Impact of liver disease after the fontan operation.
Liver disease is being reported with increased frequency in survivors of the Fontan operation. The clinical impact of structural hepatic abnormalities in these patients remains largely unknown. We sought to assess if, and how, cardiologists are screening for hepatic disease in these patients to evaluate for clinical or laboratory correlates of structural hepatic disease and determine the prevalence and clinical impact of such disease. Retrospective data analysis from tertiary institutions was performed. Hepatic imaging studies and serology performed over the last decade were reviewed and clinical and laboratory correlates of structural hepatic alterations on liver imaging or biopsy were sought. Outcomes were determined. In this cohort study, 53 of 60 adult survivors (88%) underwent hepatic imaging with computed tomography, magnetic resonance imaging, or ultrasound with a median number of 2 (0 to 10) studies over the past decade. The frequency of hepatic imaging varied widely with 70% of patients undergoing serial studies. Cirrhosis with or without abnormal hepatic nodules was seen in 29 of 53 patients (55%) at 18.4 ± 5.6 years after the Fontan procedure. Adverse hepatic-related outcome occurred in 22% of the entire patient cohort and was unrelated to time from Fontan operation. In conclusion, there exists significant variability in the type and timing of testing for hepatic complications after the Fontan procedure. Structural hepatic alterations are common and can be associated with significant morbidity and mortality. Routine imaging, and serologic evaluation, is recommended in all Fontan survivors.


Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells.
During the pathogenesis of human hepatocellular carcinoma (HCC), the CpG island encompassing the pi-class glutathione S-transferase gene (GSTP1) becomes hypermethylated. Repression of transcription accompanying CpG island hypermethylation has been proposed to be mediated by methyl-CpG binding domain (MBD) proteins. We report here that inhibition of transcription from hypermethylated GSTP1 promoters in Hep3B HCC cells, which fail to express GSTP1 mRNA or GSTP1 polypeptides, appears to be mediated by MBD2. Treatment of Hep3B cells with 5-azadeoxycytidine (5-aza-dC), a methyltransferase inhibitor, activated GSTP1 expression, whereas treatment with trichostatin A, a histone deacetylase inhibitor, had little effect. To more precisely assess the contribution of the pattern of GSTP1 CpG island methylation on GSTP1 mRNA expression, Hep3B cells were treated for 72 h with 5-aza-dC and then subjected to limiting dilution cloning. Bisulfite sequencing was used to map the methylation patterns of the GSTP1 promoter region in GSTP1-expressing and -non-expressing clones. In the clone that expressed GSTP1 mRNA determined by Northern blot analysis and quantitative reverse transcriptase (RT)-PCR, widespread demethylation of at least one GSTP1 allele was evident. Chromatin immunoprecipitation experiments revealed the presence of MBD2, but not Sp1, at the GSTP1 promoter in Hep3B cells. In contrast, Sp1 was detected at the GSTP1 promoter in a GSTP1-expressing Hep3B 5-aza-dC subclone. To test whether MBD2 might be responsible for the inhibition of GSTP1 transcription from hypermethylated GSTP1 promoters, siRNAs were used to reduce MBD2 polypeptide levels in Hep3B cells. SssI-catalyzed methylation of GSTP1 promoter sequences resulted in diminished luciferase reporter activity after transfection into Hep3B cells. However, when hypermethylated GSTP1 promoter sequences were transfected into Hep3B cells that had been treated with siRNA-targeting MBD2 mRNA, no repression of luciferase reporter expression was evident. These findings implicate MBD2 in the repression of GSTP1 expression associated with GSTP1 CpG island hypermethylation in HCC cells.


Biologic agents in the treatment of psoriasis.
Psoriasis is a cutaneous inflammatory disease, which affects 1-5% of general population and can have, particularly in its moderate-severe forms, a significant impact on the quality of life of patients. Although the etiopathogenesis of psoriasis is not yet fully understood, it has been demonstrated that the disease is the result of a complex interaction of genetic, endogenous and environmental factors, where the immune system has a pivotal role. For this reason, the immune system is the main target of many treatments for psoriasis. The most recent evolution in this field are the so-called biologic agents, custom-designed biomolecules obtained by bioengineering. This review summarizes the currently available data about efficacy, safety and undesired effects of five patented biologics officially approved for the treatment of moderate-to-severe psoriasis: adalimumab, alefacept, efalizumab, etanercept and infliximab. Some patent applications concerning possible future evolutions of the above biologics are also discussed.


Koenig total great toe implant. Preliminary report.
A new first metatarsophalangeal joint implant arthroplasty is described. The two-component, titanium alloy and polyethylene prosthesis designed for weightbearing is noncemented and press-fit. Sixteen cases involving 18 implants were evaluated over 18 months with evidence that good correction and pain free motion can be obtained.


Crystal Structure of VapBC-1 from Nontypeable Haemophilus influenzae and the Effect of PIN Domain Mutations on Survival during Infection.
Toxin-antitoxin (TA) gene pairs have been identified in nearly all bacterial genomes sequenced to date and are thought to facilitate persistence and antibiotic tolerance. TA loci are classified into various types based upon the characteristics of their antitoxins, with those in type II expressing proteic antitoxins. Many toxins from type II modules are ribonucleases that maintain a PilT N-terminal (PIN) domain containing conserved amino acids considered essential for activity. The vapBC (virulence-associated protein) TA system is the largest subfamily in this class and has been linked to pathogenesis of nontypeable Haemophilus influenzae (NTHi). In this study, the crystal structure of the VapBC-1 complex from NTHi was determined to 2.20 Å resolution. Based on this structure, aspartate-to-asparagine and glutamate-to-glutamine mutations of four conserved residues in the PIN domain of the VapC-1 toxin were constructed and the effects of the mutations on protein-protein interactions, growth of Escherichia coli, and pathogenesis ex vivo were tested. Finally, a novel model system was designed and utilized that consists of an NTHi ΔvapBC-1 strain complemented in cis with the TA module containing a mutated or wild-type toxin at an ectopic site on the chromosome. This enabled the analysis of the effect of PIN domain toxin mutants in tandem with their wild-type antitoxin under the control of the vapBC-1 native promoter and in single copy. This is the first report of a system facilitating the study of TA mutant operons in the background of NTHi during infections of primary human tissues ex vivoIMPORTANCE Herein the crystal structure of the VapBC-1 complex from nontypeable Haemophilus influenzae (NTHi) is described. Our results show that some of the mutations in the PIN domain of the VapC-1 toxin were associated with decreased toxicity in E. coli, but the mutants retained the ability to homodimerize and to heterodimerize with the wild-type cognate antitoxin, VapB-1. A new system was designed and constructed to quantify the effects of these mutations on NTHi survival during infections of primary human tissues ex vivo Any mutation to a conserved amino acid in the PIN domain significantly decreased the number of survivors compared to that of the in cis wild-type toxin under the same conditions.


Photoelectrocatalytic decolorization of methylene blue using reduced graphene oxide modified TiO2 on filter paper.
In this work, titanium dioxide (TiO2) was modified with reduced graphene oxide (rGO), and then coated on filter paper to prepare the rGT/FP photoelectrode for the photoelectrocatalytic (PEC) decolorization of methylene blue (MB). The physicochemical properties of the rGT/FP photoelectrode were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis and UV-Vis diffuse reflectance spectroscopy (DRS). The decolorization results demonstrated that the photocatalytic (PC) and electrocatalytic (EC) efficiency of the photoelectrode could be significantly improved by the modification of rGO. The improvement of PC and EC efficiency might attribute to the existence of rGO, which could extend the light-harvesting efficiency, promote the photocurrent response value and suppress the charge recombination. Furthermore, the PEC decolorization of MB using the rGT/FP photoelectrode presented higher efficiency than the sum of PC and EC decolorization, indicating the synergistic effect between the photo and electrical energy.


An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV Receptor.
Determinants and mechanisms of cell attachment and entry steer adeno-associated virus (AAV) in its utility as a gene therapy vector. Thus far, a systematic assessment of how diverse AAV serotypes engage their proteinaceous receptor AAVR (KIAA0319L) to establish transduction has been lacking, despite potential implications for cell and tissue tropism. Here, a large set of human and simian AAVs as well as in silico-reconstructed ancestral AAV capsids were interrogated for AAVR usage. We identified a distinct AAV capsid lineage comprised of AAV4 and AAVrh32.33 that can bind and transduce cells in the absence of AAVR, independent of the multiplicity of infection. Virus overlay assays and rescue experiments in nonpermissive cells demonstrate that these AAVs are unable to bind to or use the AAVR protein for entry. Further evidence for a distinct entry pathway was observed in vivo, as AAVR knockout mice were equally as permissive to transduction by AAVrh32.33 as wild-type mice upon systemic injection. We interestingly observe that some AAV capsids undergo a low level of transduction in the absence of AAVR, both in vitro and in vivo, suggesting that some capsids may have a multimodal entry pathway. In aggregate, our results demonstrate that AAVR usage is conserved among all primate AAVs except for those of the AAV4 lineage, and a non-AAVR pathway may be available to other serotypes. This work furthers our understanding of the entry of AAV, a vector system of broad utility in gene therapy.IMPORTANCE Adeno-associated virus (AAV) is a nonpathogenic virus that is used as a vehicle for gene delivery. Here, we have identified several situations in which transduction is retained in both cell lines and a mouse model in the absence of a previously defined entry receptor, AAVR. Defining the molecular determinants of the infectious pathway of this highly relevant viral vector system can help refine future applications and therapies with this vector.


