additional variables. Two investigators independently assessed all images. The age at diagnosis was < 12 months in 14, 12-24 months in 11, and > 24 months in 6 patients. The initial symptom triggering clinic referral was delayed development in 22, seizure in 5, deafness in 3, and hemiplegia in 1 patient. Of the 31 children, 30 had a white matter (WM) abnormality predominant in the deep WM of the parietal lobe (n = 25). Anterior temporal lesions were observed in 21 children. Cortical lesions were observed in 7 children, suggestive of polymicrogyria. No child had cerebellar or brainstem abnormalities. Brain CT was performed in 22 of 31 children, and 11 showed punctate cerebral calcification in the periventricular and/or deep WM. Patients with congenital CMV infection with delayed neurological symptoms show a relatively uniform pattern of parietal-dominant multifocal WM lesions and anterior temporal lesions, with or without polymicrogyria.


Mucosal immunization with a ricin toxin B subunit-rotavirus NSP4 fusion protein stimulates a Th1 lymphocyte response.
The castor-oil plant Ricinus communis A-B dimeric toxin B subunit (RTB) was genetically linked at its N-terminus with a 90 amino acid peptide from simian rotavirus SA-11 non-structural protein NSP4(90) and produced in Escherichia coli BL21 cells. Biologically active recombinant NSP4(90)-RTB fusion protein was shown to bind glycoprotein asialofetuin receptor molecules in an in vitro enzyme-linked immunosorbent assay (ELISA). Oral inoculation of the purified NSP4(90)-RTB ligand-antigen fusion protein delivered the chimeric protein to intestinal epidermal cells for mucosal immunization against rotavirus infection. Mice fed the NSP4(90)-RTB fusion protein generated higher humoral and intestinal antibody titers than mice inoculated with NSP4(90) alone. Titers of serum IgG2a antibodies were significantly higher than IgG1 titers suggesting a dominant Th1 lymphocyte immune response. ELISA measurement of cytokines secreted from splenocyte isolated from immunized mice confirmed NSP4(90)-RTB fusion protein stimulates a strong Th1 cell-mediated immune response. The experimental results demonstrate that the ricin toxin B subunit N-terminus can be used as a site for delivery of virus antigens to the gut associated lymphoid tissues for RTB-mediated immune stimulation of antiviral mucosal immune responses.


Oxytocin ameliorates KCC2 decrease induced by oral bacteria-derived LPS that affect rat primary cultured cells and PC-12 cells.
Inflammation, especially neuroinflammation, which is caused by stress, leads to central nervous system (CNS) dysfunction. Because lipopolysaccharides (LPSs) cause neuroinflammation, we investigated the effect of LPSs to CNS. In PC-12 cells, LPSs derived from oral bacteria reduced the expression of KCC2, a Cl- transporter. LPS derived from P. gingivalis (P. g) administered to rat primary cultured cells also reduced the KCC2 expression. However, LPSs derived from E. coli did not reduce the KCC2 expression. LPS treatment activated TLR4, IL-1β, and REST gene expressions, which led to KCC2 inactivation in PC-12 cells. The mechanism of KCC2 has been shown to play an important role in brain maturation, function (such as the GABA switch), and behavioral problems, we investigated the GABA function. We found that the GABA function was changed from inhibitory to excitatory by the LPS derived from P. g treatment. We demonstrated that the GSK3β also involved in the KCC2 reduction by LPS treatment. We show that oxytocin rescued the reduction in KCC2 expression caused by LPSs by inhibiting GSK3β signaling but vasopressin could not. Considered together, our results indicate that the LPSs from oral bacteria but not the LPS from E. coli increase the risk for brain disorders and oxytocin might be a candidate to overcome the abnormal behavior caused by brain disorders such as psychiatric disorders.


Hepatitis C virus seroprevalence rate among Saudis.
The aim of the study is to determine the seroprevalence of hepatitis C virus (HCV) in blood donors, children, pregnant women, hemodialysis patients and drug addicts in Saudi Arabia. Using third generation enzyme immunoassay kits, we have screened Saudi cohorts of all ages and sexes, namely infants, pre-school, school children, young adults and adults (blood donors and antenatals) for antibodies to HCV. We have also reviewed HCV seroprevalence data among high risk groups from 1998 to 2002. An overall 1.1% (6313 out of 557813) seroprevalence rate was determined among Saudi blood donors; 0.1% (5 out of 3854) in Saudi children; and 0.7% (22 out of 3127) among pregnant women. Hemodialysis patients remain at highest risk of infection at 55.7% whereas intravenous drug addicts have 14% exposure rate. We conclude that the present public health schemes have been effective in reducing hepatitis C infection in the general community in the Kingdom of Saudi Arabia but the infection among high risk groups remain a major problem that needs to be actively addressed.