Changes in the fibrinolytic components of cultured human umbilical vein endothelial cells induced by endotoxin, tumor necrosis factor-alpha and interleukin-1alpha.
Vascular fibrinolysis, a major natural defense mechanism against thrombosis, is a highly regulated process. The aim of this study was to evaluate the effect of endotoxin, tumor necrosis factor-alpha (TNFalpha) and interleukin-1alpha (IL-1alpha), on the fibrinolytic potential of cultured human umbilical vein endothelial cells (HUVEC). Samples of stimulated conditioned media were collected over a period of 24 hours to determine: plasminogen activator (PA) and plasminogen activator inhibitor (PAI) activity, PAI-1 mRNA, tissue-type plasminogen activator (t-PA) antigen and urokinase-type plasminogen activator (u-PA) antigen. Similar changes were observed after endotoxin and cytokine stimulation: there was a significant increase of PAI activity (p<0.01), starting at 6 hours, which remained 24 hours after stimulation. PAI-1 mRNA also showed an important rise with these agents, although cytokines induced an earlier and more intense inhibitor response (up to 6-fold increase). PA activity increased significantly at 6 hours (p<0.01) to drop at 24 hours and was mainly related to the presence of u-PA. We conclude that endotoxin,+TNFalpha and IL-1alpha induce profound alterations in the fibrinolytic potential of HUVEC, characterized by an initial rise of activators (u-PA) followed by a strong increase of PAI-1. These changes may be of pathophysiologic significance for thrombosis and inflammatory reactions.


Development of Amoxicillin-Loaded Electrospun Polyurethane/Chitosan/ $\beta$ -Tricalcium Phosphate Scaffold for Bone Tissue Regeneration.
Biocompatible nanocomposite electrospun fibers containing Polyurethane/Chitosan/ $\beta $ -Tri calcium phosphate with diverse concentrations were designed and produced through the electrospinning process for bone tissue engineering applications. After the production process, density measurement, viscosity, electrical conductivity, and tensile strength measurement tests were carried out as physical analyses of blended solutions. The chemical structural characterization was scrutinized using Fourier transform infrared spectrometer (FTIR), and scanning electron microscopy (SEM) was used to observe the morphological details of developed electrospun scaffolds. Cell viability, attachment, and proliferation were performed using a L929 fibroblast cell line. Based on the physical, SEM, FTIR analysis, and cell culture studies, preferable nanofiber composition was selected for further studies. Amoxicillin (AMX) was loaded to that selected nanofiber composition for examination of the drug release. In comparison with other studies on similar AMX controlled products, higher drug loading and encapsulation efficiencies were obtained. It has been clearly found that the developed nanofiber composites have potential for bone tissue engineering applications.


Age-Induced Changes in White, Brite, and Brown Adipose Depots: A Mini-Review.
Aging is a time-related process of functional decline at organelle, cellular, tissue, and organismal level that ultimately limits life. Cellular senescence is a state of permanent growth arrest in response to stress and one of the major drivers of aging and age-related disorders. Senescent cells accumulate with age, and removal of these cells delays age-related disorders in different tissues and prolongs healthy lifespan. One of the most studied aging mechanisms is the accumulation of reactive oxygen species damage in cells, organs, and organisms over time. Elevated oxidative stress is also found in metabolic diseases such as obesity, metabolic syndrome and associated disorders. Moreover, dysregulation of the energy homeostasis is also associated with aging, and many age-related genes also control energy metabolism, with the adipose organ, comprising white, brite, and brown adipocytes, as an important metabolic player in the regulation of whole-body energy homeostasis. This review summarizes transformations in the adipose organ upon aging and cellular senescence and sheds light on the reallocation of fat mass between adipose depots, on the metabolism of white and brown adipose tissue, on the regenerative potential and adipogenic differentiation capacity of preadipocytes, and on alterations in mitochondria and bioenergetics. In conclusion, the aging process is a lifelong, creeping process with gradual decline in (pre-)adipocyte function over time. Thus, slowing down the accumulation of (pre-)adipocyte damage and dysfunction, removal of senescent preadipocytes as well as blocking deleterious compounds of the senescent secretome are protective measures to maintain a lasting state of health at old age.


Brief report: pragmatic language in autism spectrum disorder: relationships to measures of ability and disability.
Pragmatic language skill is regarded as an area of universal deficit in Autism Spectrum Disorder (ASD), but little is known about factors related to its development and how it in turn might contribute to skills needed to function in everyday contexts or to the expression of ASD-related symptoms. This study investigated these relationships in 37 high-functioning children with ASD. Multiple regression analyses revealed that structural language skills significantly predicted pragmatic language performance, but also that a significant portion of variance in pragmatic scores could not be accounted for by structural language or nonverbal cognition. Pragmatic language scores, in turn, accounted for significant variance in ADOS Communication and Socialization performance, but did not uniquely predict level of communicative or social adaptive functioning on the Vineland. These findings support the notion of pragmatic language impairment as integral to ASD but also highlight the need to measure pragmatic skills in everyday situations, to target adaptive skills in intervention and to intervene in functional, community-based contexts.


The Comparison of Clinical Result between Primary Repair of the Anterior Cruciate Ligament with Additional Internal Bracing and Anatomic Single Bundle Reconstruction-A Retrospective Study.
The current standard of treatment of anterior cruciate ligament (ACL) is reconstruction (ACLR). This technique has some disadvantages: poor proprioception, donor site morbidity and the inability to restore joint kinematics. ACL repair could be an alternative treatment. The purpose of the study was to compare the stability and the function after ACL primary repair versus single-bundle ACLR. In a retrospective study, 12 patients underwent primary ACL repair with internal bracing, 15 patients underwent standard ACLR. Follow-up examinations were evaluated at up to 2 years postoperatively. One patient in the ACL repair group was lost to follow-up due to re-rupture. The absolute value of anterior tibial translation (ATT) and the side-to-side difference in the same patient (ΔATT) were evaluated using the GNRB arthrometer. The Lysholm knee scoring was obtained. Re-ruptures and other complications were recorded. Anterior tibial translation (ATT) was significantly decreased in the ACL repair group compared with the ACLR group (5.31 mm vs. 7.18 mm, respectively; p = 0.0137). Arthrometric measurements demonstrated a mean side-to-side difference (ΔATT) 1.87 (range 0.2 to 4.9) mm significantly decreased compared to ACLR 3.36 (range 1.2-5.6 mm; p = 0.0107). The mean Lysholm score was 85.3 points in the ACL repair group and 89.9 in ACLR group. No significant differences between ACL repair and ACLR were found for the Lysholm score. There was no association between AP laxity and clinical outcomes. There were two complications in the internal bracing group: one patient had re-rupture and was treated by ACLR, another had limited extension and had arthroscopic debridement. Anterior tibial translation was significantly decreased after ACL repair. Additionally, the functional results after ACL repair with internal bracing were comparable with those after ACLR. It should be noted that the two complications occurred. The current study supports further development of ACL repair techniques.


Assessment of Pain and Quality of Life in Lichtenstein Hernia Repair Using a New Monofilament PTFE Mesh: Comparison of Suture vs. Fibrin-Sealant Mesh Fixation.
Inguinal hernia repair is one of the most common operations in general surgery. The Lichtenstein tension-free operation has become the gold standard in open inguinal hernia repair. Despite the low recurrence rates, pain and discomfort remain a problem for a large number of patients. The aim of this study was to compare suture fixation vs. fibrin sealing by using a new monofilament PTFE mesh, i.e., the Infinit(®) mesh by W. L. Gore & Associates. This study was designed as a controlled prospective single-center two-cohort study. A total of 38 patients were enrolled and operated in Lichtenstein technique either standard suture mesh fixation or fibrin-sealant mesh fixation were used as described in the TIMELI trial. Primary outcome parameters were postoperative complications with the new mesh (i.e., seroma, infection), pain, and quality of life evaluated by the VAS and the SF-36 questionnaire. Secondary outcome was recurrence assessed by ultrasound and physical examination. Follow-up time was 1 year. Significantly, less postoperative pain was reported in the fibrin-sealant group compared to the suture group at 6 weeks (P = 0.035), 6 months (P = 0.023), and 1 year (P = 0.011) postoperatively. Additionally, trends toward a higher postoperative quality of life, a faster surgical procedure, and a shorter hospital stay were seen in the fibrin-sealant group. Fibrin-sealant mesh fixation in Lichtenstein hernioplasty effectively reduces acute and chronic postoperative pain. Monofilament, macro-porous, knitted PTFE meshes seem to be a practicable alternative to commonly used polypropylene meshes in open inguinal hernia repair.


Competing interests in development of clinical practice guidelines for diabetes management: Report from a multidisciplinary workshop.
To explore the complex issue of competing interests (CIs) in development of clinical practice guidelines (CPGs) in diabetes with stakeholders. A multidisciplinary panel of 26 health, methodological, legal, and bioethical experts, trainees, and lay people from across Canada participated in a workshop on CIs in CPGs. Mixed methods were used such that qualitative themes were extracted from the discussions and quantitative survey data were collected. In the discussions, participants acknowledged that potential competing interests were not uncommon among sponsoring organizations and authors of CPGs. Avoidance of all potential CIs in development of CPGs was emulated as ideal, but considered probably unrealistic, given the paucity of peer-reviewed funding opportunities for development of evidence-informed CPGs and the scarcity of knowledgeable authors without CIs. An optimal approach for management of CIs in CPGs could not be agreed upon by participants. Full disclosure of any financial CIs for authors and sponsoring organizations as well as discouragement of external financial contributors from writing involvement, were endorsed by participants in the workshop and a subsequent survey. Complete disclosure of financial CIs of sponsoring organizations and authors of CPGs is essential, yet the optimal approach to management of potential CIs is currently undefined.


Genetic hemoglobin disorders rather than iron deficiency are a major predictor of hemoglobin concentration in women of reproductive age in rural prey Veng, Cambodia.
Anemia is common in Cambodian women. Potential causes include micronutrient deficiencies, genetic hemoglobin disorders, inflammation, and disease. We aimed to investigate factors associated with anemia (low hemoglobin concentration) in rural Cambodian women (18-45 y) and to investigate the relations between hemoglobin disorders and other iron biomarkers. Blood samples were obtained from 450 women. A complete blood count was conducted, and serum and plasma were analyzed for ferritin, soluble transferrin receptor (sTfR), folate, vitamin B-12, retinol binding protein (RBP), C-reactive protein (CRP), and α1 acid glycoprotein (AGP). Hemoglobin electrophoresis and multiplex polymerase chain reaction were used to determine the prevalence and type of genetic hemoglobin disorders. Overall, 54% of women had a genetic hemoglobin disorder, which included 25 different genotypes (most commonly, hemoglobin E variants and α(3.7)-thalassemia). Of the 420 nonpregnant women, 29.5% had anemia (hemoglobin <120 g/L), 2% had depleted iron stores (ferritin <15 μg/L), 19% had tissue iron deficiency (sTfR >8.3 mg/L), <3% had folate deficiency (<3 μg/L), and 1% had vitamin B-12 deficiency (<150 pmol/L). Prevalences of iron deficiency anemia (IDA) were 14.2% and 1.5% in those with and without hemoglobin disorders, respectively. There was no biochemical evidence of vitamin A deficiency (RBP <0.7 μmol/L). Acute and chronic inflammation were prevalent among 8% (CRP >5 mg/L) and 26% (AGP >1 g/L) of nonpregnant women, respectively. By using an adjusted linear regression model, the strongest predictors of hemoglobin concentration were hemoglobin E homozygous disorder and pregnancy status. Other predictors were 2 other heterozygous traits (hemoglobin E and Constant Spring), parity, RBP, log ferritin, and vitamin B-12. Multiple biomarkers for anemia and iron deficiency were significantly influenced by the presence of hemoglobin disorders, hence reducing their diagnostic sensitivity. Further investigation of the unexpectedly low prevalence of IDA in Cambodian women is warranted.


Expression and function of protein kinase C isozymes.
Three protein kinase C (PKC) isozymes, type I, II, and III, have been identified as the major Ca2+/phospholipid-stimulated protein kinases in the various animal tissues. Based on the immunochemical analysis it was demonstrated that PKC I was encoded by gamma cDNA, PKC II by the alternatively spliced beta I and beta II cDNAs, and PKC III by alpha cDNA. The expression of these enzymes appears to be tissue-specific and developmentally regulated. The central nervous system expresses high level of all three isozymes and the peripheral tissues mainly PKC II and III. During brain development, the expression of PKC I appears to follow the progress of synaptogenesis, whereas PKC II and III increase progressively from fetus up to 2-3 weeks of age. The level of PKC I in adult brain is highest in the cerebellum, hippocampus, amygdala, and cerebral cortex especially in those cortical regions being important for visual information processing and storage. The role of PKC II and III in cellular regulation was investigated by treatment of rat basophilic leukemia cells with the phorbol ester, phorbol 12-myristate 13-acetate. This phorbol ester caused a faster degradation of PKC II than III, indicating a differential down-regulation of these two enzymes by this compound. The results presented in this study support the contention that each species of PKC has a distinct function in the regulation of a variety of cellular processes.


Effects of physical exercise on sex hormone binding globulin, high density lipoprotein cholesterol, total cholesterol and triglycerides in postmenopausal women.
This study was performed on 18 postmenopausal female volunteers in order to examine changes in sex hormone binding globulin (SHBG), high density lipoprotein cholesterol (HDLC), total cholesterol (TC) and serum triglyceride (TG) levels in a period of four months of moderate physical exercise. While SHBG decreased significantly (from 55.3 +/- 20.9 to 48.3 +/- 21.0 nM, P < 0.05), TG increased significantly (from 87 +/- 41.7 to 120.5 +/- 57.5 mg/dl, P < 0.001). These changes were accompanied by a significant decrease (P < 0.001) in body fat content. Other parameters such as HDL-cholesterol, TC and BMI did not change significantly. Plasma levels of SHBG were negatively correlated to serum TG both at the beginning (r = 0.492, P < 0.05) and at the end (r = 0.538, P < 0.05) of the period of moderate exercise. Also, changes in SHBG were negatively correlated with changes in BMI (r = 0.585, P < 0.05) and this could indicate that SHBG levels are more related to nutritional status than androgen/estrogen imbalance.


Management of chronic osteomyelitis of the lower extremity.
Chronic osteomyelitis is a frequent complication after compound fractures of the lower extremity. Essential in the treatment is the radical debridement of all scar tissue, muscle and infected bone. This often creates large tissue defects, which especially in the distal third of the tibia, can only be closed with a free tissue transfer and revascularized by a microvascular anastomosis. Ten patients were operated on for chronic osteomyelitis of the lower extremity. The latissimus dorsi or rectus abdominis muscle was used as a free flap. During the follow-up period (3-18 months) 9 patients have remained free of symptoms of recurrence.


Applications of cell- and tissue-specific 'omics to improve plant productivity.
The individual tissues and cell types of plants each have characteristic properties that contribute to the function of the plant as a whole. These are reflected by unique patterns of gene expression, protein and metabolite content, which enable cell-type-specific patterns of growth, development and physiology. Gene regulatory networks act within the cell types to govern the production and activity of these components. For the broader organism to grow and reproduce successfully, cell-type-specific activity must also function within the context of surrounding cell types, which is achieved by coordination of signalling pathways. We can investigate how gene regulatory networks are constructed and function using integrative 'omics technologies. Historically such experiments in plant biological research have been performed at the bulk tissue level, to organ resolution at best. In this review, we describe recent advances in cell- and tissue-specific 'omics technologies that allow investigation at much improved resolution. We discuss the advantages of these approaches for fundamental and translational plant biology, illustrated through the examples of specialised metabolism in medicinal plants and seed germination. We also discuss the challenges that must be overcome for such approaches to be adopted widely by the community.


Centromeres: genetic input to calibrate an epigenetic feedback loop.
Centromeres are chromatin domains maintained by a self-templating feedback loop based on nucleosomes bearing the histone H3 variant CENP-A. The underlying centromeric DNA sequence is largely dispensable, yet paradoxically, it has highly conserved features. Hoffmann et al (2020) now uncover that when the epigenetic chromatin cycle falters, a genetically hardwired mechanism offers robustness to a dynamic epigenetic feedback loop ensuring long-term centromere inheritance.


Occupational homicide of law enforcement officers in the US, 1996-2010.
To understand the circumstances surrounding the occupational homicides of law enforcement officers (LEOs) in the USA. Narrative text analysis of Federal Bureau of Investigation Law Enforcement Officers Killed and Assaulted reports. A total of 796 officers were killed in the line of duty between 1996 and 2010. The occupational homicide rate during the time peaked in 2001 at 3.76/100 000 (excluding those killed during the September 11 2001 terrorist attacks), and was lowest in 2008 at 1.92/100 000. Most LEOs (67%) were killed by short-barrel firearms; 10% were killed with their own service weapon. The most frequent encounter with a suspect prior to a homicide was responding to a disturbance call. These results should inform officer training and the policies, as well as procedures used when interacting with suspects, especially when firearms are involved.


Apoptotic cell death in rat epididymis following epichlorohydrin treatment.
Epichlorohydrin (ECH) is an antifertility agent that acts both as an epididymal toxicant and an agent capable of directly affecting sperm motility. This study identified the time course of apoptotic cell death in rat epididymides after ECH treatment. Rats were administrated with a single oral dose of ECH (50 mg/kg). ECH-induced apoptotic changes were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and its related mechanism was confirmed by Western blot analysis and colorimetric assay. The TUNEL assay showed that the number of apoptotic cells increased at 8 h, reached a maximum level at 12 h, and then decreased progressively. The Western blot analysis demonstrated no significant changes in proapoptotic Bcl-2-associated X (Bax) and anti-apoptotic Bcl-2 expression during the time course of the study. However, phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and phospho-c-Jun amino-terminal kinase (p-JNK) expression increased at 8-24 h. Caspase-3 and caspase-8 activities also increased at 8-48 h and 12-48 h, respectively, in the same manner as p-p38 MAPK and p-JNK expression. These results indicate that ECH induced apoptotic changes in rat epididymides and that the apoptotic cell death may be related more to the MAPK pathway than to the mitochondrial pathway.


Presurgical changes in unilateral cleft palate subjects.
This investigation utilizes computerized measuring and statistical techniques, stereophotogrammetry, and a newly developed method of measuring palatal surface areas to study changes in the maxillary arch dimensions at birth and at 4 months in 3 groups of subjects: (1) 30 complete unilateral cleft lip and palate cases who were treated by presurgical maxillary orthopaedics; (2) 15 similar cases who had no such treatment and served as controls; and (3) 30 normal children. The changes occurring in the 3 groups over the 4-month period were compared. In particular, it was noted that presurgical treatment had a constrictive effect on general arch growth and that it also retarded the growth of palatal tissue. The significance of this in relation to other findings and to presurgical treatment in general is discussed.


Is insulin resistance caused by defects in insulin's target cells or by a stressed mind?
The importance of understanding insulin action is emphasized by the increasing prevalence of insulin resistance in various populations and by the fact that it plays an important pathophysiological role in many common disorders, for example, diabetes, obesity, hypertension and dyslipidemia. The primary factors responsible for the development of insulin resistance are so far unknown, although both genetic and environmental factors are involved. The genetic defects responsible for the common forms of insulin resistance, for example, in type 2 diabetes, are largely unidentified. Some studies from our group as well as by other investigators suggest that cellular insulin resistance is reversible and that it may be secondary to factors in the in vivo environment. These may include insulin-antagonistic action of hormones like catecholamines, glucocorticoids, sex steroids and adipokines as well as dysregulation of autonomic nervous activity and they could contribute to the early development of insulin resistance. Some of these factors can directly impair glucose uptake capacity and this might be due to alterations in key proteins involved in insulin's intracellular signaling pathways. This article briefly summarizes proposed mechanisms behind cellular and whole-body insulin resistance. In particular, we question the role of intrinsic defects in insulin's target cells as primary mechanisms in the development of insulin resistance in type 2 diabetes and we suggest that metabolic and neurohormonal factors instead are the main culprits.