Postoperative intensity-modulated arc therapy for cervical and endometrial cancer: a prospective report on toxicity.
To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m(2), weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. Regarding acute toxicity (n = 65), Grade 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of EC patients experienced Grade 2 fatigue and skin toxicity, respectively. Adding cisplatin led to an increase in Grade >2 nausea (57% vs. 9%; p = 0.01), Grade 2 nocturia (24% vs. 4%; p = 0.03), Grade ≥ 2 hematologic toxicity (38% vs. nil, p = 0.003), Grade ≥ 2 leukopenia (33% vs. nil, p = 0.009), and a strong trend toward more fatigue (14% vs. 2%; p = 0.05). Para-aortic lymph node irradiation led to an increase of Grade 2 nocturia (31% vs. 4%, p = 0.008) and a strong trend toward more Grade >2 nausea (44% vs. 18%; p = 0.052). Regarding late toxicity (n = 45), no Grade 3 or 4 late toxicity occurred. Grade 2 gastrointestinal toxicity, genitourinary toxicity, and fatigue occurred in 4%, 9%, and 1% of patients. Neither concomitant cisplatin nor PALN irradiation increased late toxicity rates. Postoperative IMAT for EC or CC is associated with low acute and late toxicity. Concomitant chemotherapy and PALN irradiation influences acute but not late toxicity.


Transient autonomic responses during sustained attention in high and low fit young adults.
Maintaining vigilance over long periods of time is especially critical in performing fundamental everyday activities and highly responsible professional tasks (e.g., driving, performing surgery or piloting). Here, we investigated the role of aerobic fitness as a crucial factor related to the vigilance capacity. To this end, two groups of young adult participants (high-fit and low-fit) were compared in terms of reaction time (RT) performance and event-related heart rate responses in a 60' version of the psychomotor vigilance task. The results showed shorter RTs in high-fit participants, but only during the first 24' of the task. Crucially, this period of improved performance was accompanied by a decelerative cardiac response pattern present only in the high-fit group that also disappeared after the first 24'. In conclusion, high aerobic fitness was related to a pattern of transient autonomic responses suggestive of an attentive preparatory state that coincided with improved behavioural performance, and that was sustained for 24'. Our findings highlight the importance of considering the role of the autonomic nervous system reactivity in the relationship between fitness and cognition in general, and sustained attention in particular.


Uncertainty in the niches that maintain haematopoietic stem cells.
Haematopoietic stem cell (HSC) niches are specialized microenvironments that contain stem cells and regulate their maintenance. Cells at the interface of bone and the bone marrow (the endosteum) contribute to the creation of HSC niches. It remains uncertain whether this interface itself is a niche, or whether endosteal cells secrete factors that diffuse to nearby niches. Vascular and/or perivascular cells may also create niches as many HSCs are observed around sinusoidal blood vessels, and perivascular cells secrete factors that regulate HSC maintenance. Do endosteal and perivascular cells create distinct niches, or do they contribute to a common niche? We discuss a range of niche models consistent with recent evidence.