Assessment of tools for protection of quality of water: Uncontrollable discharges of pollutants.
Selecting an appropriate crisis management plans during uncontrollable loading of pollution to water systems is crucial. In this research the quality of water resources against uncontrollable pollution is protected by use of suitable tools. Case study which was chosen in this investigation was a river-reservoir system. Analytical and numerical solutions of pollutant transport equation were considered as the simulation strategy to calculate the efficient tools to protect water quality. These practical instruments are dilution flow and a new tool called detention time which is proposed and simulated for the first time in this study. For uncontrollable pollution discharge which was approximately 130% of the river's assimilation capacity, as long as the duration of contact (Tc) was considered as a constraint, by releasing 30% of the base flow of the river from the upstream dilution reservoir, the unallowable pollution could be treated. Moreover, when the affected distance (Xc) was selected as a constraint, the required detention time that the rubber dam should detained the water to be treated was equal to 187% of the initial duration of contact.


Clinical and microbiological characteristics of vancomycin-resistant Enterococcus faecium bloodstream infection in Central Taiwan.
Bloodstream infections (BSIs) due to vancomycin-resistant Enterococcus faecium (VREfae) remain a therapeutic challenge. This study aimed to evaluate mortality from BSIs due to VREfae in Central Taiwan.We retrospectively analyzed patients with significant VREfae BSIs in the Changhua Christian Hospital System between January 1, 2010 and December 31, 2014.Of the 152 patients with Enterococcal BSI, 56 patients (36.8%) were admitted to intensive care units (ICUs) at the onset of BSI and 20 (13.2%) patients were associated with polymicrobial bacteremia. VREfae BSI was observed in 36 (23.7%) patients. Van A (100%) is the prevalence genotype, and ST 17 (41.7%) is the predominant ST type among 36 VREfae isolates during the study period. The 30-day mortality rate was 13.2% (20/152). The multivariate logistic regression analysis showed that the onset of VREfae BSI in the ICU (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 1.7-10.0, P = .002) was a significant risk factor for 30-day mortality, whereas an appropriate antimicrobial therapy was a protective factor for 30-day mortality (OR = 0.33, 95% CI = 0.14-0.79, P = .013).Our results underscore the need to assist patients who are admitted to ICUs with VREfae BSIs. We emphasize the use of an appropriate antimicrobial therapy for VREfae BSI with the aim to treat more patients with these infections.


Mononuclear iron(ii) complexes containing a tripodal and macrocyclic nitrogen ligand: synthesis, reactivity and application in cyclohexane oxidation catalysis.
Two novel tripodal ligands L1 and L2 based on a tris(methylpyridyl)amine (TPA) motif have been prepared and reacted with two different iron(ii) salts. The ligand L1 contains a bis(amino-phenyl)-TPA group whereas the macrocyclic ligand L2 displays two different coordinating cores, namely TPA and pyridine-dicarboxamide. The resulting mononuclear complexes 1-4 have been characterized in the solid state and in solution by spectroscopic and electrochemical methods. All complexes are high spin and mainly pentacoordinated. X-ray diffraction analyses of the crystals of complexes 2 and 3 demonstrate that the coordination sphere of the iron(ii) centre adopts either a distorted bipyramidal-trigonal or square pyramidal geometry. In the absence of an exogenous substrate, oxidation of complex 2 by H2O2 induces an intramolecular aromatic hydroxylation, as shown by the X-ray structure of the resulting dinuclear complex 2'. Catalytic studies in the presence of a substrate (cyclohexane) show that the reaction process is strongly impacted by the macrocyclic topology of the ligand and the nature of the counter-ion.


The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers.
Microtubule targeting agents are among the most widely used chemotherapeutics for both solid and hematological malignancies. This study characterizes the diaryl-oxazole based anticancer agent PC-046, which was originally identified for development based on selective activity in deleted in pancreas cancer locus 4 (DPC4/SMAD4) deficient tumors. PC-046 has growth inhibitory activity in a variety of tumor types in vitro, and efficacy in SCID mice was shown in human tumor xenografts of MV-4-11 acute myeloid leukemia, MM.1S multiple myeloma, and DU-145 prostate cancer. Pharmacokinetic studies demonstrated relatively high oral bioavailability (71%) with distribution to both plasma and bone marrow. No myelosuppression was seen in non-tumor bearing SCID mice given a single dose just under the acute lethal dose. The COMPARE algorithm in the NCI-60 cell line panel demonstrated that PC-046 closely correlated to other known tubulin destabilizing agents (correlation coefficients ≈0.7 for vincristine and vinblastine). Mechanism of action studies showed cell cycle arrest in metaphase and inhibition of tubulin polymerization. Overall, these studies show that PC-046 is a synthetically-derived, small molecule microtubule destabilizing agent. Advantages over existing microtubule destabilizing agents include ease of synthesis, lack of MDR cross-resistance, good oral bioavailability and the lack of acute myelotoxicity.


Anodal tDCS of the swallowing motor cortex for treatment of dysphagia in multiple sclerosis: a pilot open-label study.
Swallowing difficulties are a common symptom of multiple sclerosis (MS). The early detection and treatment of dysphagia is critical to prevent complications, including poor nutrition, dehydration, and lung infections. Recently, transcranial direct current stimulation (tDCS) has been proven to be effective in ameliorating swallowing problems in stroke patients. In this pilot study, we aimed to assess safety and efficacy of transcranial direct current stimulation (tDCS) in the treatment of dysphagia in MS patients. We screened 30 patients by using the 10-item DYsphagia in MUltiple Sclerosis (DYMUS) questionnaire, and patients at risk for dysphagia underwent a clinical and fiberoptic endoscopic evaluation of swallowing (FEES). Six patients who presented with mild to moderate dysphagia underwent the experimental procedures. These consisted of 5 sessions of anodal tDCS applied in consecutive days over the right swallowing motor cortex. Patients were followed-up at 1 week, 1 month and 3 months after treatment, and changes in the Dysphagia Outcome and Severity Scale (DOSS) score between baseline and post-tDCS were assessed. Our results showed that in all patients, the tDCS treatment determined a mild but significant clinical benefit (one-point improvement in the DOSS score) lasting up to 1 month. In conclusion, our preliminary results show that anodal tDCS has therapeutic potential in the treatment of swallowing problems in patients suffering with MS. However, future double-blind, randomized, and sham-controlled studies are needed to confirm the present findings.


Handlebar vibration of a motorcycle during operation on different road surfaces.
In Japan daily motorcycle mail deliverers have been exposed to vibration from the handlebars of their motorcycles. Handlebar vibration was measured during the operation of a motorcycle in order to evaluate the hazardous effects of vibration and to identify preventive measures against the vibration hazards. Tests were made on asphalted, unpaved, and packed-snow road surfaces. The tested motorcycles were selected from the many motorcycles in daily use. The test motorcycle was a 1-cylindered, 89-cm3, 4-cycle machine. The direction showing the maximum value of vibration acceleration was not always in the directions of X, Y, and Z proposed by the International Organization for Standardization (ISO). The maximum vibration acceleration level exceeded the exposure guideline of ISO, while its frequency corresponded to that of the engine speed during operation. Vibration of greater than 20 Hz was transmitted through the front forks from the road surface and tires.


A new hadrosauroid dinosaur from the early late cretaceous of Shanxi Province, China.
The origin of hadrosaurid dinosaurs is far from clear, mainly due to the paucity of their early Late Cretaceous close relatives. Compared to numerous Early Cretaceous basal hadrosauroids, which are mainly from Eastern Asia, only six early Late Cretaceous (pre-Campanian) basal hadrosauroids have been found: three from Asia and three from North America. Here we describe a new hadrosauroid dinosaur, Yunganglong datongensis gen. et sp. nov., from the early Late Cretaceous Zhumapu Formation of Shanxi Province in northern China. The new taxon is represented by an associated but disarticulated partial adult skeleton including the caudodorsal part of the skull. Cladistic analysis and comparative studies show that Yunganglong represents one of the most basal Late Cretaceous hadrosauroids and is diagnosed by a unique combination of features in its skull and femur. The discovery of Yunganglong adds another record of basal Hadrosauroidea in the early Late Cretaceous, and helps to elucidate the origin and evolution of Hadrosauridae.


Epidemiology of asthma in childhood.
The epidemiology of asthma in childhood is undergoing changes in many parts of the world. Prevalence, rates of hospitalization and mortality are all on the rise. In the United States, urban dwellers and minorities have experienced the greatest acceleration in rates. Elsewhere, some countries have experienced large increases in asthma morbidity and mortality, while others have not. Inconsistency in defining asthma and variations in methodology complicate epidemiologic investigation, but recent studies confirm the disturbing trend toward increased morbidity and mortality from childhood asthma and offer some insights into possible contributing factors.


Can women in labor give informed consent to epidural analgesia?
There are reasons to believe that decision-making capacity (mental competence) of women in labor may be compromised in relation to giving informed consent to epidural analgesia. Not only severe labor pain, but also stress, anxiety, and premedication of analgesics such as opioids, may influence women's decisional capacity. Decision-making capacity is a complex construct involving cognitive and emotional components which cannot be reduced to 'understanding' alone. A systematic literature search identified a total of 20 empirical studies focused on women's decision-making about epidural analgesia for labor pain. Our review of these studies suggests that empirical evidence to date is insufficient to determine whether women undergoing labor are capable of consenting to epidural analgesia. Given such uncertainties, sufficient information about pain management should be provided as part of prenatal education and the consent process must be carefully conducted to enhance women's autonomy. To fill in the significant gap in clinical knowledge about laboring women's decision-making capacity, well-designed prospective and retrospective studies may be required.


Younger and Older Adults' "Good-Enough" Interpretations of Garden-Path Sentences.
We report 3 experiments that examined younger and older adults' reliance on "good-enough" interpretations for garden-path sentences (e.g., "While Anna dressed the baby played in the crib") as indicated by their responding "Yes" to questions probing the initial, syntactically unlicensed interpretation (e.g., "Did Anna dress the baby?"). The manipulation of several factors expected to influence the probability of generating or maintaining the unlicensed interpretation resulted in 2 major age differences: Older adults were generally more likely to endorse the incorrect interpretation for sentences containing optionally transitive verbs (e.g., hunted, paid), and they showed decreased availability of the correct interpretation of subordinate clauses containing reflexive absolute transitive verbs (e.g., dress, bathe). These age differences may in part be linked to older adults' increased reliance on heuristic-like good-enough processing to compensate for age-related deficits in working memory capacity. The results support previous studies suggesting that syntactic reanalysis may not be an all-or-nothing process and might not be completed unless questions probing unresolved aspects of the sentence structure challenge the resultant interpretation.


Dual function of polysialic acid during zebrafish central nervous system development.
Polysialic acid (PSA), a carbohydrate epitope attached to the neural cell adhesion molecule, serves as a modulator of axonal interactions during vertebrate nervous system development. We have used PSA-specific antibodies and whole-mount immunocytochemistry to describe the spatiotemporal expression pattern of PSA during zebrafish central nervous system development. PSA is transiently expressed on all cell bodies and, except for the posterior commissure, it is not found on axons. Floorplate cells in the spinal cord and hindbrain strongly express PSA throughout development. Enzymatic removal of PSA leads to a defasciculated growth pattern of the posterior commissure and also affects distinct subsets of commissural axons in the hindbrain, which fail to cross the midline. Whereas the disordered growth pattern of hindbrain commissures produced by PSA-removal could be mimicked by injections of soluble PSA, the growth of axons in the posterior commissure was unaffected by such treatment. These results suggest that there are distinct mechanisms for PSA action during axon growth and pathfinding in the developing zebrafish CNS.


Favorable effects of insulin sensitizers pertinent to peripheral arterial disease in type 2 diabetes: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.
The aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5-year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91-1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI≤0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes. During an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P<0.001). The difference was significant in time-to-event analysis (hazard ratio 0.66 [95% CI 0.51-0.83], P<0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59-0.96], P=0.02). In participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes.


AFLP to assess genetic variation in laboratory gerbils (Meriones unguiculatus).
The amplified fragment length polymorphism (AFLP) technique has been increasingly employed for characterizing inbred breeds of animals and detecting strain-specific polymorphisms. The majority of animals studies conducted in biomedical research are performed on rodent species, among which laboratory-reared Mongolian gerbils can be included. Despite the wide use of gerbils in scientific studies, their genetics has rarely been studied. Therefore we investigated the genetic differentiation of laboratory bred gerbils by means of AFLP markers. Six EcoRI/TaqI primer combinations were selected among 13 different combinations to assess the genetic polymorphisms in four stocks of animals: Charles River (CR), Harlan (Ha), Parma (Pr), and Crossbred (Cb). CR and Ha gerbils were purchased from commercial vendors, while Pr and Cb were derived from animals bred in our animal colony. A total of 228 fragments ranging between 70 and 650 bp were obtained. The mean percentage of polymorphic loci across primer combinations was 7.5%. Calculation of genetic distances through application of different algorithms (Nei's, BSI, and Jaccard's indexes) confirmed the poor genetic diversity between stocks. Nevertheless, a differentiation of the Pr and Cb stocks from the more homogeneous CR and Ha was revealed, in agreement with the different breeding derivation and management of the stocks.


Improved arterial visualization in cerebral CT perfusion-derived arteriograms compared with standard CT angiography: a visual assessment study.
Invasive cerebral DSA has largely been replaced by CTA, which is noninvasive but has a compromised arterial view due to superimposed bone and veins. The purpose of this study was to evaluate whether arterial visualization in CTPa is superior to standard CTA, which would eliminate the need for an additional CTA scan to assess arterial diseases and therefore reduce radiation dose. In this study, we included 24 patients with subarachnoid hemorrhage for whom CTA and CTP were available. Arterial quality and presence of superimposed veins and bone in CTPa were compared with CTA and scored by 2 radiologists by using a VAS (0%-100%). Average VAS scores were determined and VAS scores per patient were converted to a 10-point NRS. Arterial visualization was considered to be improved when the highest rate (NRS 10, VAS > 90%) was scored for arterial quality, and the lowest rate (NRS 1, VAS < 10%), for the presence of superimposed veins and bone. A sign test with continuity correction was used to test whether the number of cases with these rates was significant. Average VAS scores in the proximal area were 94% (arterial quality), 4% (presence of bone), and 7% (presence of veins). In this area, the sign test showed that a significant number of cases scored NRS 10 for arterial quality (P < .02) and NRS 1 for the presence of superimposed veins and bone (P < .01). Cerebral CTPa shows improved arterial visualization in the proximal area compared with CTA, with similar arterial quality but no superimposed bone and veins.


Evaluation of primary health and medical care: the current state of the art.
Evaluation is a subjective process which depends upon the perspective of the evaluator and the criteria he chooses. A review of past efforts at primary care evaluation indicates a preoccupation with the structure and process of care. Methods for the measurement of the outcome of primary care are at last being developed.


The effectiveness of a balance training intervention in reducing the incidence of noncontact ankle sprains in high school football players.
A high body mass index and previous ankle sprains have been shown to increase the risk of sustaining noncontact inversion ankle sprains in high school football players. Stability pad balance training reduces the incidence of noncontact inversion ankle sprains in football players with increased risk. Cohort study; Level of evidence, 2. Height, body mass, history of previous ankle sprains, and current ankle brace/tape use were documented at the beginning of preseason training in 2 high school varsity football teams for 3 consecutive years (175 player-seasons). Players were categorized as minimal risk, low risk, moderate risk, and high risk based on the history of previous ankle sprain and body mass index. Players in the low-, moderate-, and high-risk groups (ie, any player with a high body mass index and/or a previous ankle sprain) were placed on a balance training intervention on a foam stability pad. Players balanced for 5 minutes on each leg, 5 days per week, for 4 weeks in preseason and twice per week during the season. Postintervention injury incidence was compared with preintervention incidence (107 players-seasons) for players with increased risk. Injury incidence for players with increased risk was 2.2 injuries per 1000 exposures (95% confidence interval, 1.1-3.8) before the intervention and 0.5 (95% confidence interval, 0.2-1.3) after the intervention (P < .01). This represents a 77% reduction in injury incidence (95% confidence interval, 31%-92%). The increased risk of a noncontact inversion ankle sprain associated with a high body mass index and a previous ankle sprain was eliminated by the balance training intervention.


Surgical versus nonsurgical treatment in first traumatic anterior dislocation of the shoulder in athletes.
Anterior traumatic dislocation is a common problem faced by orthopedic surgeons. After the first episode of shoulder dislocation, a combination of lesions can lead to chronic instability. The management in treatment of young athletes after the first acute anterior shoulder dislocation is controversial. The available literature supports early surgical treatment for young male athletes engaged in highly demanding physical activities after the first episode of traumatic dislocation of the shoulder. This is because of the best functional results and lower recurrence rates obtained with this treatment in this population. However, further clinical trials of good quality comparing surgical versus nonsurgical treatment for well-defined lesions are needed, especially for categories of patients who have a lower risk of recurrence.


Focal toxicity of oxysterols in vascular smooth muscle cell culture. A model of the atherosclerotic core region.
Cell necrosis and reactive cellular processes in and near the atherosclerotic core region might result from short-range interactions with toxic lipids. To model these interactions in cell culture, focal crystalline deposits of cholestane-3 beta,5 alpha,6 beta-triol, 25-OH cholesterol, and cholesterol were overlaid by a collagen gel, on which canine aortic smooth muscle cells were seeded. Oxysterols, but not cholesterol, caused focally decreased plating efficiency and cell death, leading to the formation of a persistent circular gap in the cell culture. Cholestanetriol was largely removed from the culture dishes over 3 to 4 weeks, whereas cholesterol and 25-OH cholesterol were largely retained. Smooth muscle cells were motile even in proximity to oxysterol crystals, with occasional suicidal migration toward the crystals. Chemoattraction, however, could not be demonstrated. Despite toxicity, cholestanetriol did not appear to alter the fraction of cells exhibiting 3H-thymidine uptake, even in areas close to the crystals. Thus, oxysterols may be toxic to some cells, without causing major impairment of the migration and proliferation of nearby cells. This would allow the simultaneous occurrence of cell death and proliferation evident in atherosclerosis.


Telemedicine is as effective as in-person visits for patients with asthma.
Access to asthma specialists is a problem, particularly in rural areas, thus presenting an opportunity for management using telemedicine. To compare asthma outcomes during 6 months in children managed by telemedicine vs in-person visits. Children with asthma residing in 2 remote locations were offered the choice of an in-person visit or a telemedicine session at a local clinic. The telemedicine process involved real-time use of a Remote Presence Solution (RPS) equipped with a digital stethoscope, otoscope, and high-resolution camera. A telefacilitator operated the RPS and performed diagnostic and educational procedures, such as spirometry and asthma education. Children in both groups were assessed initially, after 30 days, and at 6 months. Asthma outcome measures included asthma control using validated tools (Asthma Control Test, Childhood Asthma Control Test, and Test for Respiratory and Asthma Control in Kids) and patient satisfaction (telemedicine group only). Noninferiority analysis of asthma control was performed using the minimally important difference of an adjusted asthma control test that combined the 3 age groups. Of 169 children, 100 were seen in-person and 69 via telemedicine. A total of 34 in-person and 40 telemedicine patients completed all 3 visits. All had a small, although statistically insignificant, improvement in asthma control over time. Telemedicine was noninferior to in-person visits. Most of the telemedicine group subjects were satisfied with their experience. Children with asthma seen by telemedicine or in-person visits can achieve comparable degrees of asthma control. Telemedicine can be a viable alternative to traditional in-person physician-based care for the treatment and management of asthma.