On the effects of the Fusarium toxin deoxynivalenol (DON) administered per os or intraperitoneal infusion to sows during days 63 to 70 of gestation.
Six pregnant sows of 180.6 ± 5.6 kg were fed either a Fusarium-contaminated (4.42 mg DON and 48.3 µg ZON per kg, DON per os, n = 3) or a control diet (0.15 mg DON and 5 µg ZON/kg) in the period of days 63 and 70 of gestation. On day 63 of gestation, sows fed the control diet were implanted with an intraperitoneal osmotic minipump (delivery rate of 10 µL/h, for 7 days) containing 50 mg pure (98%) DON in 2 ml 50% DMSO (DON ip, n = 3). Frequent plasma samples were taken to estimate the kinetics after oral and ip DON exposure. The intended continuous delivery of DON by the intraperitoneal minipump could not be shown, as there was a plasma peak (Cmax) of 4.2-6.4 ng DON/mL either immediately (sow IP-2+3) or 2.5 h (sow IP-1) after implantation of the pump followed by a one-exponential decline with a mean half-time (t1/2) of 1.75-4.0 h and only negligible DON plasma concentrations after 12 h. Therefore, the DON ip exposure has to be regarded as one single dose 1 week before termination of experiment. The DON per os sows showed a mean basis level (after achieving a steady state) of DON plasma concentration of about 6-8 ng/mL, as also indicated by the plasma DON concentration at the termination of the experiment. On day 70, caesarean section was carried out, the fetuses were killed immediately after birth, and samples of plasma, urine, and bile were taken to analyze the concentration of DON and its metabolite de-epoxy-DON. At necropsy there were no macroscopic lesions observed in any organ of either sows or piglets. Histopathological evaluation of sows liver and spleen revealed no alterations. The proliferation rate of peripheral blood mononuclear cells (PBMC) with or without stimulation was not affected by the kind of DON treatment. The exposure of pregnant sows at mid-gestation (days 63-70, period of organogenesis) to a Fusarium toxin-contaminated diet (4.42 mg DON and 0.048 mg ZON per kg) or pure DON via intraperitoneal osmotic minipump did not cause adverse effects on health, fertility, maintenance of pregnancy, and performance of sows and their fetuses. However, DON was detected in fetus plasma, indicating that this toxin can pass the placental barrier and may cause changes in the proportion of white blood cells (lower monocyte and neutrophil and higher lymphocyte proportion in DON per os fetuses).


Quality and cost evaluation of a medical financial assistance program.
Kaiser Permanente Colorado has been responding to the financial challenges of its members by providing a medical financial assistance (MFA) program since 1992. However, there have been no evaluations of the effect of this program on members' use of health services or their health outcomes. A prospective cohort study of 308 MFA program members who were enrolled between May 16, 2008, and May 16, 2009, examined changes in their use of health services, costs, and self-reported physical and mental health after enrollment in the MFA program. Use of services was analyzed with multiple regression, and costs of services with generalized linear models. MFA increased members' access to health services. There were no changes in physical or mental health status. For each health care visit before the MFA award, patients used the health care system 0.23 visits less. The MFA amount was not associated with an increase or decrease in use. There was no significant difference in total overall cost. Hospital costs were lower, but costs for clinic visits, pharmacy services, phone calls, and radiology services were significantly higher, resulting in service cost neutrality, possibly because financial barriers before MFA award led to accumulated demand for services. Use of services decreased after MFA was received. There was no significant change in total service cost. MFA improved members' ability to pay for medical services and increased their satisfaction with health services.


Retroperitoneoscopic Cutaneous Ureterostomy in the Supine Position to Relieve Painful Urinary-related Symptoms in an Advanced Anal Canal Cancer Patient.
A case of advanced anal canal cancer with skin metastases that extended to the scrotum, penis, and lower abdomen is presented. The patient had severe pain on contact with voided urine because of skin tumors. The curved penis did not allow insertion of catheter to treat painful urination, and suprapubic cystostomy insertion was also impossible because of skin tumors. A right cutaneous ureterostomy was performed using the retroperitoneoscopic approach in supine position, and the left renal artery was embolized using ethanol to eliminate left kidney function. The patient became completely free from all urinary-related pains until he died of progressive disease.


Complete Genome Sequence of Geobacillus sp. Strain GHH01, a Thermophilic Lipase-Secreting Bacterium.
Geobacillus sp. strain GHH01 was isolated during a screening for producers of extracellular thermostable lipases. The completely sequenced and annotated 3.6-Mb genome encodes 3,478 proteins. The strain is genetically equipped to utilize a broad range of different substrates and might develop natural competence.


An integrated spectral-textural approach for environmental change monitoring and assessment: analyzing the dynamics of green covers in a highly developing region.
The present study compares the effectiveness of two common preclassification change detection (CD) methods that use two-dimensional data space of spectral-textural (S-T) change information. The methods are principal component analysis (PCA) and change vector analysis (CVA) in the Gorgan Township area, Golestn Province, Iran. A series of texture-based information was calculated mainly to separate those land use/land cover (LULC) conversions that are spectrally indistinguishable and also to provide a basis for automatic classification of S-T data space. Both methods were evaluated in terms of accuracy and the required time and expertise. Having the two-dimensional S-T data space generated, support vector machine (SVM) classifier was implemented to automatically extract changed pixels and the receiving operator characteristic (ROC) was employed to assess the accuracy of the output. According to the results, the study area has witnessed substantial mutual transformations between various LULCs among agricultural lands were the most dynamic category in the region. The PCA method applied to the S-T information achieved a ROC of 0.90-indicating an acceptable performance-while the S-T CVA method achieved a lower value of 0.75. The S-T PCA method was considerably less time-consuming and less expertise demanding as well as more accurate in our study area.