Developing Smartphone-Based Objective Assessments of Physical Function in Rheumatoid Arthritis Patients: The PARADE Study.
Digital biomarkers that measure physical activity and mobility are of great interest in the assessment of chronic diseases such as rheumatoid arthritis, as it provides insights on patients' quality of life that can be reliably compared across a whole population. To investigate the feasibility of analyzing iPhone sensor data collected remotely by means of a mobile software application in order to derive meaningful information on functional ability in rheumatoid arthritis patients. Two objective, active tasks were made available to the study participants: a wrist joint motion test and a walk test, both performed remotely and without any medical supervision. During these tasks, gyroscope and accelerometer time-series data were captured. Processing schemes were developed using machine learning techniques such as logistic regression as well as explicitly programmed algorithms to assess data quality in both tasks. Motion-specific features including wrist joint range of motion (ROM) in flexion-extension (for the wrist motion test) and gait parameters (for the walk test) were extracted from high quality data and compared with subjective pain and mobility parameters, separately captured via the application. Out of 646 wrist joint motion samples collected, 289 (45%) were high quality. Data collected for the walk test included 2,583 samples (through 867 executions of the test) from which 651 (25%) were high quality. Further analysis of high-quality data highlighted links between reduced mobility and increased symptom severity. ANOVA testing showed statistically significant differences in wrist joint ROM between groups with light-moderate (220 participants) versus severe (36 participants) wrist pain (p < 0.001) as well as in average step times between groups with slight versus moderate problems walking about (p < 0.03). These findings demonstrate the potential to capture and quantify meaningful objective clinical information remotely using iPhone sensors and represent an early step towards the development of patient-centric digital endpoints for clinical trials in rheumatoid arthritis.


Infective endocarditis treated in a secondary hospital: epidemiological, clinical, microbiological characteristics and prognosis, with special reference to patients transferred to a third level hospital.
To analyse the clinical and epidemiological characteristics and mortality-related factors of patients admitted to a secondary hospital with Infective Endocarditis (IE). Observational study of a cohort of patients who have been diagnosed with IE in a secondary hospital and evaluated in accordance with a pre-established protocol. A total of 101 cases were evaluated (years 2000-2017), with an average age of 64 years and a male-to-female ratio of 2:1. 76% of the cases had an age-adjusted Charlson comorbidity index of >6, with 21% having had a dental procedure and 36% with a history of heart valve disease. The most common microorganism was methicillin-susceptible S. aureus (36%), with bacterial focus of unknown origin in 54%. The diagnostic delay time was 12 days in patients who were transferred, compared to 8 days in patients who were not transferred (p=0.07); the median surgery indication delay time was 5 days (IQR 13.5). The in-hospital mortality rate was 34.6% and the prognostic factors independently associated with mortality were: cerebrovascular events (OR 98.7%, 95% CI, 70.9-164.4); heart failure (OR 27.3, 95% CI, 10.2-149.1); and unsuitable antibiotic treatment (OR 7.2, 95% CI, 1.5-10.5). The mortality rate of the patients who were transferred and who therefore underwent surgery was 20% (5/25). The onset of cerebrovascular events, heart failure and unsuitable antibiotic treatment are independently and significantly associated with in-hospital mortality. The mortality rate was higher than the published average (35%); the diagnostic delay was greater in patients for whom surgery was indicated.


Histone H3 lysine 36 methyltransferase Whsc1 promotes the association of Runx2 and p300 in the activation of bone-related genes.
The orchestration of histone modifiers is required to establish the epigenomic status that regulates gene expression during development. Whsc1 (Wolf-Hirschhorn Syndrome candidate 1), a histone H3 lysine 36 (H3K36) trimethyltransferase, is one of the major genes associated with Wolf-Hirshhorn syndrome, which is characterized by skeletal abnormalities. However, the role of Whsc1 in skeletal development remains unclear. Here, we show that Whsc1 regulates gene expression through Runt-related transcription factor (Runx) 2, a transcription factor central to bone development, and p300, a histone acetyltransferase, to promote bone differentiation. Whsc1-/- embryos exhibited defects in ossification in the occipital bone and sternum. Whsc1 knockdown in pre-osteoblast cells perturbed histone modification patterns in bone-related genes and led to defects in bone differentiation. Whsc1 increased the association of p300 with Runx2, activating the bone-related genes Osteopontin (Opn) and Collagen type Ia (Col1a1), and Whsc1 suppressed the overactivation of these genes via H3K36 trimethylation. Our results suggest that Whsc1 fine-tunes the expression of bone-related genes by acting as a modulator in balancing H3K36 trimethylation and histone acetylation. Our results provide novel insight into the mechanisms by which this histone methyltransferase regulates gene expression.


Building capacity for childhood obesity prevention and treatment in the medical community: call to action.
Large gaps exist in the capacity of the US medical system to participate meaningfully in childhood obesity-prevention efforts and to meet the treatment needs of obese children. Current primary care practice for the prevention and treatment of childhood obesity often varies from evidence-based recommendations. Childhood obesity specialists have partnered successfully with schools of medicine, professional societies, and other organizations to collaboratively engage with primary care providers in quality improvement for obesity prevention and treatment. This review and commentary targets 2 audiences. For childhood obesity experts and their organizational partners, methods to support change in primary practice and the evidence supporting their use are outlined. For primary care providers and non-obesity specialists, effective strategies for changing practice and the potential benefits of addressing childhood obesity systematically are discussed.


Efficacy of budesonide and interleukin-10 in an experimental rat model with isolated bilateral pulmonary contusion created by blunt thoracic trauma.
In our study, we aimed to investigate the anti-inflammatory mediator effects of budesonide (BS), an inhaled corticosteroid and interleukin-10 (IL-10) on a pulmonary contusion in an experimental rat model in which an isolated bilateral pulmonary contusion was created by blunt thoracic trauma. Fifty-five male Sprague-Dawley rats were used in the study. Sham, control, BS and IL-10 groups were created. A pulmonary contusion was created by performing isolated blunt thoracic trauma in all groups except for the sham group. The trauma's severity was determined as 1.45 J. BS and IL-10 were administered orogastrically to the respective groups 30 min before trauma, and orogastrically and intraperitoneally, respectively, on the first and second days after the trauma. Only the blunt thoracic trauma was performed for the control group. SatO(2), PaO(2) and PaCO(2), blood glutathione, malondialdehyde (MDA) and tumour necrosis factor-α (TNFα) values were recorded on the zeroth, first, second and third days. The histopathological examination and the bronchoalveolar lavage cell count were performed on pulmonary tissues. Blood gas analysis revealed that SatO(2) and PaO(2) values on the first and second days were significantly lower in the control, BS and IL-10 groups compared with the sham group (P < 0.05). The SatO(2) and PaO(2) values on the third day in the BS and IL-10 groups were higher than in the control group (P < 0.05). The mean MDA in the control group was higher than in the sham, BS and IL-10 groups (P < 0.05). The mean TNFα in the control group was higher than in the sham, BS and IL-10 groups (P < 0.05). Pulmonary pathology scoring in the control group was observed to be higher than in the sham, BS and IL-10 groups (P < 0.05). In this rat experiment model in which an isolated pulmonary contusion was created by blunt trauma, BS and IL-10 were observed to reduce contusion severity in the lung and minimize the inflammatory reaction.


Case series of mercury toxicity among children in a hot, closed environment.
Mercury poisoning is much more prevalent in the general population than possibly many physicians realize. We present data on 26 pediatric cases with mercury intoxication from exposure to mercury by inhalation or skin contact as a result of a broken thermometer in a school laboratory. This is the largest pediatric series in Turkey. During a 3-month period, the study team observed the children for clinical symptoms, physical findings, and blood and mercury levels. Of all patients, 21 inhaled, 3 inhaled and touched the element, and 2 took the mercury home. Sixteen children were symptomatic at admission, although blood mercury levels in the symptomatic children were higher than those in asymptomatic children (P = 0.003). The urine mercury levels were not statistically different between the groups at the admission (P > 0.05). The exposure times were 3.5 and 2 hours for symptomatic and asymptomatic children, respectively (P = 0.003). The 2 children who took the mercury home had the highest blood mercury levels and the most prolonged exposure time. N-acetylcysteine and chelation treatments were started in 21 children who had symptoms of mercury intoxication and high mercury levels in their blood or urine. No adverse effects were observed during chelation therapy. Prompt removal of children from contaminated environments and proper decontamination or elimination of devices containing large amounts of mercury from schools are necessary to prevent serious complications caused by exposure to mercury.


English springer spaniels with significant bradyarrhythmias--presentation, troponin I and follow-up after pacemaker implantation.
English springer spaniels (ESS) are one of the most frequently presented breeds for pacemaker implantation in the UK and may do so at an early age. In comparison to dogs of other breeds (non-ESS) presenting for pacemaker implantation, cardiac troponin I (cTnI), the outcome and survival of ESS were investigated. Case records of dogs receiving pacemaker implantation were retrospectively reviewed. Between September 2004 and October 2008, 58 dogs were presented to the Small Animal Teaching Hospital, University of Liverpool for pacemaker implantation. ESS (n=10) was the second most commonly presented breed. ESS were significantly younger than non-ESS (P=0.022). cTnI values were elevated on presentation and a significant reduction was present after pacemaker implantation (P=0.008) in all dogs. No significant difference in initial cTnI was identified comparing ESS and non-ESS (P=0.45) and median survival times were similar (P=0.37). ESS may be predisposed to bradyarrhythmias requiring pacemaker implantation. They present at a significantly younger age than non-ESS. Survival times between ESS and non-ESS were similar, despite ESS being paced at a younger age. However, pacemaker implantation is recommended in ESS, as median survival times of 30 months with a good quality of life were achieved.