[Effect of tin on rats. 1. Inverse voltammetric determination of tin in the presence of lead in biological material after extraction].
By means of inverse polarography, the authors determined tin selectively after double extraction with diethylammonium diethyl dithiocarbamate (DADDTC) in perchloric solution. The recovery rates were: in potatoes, 91.7 +/- 5.8%; in beef kidney, 85.0 +/- 22.7%; in beef liver 79.9 +/- 13.8%; and in milk, 69.8 +/- 11.4%. Possible interferences from other elements with the tin determination are discussed.


Leaflet suspension to the contralateral annulus to address restriction or tethering-induced mitral and tricuspid regurgitation in children: results of a case-control study.
Acceptable coaptation cannot always be obtained using standard repair techniques. We assessed the safety and mid-term results using a novel technique to address leaflet retraction or tethering in children with type III mitral or tricuspid regurgitation as an addition to standard valve repair techniques. Forty children were included, 36 for the mitral valve and 4 for the tricuspid valve, with a mean age of 11.3 ± 3.9 years. A polypropylene suture was placed on the free edge of the retracted or tethered leaflet segment and anchored to the atrial side of the opposite annulus. This avoided valve replacement in all patients. An additional 40 children were matched for age, etiology, leaflet retraction or tethering, and surgery in which the suspension stitch was not used and constituted the control group. The mean aortic crossclamp and cardiopulmonary bypass time was 36 ± 9 and 57 ± 9 minutes, respectively. No early or late deaths occurred. At discharge, no patient had more than mild regurgitation with a gradient of 4.4 ± 2.4 mm Hg in the mitral position and 2 ± 1.75 mm Hg in the tricuspid position. The results were not significantly different than those of the control group. During a follow-up of 37.7 ± 18.4 months, 3 patients required reoperation for mitral valve replacement in the suspension stitch group and 2 within the control group. At echocardiography of the remaining patients, the repair remained stable, with no suspension suture breakage. This suspension technique improved coaptation and resulted in avoidance or delay of valve replacement in patients with type III regurgitation, with an acceptable transvalvular gradient in most patients that did not significantly increase with growth.


Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-alpha release by reducing calcium-dependent activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2.
Bacterial lipopolysaccharide (LPS) activates the immune system and promotes inflammation via Toll-like receptor (TLR) 4, which regulates the synthesis and release of tumor necrosis factor (TNF)-alpha and other inflammatory cytokines. Previous studies have shown that the nucleoside adenosine suppresses LPS-stimulated TNF-alpha release in human UB939 macrophages by activating an adenosine A(3) receptor (A(3)AR) subtype on these cells. In this study, we examined the mechanism(s) underlying A(3)AR-dependent inhibition of TNF-alpha release in a mouse (RAW 264.7) cell line. Treatment of RAW 264.7 cells with LPS (3 mug/ml) increased TNF-alpha release, which was reduced in a dose-dependent manner by adenosine analogs N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and R-phenylisopropyladenosine and reversed by selective A(3)AR blockade. The increase in TNF-alpha release was preceded by an increase in intracellular Ca(2+) levels. Inhibition of intracellular Ca(2+) release by IB-MECA, a selective agonist of the A(3)AR, or with BAPTA-AM, an intracellular Ca(2+) chelator, reduced LPS-stimulated TNF-alpha release. Activation of the A(3)AR or inhibition of intracellular Ca(2+) release also reduced LPS-stimulated nuclear factor-kappaB (NF-kappaB) activation and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Similar inhibition by A(3)AR was observed for LPS-stimulated inducible nitric-oxide synthase. These data support the contention that inhibition of LPS-stimulated release of inflammatory molecules, such as TNF-alpha and NO via the A(3)AR, involves suppression of intracellular Ca(2+)signaling, leading to suppression of NF-kappaB and ERK1/2 pathways.


An FTIR study of the effects of artificial saliva on the physical characteristics of the glass ionomer cements used for art.
To investigate the physical and chemical changes of five esthetic restorative materials in an artificial saliva using Fourier transform infrared spectroscopy (FTIR). The materials included two glass polyalkenoate (ionomer) cements, one polyacid-modified resin composite, and two resin composites. Five fresh and 20 aged specimens for each material were immersed in 2 ml of artificial saliva at 37 degrees C for 1 week, 2 weeks, 1 month, and 2 months. They were examined by laser surface profilometer and FTIR. Surface roughness average (Ra) value showed significant differences among the physical properties of glass ionomers, polyacid-modified resin composite, and resin composites. FTIR spectra showed that a major chemical changes in Fuji IX GP Fast glass ionomer cement in P-NH2 group bonding (900-1000 cm(-1)) that may explain the previously reported increase in microhardness after immersion. There was no direct correlation between surface roughness and spectral changes of the materials tested.


Assembling custom side chains on proteoglycans to interrogate their function in living cells.
Proteoglycans (PGs) are composed of a core protein and one or more chains of glycosaminoglycans (GAGs). The highly heterogeneous GAG chains play an irreplaceable role in the functions of PGs. However, the lack of an approach to control the exact structure of GAG chains conjugated to PGs tremendously hinders functional studies of PGs. Herein, by using glypican-3 as a model, we establish an aldehyde tag-based approach to assemble PGs with specific GAG chains on the surface of living cells. We show that the engineered glypican-3 can regulate Wnt and Hedgehog signaling like the wild type. Furthermore, we also present a method for studying the interaction of PGs with their target glycoproteins by combining the assembly of PGs carrying specific GAG chains with metabolic glycan labeling, and most importantly, we obtain evidence of GPC3 directly interacting with Frizzled. In conclusion, this study provides a very useful platform for structural and functional studies of PGs with specific GAG chains.


Marketing techniques, health, and nutritional claims on processed foods and beverages before and after the implementation of mandatory front-of-package warning labels in Peru.
In June 2019, mandatory front-of-package warning labels (FOPL) were implemented in Peru. The aim of the study was to describe changes in marketing strategies on packaging: marketing techniques (MT), health claims (HC), and nutritional claims (NC) on the packaging of products frequently consumed by children before and after the FOPL implementation. Product photos were taken pre- (March 2019) and post-implementation (March-October 2020) in three supermarkets in Lima, Peru. Following INFORMAS protocols and Peruvian Technical Norms, the presence of MT, HC, and NC was assessed on all package sides. Products were classified as "high-in" and "not high-in" based on the regulation threshold for critical nutrients. Differences in the proportion of products with each strategy in both periods were evaluated. Also, a subsample of products was matched according to the barcode and exact McNemar test was used to compare proportions of strategies pre/post-implementation. We included 883 and 1,035 products in pre- and post-implementation, respectively. In both periods, MT appeared on almost 70% of all products. The presence of HC increased significantly only for beverages (24.5-38.1%, p < 0.001). In both phases, NC were commonly used on beverages (>80%). Overall, the prevalence of "high-in" products using MT increased (73.6-82.1%, p = 0.007), while use of HC increased among "not high-in" products (32.9-41.6%, p < 0.001). There is a high frequency of MT on all products and NC on beverages. The increase in MT in "high-in" products may be an industry response to minimize the impact of the FOPL on food choices and sales. New regulatory aspects regarding labeling should be implemented to strengthen the current policy.


Interleukin-8 and the chemokine family.
Two subfamilies of chemokines are distinguished depending on the arrangement of the first two of four conserved cysteines, which are either separated by one amino acid (CXC chemokines) or adjacent (CC chemokines). IL-8 and the other CXC chemokines act preferentially on neutrophils, while the CC chemokines (MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta) act on monocytes, but not neutrophils, and have additional activities toward basophil and eosinophil granulocytes, and T-lymphocytes. Several chemokine receptors have been identified, all of which belong to the seven-transmembrane-domain type and are coupled to G-proteins. The discovery of chemokines has provided the basis for the understanding of leukocyte recruitment and activation in inflammation and other disturbances of tissue homeostasis.


MAGE-A3 and MAGE-A4 specific CD4(+) T cells in head and neck cancer patients: detection of naturally acquired responses and identification of new epitopes.
Frequent expression of cancer testis antigens (CTA) has been consistently observed in head and neck squamous cell carcinomas (HNSCC). For instance, in 52 HNSCC patients, MAGE-A3 and -A4 CTA were expressed in over 75% of tumors, regardless of the sites of primary tumors such as oral cavity or hypopharynx. Yet, T-cell responses against these CTA in tumor-bearing patients have not been investigated in detail. In this study, we assessed the naturally acquired T-cell response against MAGE-A3 and -A4 in nonvaccinated HNSCC patients. Autologous antigen-presenting cells pulsed with overlapping peptide pools were used to detect and isolate MAGE-A3 and MAGE-A4 specific CD4(+) T cells from healthy donors and seven head and neck cancer patients. CD4(+) T-cell clones were characterized by cytokine secretion. We could detect and isolate MAGE-A3 and MAGE-A4 specific CD4(+) T cells from 7/7 cancer patients analyzed. Moreover, we identified six previously described and three new epitopes for MAGE-A3. Among them, the MAGE-A3(111-125) and MAGE-A3(161-175) epitopes were shown to be naturally processed and presented by DC in association with HLA-DP and DR, respectively. All of the detected MAGE-A4 responses were specific for new helper epitopes. These data suggest that naturally acquired CD4(+) T-cell responses against CT antigens often occur in vivo in HNSCC cancer patients and provide a rationale for the development of active immunotherapeutic approaches in this type of tumor.


CRISPR interference of nucleotide biosynthesis improves production of a single-domain antibody in Escherichia coli.
Growth decoupling can be used to optimize the production of biochemicals and proteins in cell factories. Inhibition of excess biomass formation allows for carbon to be utilized efficiently for product formation instead of growth, resulting in increased product yields and titers. Here, we used CRISPR interference to increase the production of a single-domain antibody (sdAb) by inhibiting growth during production. First, we screened 21 sgRNA targets in the purine and pyrimidine biosynthesis pathways and found that the repression of 11 pathway genes led to the increased green fluorescent protein production and decreased growth. The sgRNA targets pyrF, pyrG, and cmk were selected and further used to improve the production of two versions of an expression-optimized sdAb. Proteomics analysis of the sdAb-producing pyrF, pyrG, and cmk growth decoupling strains showed significantly decreased RpoS levels and an increase of ribosome-associated proteins, indicating that the growth decoupling strains do not enter stationary phase and maintain their capacity for protein synthesis upon growth inhibition. Finally, sdAb production was scaled up to shake-flask fermentation where the product yield was improved 2.6-fold compared to the control strain with no sgRNA target sequence. An sdAb content of 14.6% was reached in the best-performing pyrG growth decoupling strain.


Child Sexual Abuse and Pregnancy: A Systematic Review of the Literature.
Child sexual abuse is related to many negative outcomes but less known is the effect on pregnancy and childbirth. This review critically examined the literature on the occurrence of child sexual abuse and outcomes associated with this abuse during pregnancy and childbirth. Five databases were searched over 50 years using an iterative approach and the terms pregnancy, sexual abuse/assault, childbirth/labour, identifying 49 studies. The prevalence of child sexual abuse in pregnant women ranged from 2.63% to 37.25 with certain characteristics more common with a higher (e.g., specific questions, low income) or lower (broad questions, higher education) prevalence. Compared to women with no history of abuse, child sexual abuse survivors may have more concerns with their care, greater health complaints, fear childbirth and have difficulties with delivery. They also had a higher likelihood of PTSD symptomology and anxiety, consumed more harmful substances (e.g., alcohol, cigarettes, and drugs) and had greater concerns with their appearance, poorer health, sleep and may also have a higher risk of re-victimisation. The balance of evidence suggests that compared to non-abused women, women with a child abuse history have more adverse experiences with pregnancy, childbirth, and care, with their abuse history, likely contributes to harmful behaviours and psychopathology. However, variability in operationalisation and measurement of abuse may contribute to these findings so tentative conclusions are drawn. Future research should examine the generalisability of the findings (relating to scale limitations) and recommendations for screening (e.g., sensitive items, scoring). Clinical implications of the findings point to the need for early identification of women with a child abuse history as such women require trauma-sensitive care and consideration. A useful tool is the Pregnancy-related Anxiety Scale which provides insights into specific areas of concern.