Surgical management of the aging neck.
Blunting of the cervicomental angle with age is caused by progressive laxity of the skin and subcutaneous tissues, along with proliferation of fatty deposits and platysma muscle banding. This contributes to a loss of the slender neckline associated with youth, often a primary point of concern for patients. Surgeons may avail themselves of several surgical techniques in common use to restore definition to this region. A thorough evaluation of bone and soft tissue anatomy informs the appropriate surgical approach and allows successful rejuvenation of the aging neck. The lead author's tactics for enhancement of the neck are outlined.


Depletion-Mediated Uniform Deposition of Nanorods with Patterned, Multiplexed Assembly.
Device-scale, uniform, and controllable deposition of nanoparticles on various substrates is fundamentally important not only for the fabrication of thin-film devices but also for the large sample statistics of single-particle performances. However, it is challenging to obtain such predefined depositions using a simple and efficient method. Here, we present a novel strategy for obtaining the uniform and particle density/spacing-tunable deposition of nanorods on a linker-free substrate. The deposition is driven by the tailored particle-substrate depletion attraction owing to the size-matched design of the substrate roughness and the nanorod diameter. Both gold nanorods and upconversion nanorods were applied to demonstrate the generality of the method. The high particle density of more than 21 per μm2 and correspondingly the small particle spacing of fewer than 0.3 μm were achieved on a scalable substrate template. On this basis, orientational ordering and pattern-selective deposition of nanorods were realized by controlling the liquid flow rate and employing the substrate with patterned roughness areas, respectively. With the roughness-directed density-tunable depositions of nanorods integrated onto a single platform, multiplexed gold nanorod assembly and programmable surface-enhanced Raman mapping were achieved, with a promising prospect in information encoding by using the Raman signals as the translation units. The thermal stability and related transition temperature of about 160 °C of gold nanorods were also revealed as an application of single-particle statistics. This practical method could be extended to wide ranges of potential applications in plasmonic coupling devices, cryptography, or single-particle performance statistics with the feature of the high-throughput, low-cost, and scalable fabrication.


Exome Array Analysis of Early-Onset Ischemic Stroke.
The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6). Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.


Reliability of the Southern California Postrotary Nystagmus Test with learning-disabled children.
The Southern California Postrotary Nystagmus Test (SCPNT) provides an objective assessment of nystagmus. Although depressed nystagmus duration as measured by the SCPNT is considered a major sign of vestibular dysfunction in learning-disabled children, the reliability of the SCPNT with this population has not been established. To study reliability of nystagmus duration in this population, 89 learning-disabled children were evaluated with the SCPNT. The results demonstrated that this sample had significantly depressed scores and more variability in scores than normal children. Intrascorer and test-retest reliabilities, although statistically significant, were lower than those established with normal children. A test-retest study of the reliability of placing a child in a deviant duration range over time significantly reduced reliability estimates. Clinicians using nystagmus duration scores in the evaluation of vestibular dysfunction in learning-disabled children should be sensitive to the variation in this measure in this population.


The role of lipids in plastid protein transport.
The elaborate compartmentalization of plant cells requires multiple mechanisms of protein targeting and trafficking. In addition to the organelles found in all eukaryotes, the plant cell contains a semi-autonomous organelle, the plastid. The plastid is not only the most active site of protein transport in the cell, but with its three membranes and three aqueous compartments, it also represents the most topologically complex organelle in the cell. The chloroplast contains both a protein import system in the envelope and multiple protein export systems in the thylakoid. Although significant advances have identified several proteinaceous components of the protein import and export apparatuses, the lipids found within plastid membranes are also emerging as important players in the targeting, insertion, and assembly of proteins in plastid membranes. The apparent affinity of chloroplast transit peptides for chloroplast lipids and the tendency for unsaturated MGDG to adopt a hexagonal II phase organization are discussed as possible mechanisms for initiating the binding and/or translocation of precursors to plastid membranes. Other important roles for lipids in plastid biogenesis are addressed, including the spontaneous insertion of proteins into the outer envelope and thylakoid, the role of cubic lipid structures in targeting and assembly of proteins to the prolamellar body, and the repair process of D1 after photoinhibition. The current progress in the identification of the genes and their associated mutations in galactolipid biosynthesis is discussed. Finally, the potential role of plastid-derived tubules in facilitating macromolecular transport between plastids and other cellular organelles is discussed.


Diabetes-related morbidity and mortality in a national sample of U.S. elders.
Although the number of elders with diabetes has increased dramatically, there are few data on rates of mortality and serious complications in older populations with diabetes. To determine such rates, we conducted a population-based, nonconcurrent cohort study using claims data from the 1994-1996 Medicare 5% Standard Analytical File. Codes from the ICD-9 were used to identify diabetes and the following complications: amputation, lower extremity infection, gangrene, blindness, acute myocardial infarction, ischemic heart disease, stroke, and metabolic disorders. Using these codes, we assembled a cohort of 148,562 Medicare Part A and B beneficiaries who were > or = 65 years of age, who were alive on 1 January 1995, who were not in managed care in 1994, and who had a diabetes-related claim in 1994. Age-specific rates of death and complications were then calculated. During 24 months of follow-up, 22,044 (14.8%) elders with diabetes died. Death rates in men and women increased significantly with age. Compared with their counterparts in the general U.S. population, elders with diabetes suffered excess mortality at every age group, corresponding to an overall standardized mortality ratio of 1.41 (95% CI 1.39,1.43). The incidence of ischemic heart disease and stroke was 181.5 and 126.2 per 1,000 person-years, respectively, which was higher than the incidence of all other diabetes-related complications. In every age group, elders with diabetes have significantly higher all-cause mortality rates than the general population. Medicare data may be useful in monitoring trends in diabetes-related morbidity and total mortality in U.S. elders with diabetes.


Chaos-hyperchaos transition in three identical quorum-sensing mean-field coupled ring oscillators.
We investigate the dynamics of three identical three-dimensional ring synthetic genetic oscillators (repressilators) located in different cells and indirectly globally coupled by quorum sensing whereby it is meant that a mechanism in which special signal molecules are produced that, after the fast diffusion mixing and partial dilution in the environment, activate the expression of a target gene, which is different from the gene responsible for their production. Even at low coupling strengths, quorum sensing stimulates the formation of a stable limit cycle, known in the literature as a rotating wave (all variables have identical waveforms shifted by one third of the period), which, at higher coupling strengths, converts to complex tori. Further torus evolution is traced up to its destruction to chaos and the appearance of hyperchaos. We hypothesize that hyperchaos is the result of merging the saddle-focus periodic orbit (or limit cycle) corresponding to the rotating wave regime with chaos and present considerations in favor of this conclusion.


Bone and Lean Mass Loss and Cognitive Impairment for Healthy Elder Adults: Analysis of the Nutrition and Health Survey in Taiwan 2013-2016 and a Validation Study With Structural Equation Modeling.
Purpose: Bone and lean mass loss and cognitive impairment are prevalent in elder adults and have been hypothesized to share a potential link. Methods: This nationwide cross-sectional study systemically sampled elder adults aged ≥65 years and conducted the door-to-door survey. The causal diagrams help to decide which covariates were included in the generalized linear mixed models (GLMMs). The structural equation modeling (SEM) was performed for the validation. Results: A total of 535 participants were enrolled and categorized into the normal (67.3%), mild cognitive impairment (18.3%), and dementia groups (14.4%). With increasing in the severity of cognitive impairment, the bone marrow density and lean mass consistently showed the trend of decreasing values. In the GLMMs, a significant association existed between the decrease of the bone mineral density (BMD) and the Mini-Mental State Examination (MMSE) (β = 5.819 scores per g/cm2 decrease, p = 0.0305) with adjustment of the age, sex, and physical activity. The SEM models confirmed that the MMSE was significantly and directly predicted by the age (β = 0.1363, p = 0.0003) and BMD (β = 0.1251, p = 0.0006) independently and indirectly predicted by lean mass (β = 0.1138, p = 0.0003) through the bone density path. Conclusion: In conclusion, an independent association between bone loss and cognitive impairment was existed rather than the confounding effect and the decrease of lean mass indirectly contributed to cognitive impairment by influencing the bone density.


Isolation and structural characterization of exopolysaccharide from the Cordyceps cicadae and the immunomodulatory activity on RAW264.7 cells.
A new exopolysaccharide component named as PC-EPS was isolated from Cordyceps cicadae, and its structure was determined. PC-EPS was identified to be constituted of mannose, glucose, and galactose (28.84:1:19.42), with an average molecular weight of 3.72 × 106 Da, according to the results of monosaccharide composition, Fourier transform infrared, nuclear magnetic resonance, periodate oxidation and Smith degradation, and methylation studies. According to structural characterization, PC-EPS's connection type was made up of →6) -α-d-Manp (1→, →2) -β-d-Manp (1→, →4) -α-d-Manp (1→, →2) -α-d-Galf (1→, and →4) -α-d-Galp (1→. PC-EPS may significantly increase phagocytosis and RAW264.7 cell proliferation. Additionally, by boosting intracellular lysozyme, cellular acid phosphatase, and cellular superoxide dismutase enzyme concentrations, as well as by promoting the generation of cellular NO, it is the potential to regulate the immunological activity of RAW264.7 cells. Additionally, the effects of PC-EPS on RAW264.7 cells increased their capacities to create tumor necrosis factor-α and interleukin 6 cytokines, all of which suggested that PC-EPS had the potential to improve immunomodulatory activity.


Chromosome isolation by flow sorting in Aegilops umbellulata and Ae. comosa and their allotetraploid hybrids Ae. biuncialis and Ae. geniculata.
This study evaluates the potential of flow cytometry for chromosome sorting in two wild diploid wheats Aegilops umbellulata and Ae. comosa and their natural allotetraploid hybrids Ae. biuncialis and Ae. geniculata. Flow karyotypes obtained after the analysis of DAPI-stained chromosomes were characterized and content of chromosome peaks was determined. Peaks of chromosome 1U could be discriminated in flow karyotypes of Ae. umbellulata and Ae. biuncialis and the chromosome could be sorted with purities exceeding 95%. The remaining chromosomes formed composite peaks and could be sorted in groups of two to four. Twenty four wheat SSR markers were tested for their position on chromosomes of Ae. umbellulata and Ae. comosa using PCR on DNA amplified from flow-sorted chromosomes and genomic DNA of wheat-Ae. geniculata addition lines, respectively. Six SSR markers were located on particular Aegilops chromosomes using sorted chromosomes, thus confirming the usefulness of this approach for physical mapping. The SSR markers are suitable for marker assisted selection of wheat-Aegilops introgression lines. The results obtained in this work provide new opportunities for dissecting genomes of wild relatives of wheat with the aim to assist in alien gene transfer and discovery of novel genes for wheat improvement.


Human Genomic Diversity Where the Mediterranean Joins the Atlantic.
Throughout the past few years, a lively debate emerged about the timing and magnitude of the human migrations between the Iberian Peninsula and the Maghreb. Several pieces of evidence, including archaeological, anthropological, historical, and genetic data, have pointed to a complex and intermingled evolutionary history in the western Mediterranean area. To study to what extent connections across the Strait of Gibraltar and surrounding areas have shaped the present-day genomic diversity of its populations, we have performed a screening of 2.5 million single-nucleotide polymorphisms in 142 samples from southern Spain, southern Portugal, and Morocco. We built comprehensive data sets of the studied area and we implemented multistep bioinformatic approaches to assess population structure, demographic histories, and admixture dynamics. Both local and global ancestry inference showed an internal substructure in the Iberian Peninsula, mainly linked to a differential African ancestry. Western Iberia, from southern Portugal to Galicia, constituted an independent cluster within Iberia characterized by an enriched African genomic input. Migration time modeling showed recent historic dates for the admixture events occurring both in Iberia and in the North of Africa. However, an integrative vision of both paleogenomic and modern DNA data allowed us to detect chronological transitions and population turnovers that could be the result of transcontinental migrations dating back from Neolithic times. The present contribution aimed to fill the gaps in the modern human genomic record of a key geographic area, where the Mediterranean and the Atlantic come together.


Extensive longitudinal immune profiling reveals sustained innate immune activation in COVID-19 patients with unfavorable outcome
COVID-19 differs substantially between individuals, ranging from mild to severe or even fatal. Heterogeneity in the immune response against SARS-COV-2 likely contributes to this. Therefore, we explored the temporal dynamics of key cellular and soluble mediators of innate and adaptive immune activation in relation to COVID-19 severity and progression. Forty-four patients with a PCR-proven diagnosis of COVID-19 were included. Extensive cellular (leukocytes and T-lymphocyte subsets) and serological immune profiling (cytokines, soluble cell surface molecules, and SARS-CoV-2 antibodies) was performed at hospital admission and every 3-4 days during hospitalization. Measurements and disease outcome were compared between patients with an unfavorable (IC admission and/or death) and favorable (all others) outcome. Patients with an unfavorable outcome had higher leukocyte numbers at baseline, mostly due to increased neutrophils, whereas lymphocyte and monocyte numbers were reduced. CRP, IL-6, CCL2, CXCL10, and GM-CSF levels were higher at baseline in the unfavorable group, whereas IL-7 levels were lower. SARS-CoV-2 antibodies were more frequently absent in the unfavorable group. Longitudinal analysis revealed delayed kinetics of activated CD4 and CD8 T-lymphocyte subsets in the unfavorable group. Furthermore, whereas CRP, IL-6, CXCL10, and GM-CSF declined in the favorable group, these cytokines declined with delayed kinetics, remained increased, or even increased further in the unfavorable group. Our data indicate a state of increased innate immune activation in COVID19-patients with an unfavorable outcome at hospital admission, which remained over time, as compared with patients with a favorable outcome.


6-Shogaol protects against isoproterenol-induced cardiac injury in rats through attenutating oxidative stress, inflammation, apoptosis and activating nuclear respiratory factor-2/heme oxygenase-1 signaling pathway.
The current study investigated the preventive effect of 6-Shogaol on isoproterenol hydrochloride (ISO)-induced myocardial cardiac injury. 6-Shogaol (50 mg/kg b.w.) was administered for 14 days at pretreatment and ISO-induction (85 mg/kg b.w.) for the last two days (13th and 14th days) by subcutaneous injection. Cardiac markers in serum like creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponins T (cTn T) and I (cTn I) increased in ISO-induced rats. Moreover, lipid peroxidative markers like thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH) were raised, and the activities/level of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) were diminished in ISO-treated heart tissue. In addition, inflammatory and nuclear respiratory factor (Nrf)-2 signalling molecules were upregulated in ISO-induced ischemic rats. 6-Shogaol pretreatment decreased the activities of cardiac and lipid peroxidative markers and enhanced the antioxidant status in ISO-induced cardiac injury rats. Further, 6-Shogaol pretreatment inhibited serum inflammatory markers: tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), nuclear factor-kappaB (NF-κB), Nrf-2 molecule and heme oxygenase (HO)-1 in ISO-induced cardial damage rats. We noticed the effect of 6-Shogaol inhibited pro-apoptotic genes like B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Fas, caspase-3, -8, -9, cytochrome C, and inflammatory genes and increased Bcl-2 expression in ISO-treated rats. The cardioprotective activity of 6-Shogaol in rats with ISO-induced myocardial damage may be due to its ability to reduce oxidative stress, inflammation, and apoptosis, perhaps via the Nrf-2/HO-1 signalling pathway.


[Leukonychia totalis and ectodermal dysplasia. Report of 2 cases].
The authors describe two brothers showing leukonychia totalis in association with deafness, hyperkeratosis palmaris and plantaris, scalp modifications and dental lesions. The onychopathia began during early childhood and was also present in four other members of the same family. All nails of both hands and feet were affected and appeared white, dull and with inconspicuous lunulae. The hair was rough, dark, bristly, looking like steel wire. In particular, the changes of the hair shaft were studied under scanning electron microscope. Hair dysplasia, accompanied by structural changes such as complete and incomplete twistings, longitudinal grooves and modified imbrication, was found. After briefly reviewing the literature on the subject, the authors point out the suggestive hypothesis that all these manifestations might possibly we ascribed to a single genetic defect, in spite of their different clinical features in the various patients.


Exercise training and inspiratory muscle training in patients with bronchiectasis.
Bronchiectasis is a chronic suppurative lung disease often characterised by airflow obstruction and hyperinflation, and leading to decreased exercise tolerance and reduced health status. The role of pulmonary rehabilitation (PR) and inspiratory muscle training (IMT) has not been investigated in this group of patients. Thirty two patients with idiopathic bronchiectasis were randomly allocated to one of three groups: PR plus sham IMT (PR-SHAM), PR plus targeted IMT (PR-IMT), or control. All patients (except the control group) underwent an 8 week training programme of either PR or PR plus targeted IMT. Exercise training during PR was performed three times weekly at 80% of the peak heart rate. IMT was performed at home for 15 minutes twice daily over the 8 week period. PR-SHAM and PR-IMT resulted in significant increases in the incremental shuttle walking test of 96.7 metres (95% confidence interval (CI) 59.6 to 133.7) and 124.5 metres (95% CI 63.2 to 185.9), respectively, and in endurance exercise capacity of 174.9% (95% CI 34.7 to 426.1) and 205.7% (95% CI 31.6 to 310.6). There were no statistically significant differences in the improvements in exercise between the two groups. Significant improvements in inspiratory muscle strength were also observed both in the PR-IMT group (21.4 cm H2O increase, 95% CI 9.3 to 33.4; p = 0.008) and the PR-SHAM group (12.0 cm H2O increase, 95% CI 1.1 to 22.9; p = 0.04), the magnitude of which were also similar (p = 0.220). Improvements in exercise capacity were maintained in the PR-IMT group 3 months after training, but not in the PR-SHAM group. PR is effective in improving exercise tolerance in bronchiectasis but there is no additional advantage of simultaneous IMT. IMT may, however, be important in the longevity of the training effects.


To what degree do shoulder outcome instruments reflect patients' psychologic distress?
Psychologic distress contributes to symptom severity in patients with several musculoskeletal disorders. While numerous shoulder outcome instruments are used it is unclear whether and to what degree psychologic distress contributes to the scores. We asked (1) to what degree shoulder outcome instruments reflect patients' psychologic distress, and (2) whether patients who are strongly affected by psychologic distress can be identified. We prospectively evaluated 119 patients with chronic shoulder pain caused by degenerative or inflammatory disorders using the Constant-Murley scale, Simple Shoulder Test (SST), and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. To evaluate psychologic distress, we measured depression using the Center for Epidemiologic Studies-Depression (CES-D) scale and pain anxiety using the Pain Anxiety Symptom Scale (PASS). Demographic and clinical parameters, such as pain scores, ROM, and abduction strength, also were measured. We then assessed the relative contributions made by psychologic distress and other clinical parameters to the quantitative ratings of the three shoulder outcome instruments. Quantitative ratings of shoulder outcome instruments correlated differently with psychologic distress. Constant-Murley scores did not correlate with psychologic measures, whereas SST scores correlated with PASS (r = 0.32) and DASH scores correlated with PASS and CES-D (r = 0.36 and r = 0.32). Psychologic distress contributed to worsening SST and DASH scores but not to Constant-Murley scores. DASH scores were more strongly influenced by pain anxiety and depression than the other two outcome instruments. Shoulder outcome measures reflected different psychologic aspects of illness behavior, and the contributions made by psychologic distress to different shoulder outcome instruments apparently differed. Physicians should select and interpret the findings of shoulder outcome instruments properly by considering their psychologic implications. Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence.