Hemosiderotic fibrohistiocytic lipomatous lesion: early pleomorphic hyalinizing angiectatic tumor?
Hemosiderotic fibrohistiocytic lipomatous lesion (HFLL) and early pleomorphic hyalinizing angiectatic tumor (PHAT) are characterized histologically by an admixture of fat, moderately cellular fascicles of hemosiderin-laden spindle cells growing in a perivascular, periadipocytic and septal pattern, as well as the presence of macrophages and chronic inflammatory cells. In contrast to a suggested reactive nature of HFLL, PHAT is regarded as a non-metastasizing tumor of uncertain lineage in the recent World Health Organization classification of soft tissue tumors. Reported herein is the case of a 47-year-old woman with an unencapsulated and irregularly circumscribed recurring lesion in the ankle/foot region that developed following ankle distortion and that fulfills histological criteria for both HFLL and early PHAT. In summary, the present case suggests a reactive over-neoplastic nature of HFLL and confirms profound histological similarities with early PHAT. Until more data become available on the biological potential of HFLL/early PHAT, radical surgical excision and follow up of the patient remains the best treatment option.


Feasibility of multifocal intra-ocular lens exchange and conversion to the bag-in-the-lens implantation.
Our purpose was to evaluate the surgical outcome after intra-ocular lens exchange in patients who presented impairing visual complaints after primary multifocal intra-ocular lens (MIOL) implantation. In particular, the study was undertaken to look at the number of eyes that could be equipped with the bag-in-the-lens (BIL) IOL after MIOL exchange. This series consisted of 30 eyes of 21 consecutive patients scheduled for MIOL exchange. In 15 out of the 30 eyes, IOL misalignment was measured on slit lamp anterior segment photo's after defining the mathematical centres of the IOL optic, pupil and limbus. Diffractive MIOL was more frequently explanted (25; 83%) when compared with refractive MIOL (4; 13%) and progressive optic IOL (1; 4%). In 21 out of the 30 eyes (70%) a bag-in-the-lens could be implanted. In 7 out of the 30 eyes (23%), the capsule was not considered sufficiently stable to accommodate an IOL. An iris-fixated IOL or a sulcus-fixated IOL was then implanted. In 2 out of the 30 eyes (6%) the remaining capsular bag could accommodate a traditional lens-in-the-bag only. Eyes that underwent Nd:YAG laser capsulotomy prior to the MIOL exchange needed anterior vitrectomy peroperatively (11 eyes; 37%). Visual acuity improved postoperatively in 13 out of the 30 eyes and remained stable in 17 out of the 30 eyes. Since the BIL technique requires a very well-preserved capsular bag for the purpose of the IOL implantation, the success rate of BIL implantation after MIOL is a good indicator to evaluate the degree of difficulty to exchange MIOL.


Diurnal variation of hematology parameters in healthy young males: the Bispebjerg study of diurnal variations.
To evaluate the influence of time of day on the circulating concentrations of 21 hematology parameters. Venous blood samples were obtained under standardized circumstances from 24 healthy young men every third hour through 24 hours, nine time points in total. At each time point, the level of melatonin, iron, transferrin, transferrin saturation, ferritin, cobalamin, folate, red blood cells and white blood cells was measured. The data were analysed by rhythmometric statistical methods. The biological variations were calculated. Significant oscillation of melatonin (p < 0.0001) with an amplitude (amp) of 19.84 pg/ml and a peak level at 03:34 h confirmed the normal 24-hour rhythms of the participants. Erythrocytes (p < 0.0001, amp = 0.15 × 10(12)/L), hemoglobin (p < 0.0001, amp = 0.29 mmol/L), hematocrit (p < 0.0001, amp = 0.01), iron (p < 0.0001, amp = 4.00μmol/L), transferrin (p = 0.03, amp = 1.41μmol/L), transferrin saturation (p < 0.0001, amp = 6.37%) and folate (p < 0.0001, amp = 1.55nmol/L) oscillated significantly, with gradually falling mean levels through the day to nadir around midnight. Leukocyte count (p < 0.0001, amp = 0.78 × 10(9)/L), neutrophils (p = 0.001, 0.31 × 10(9)/L), eosinophils (p < 0.0001, amp = 0.04 × 10(9)/L), monocytes (p = 0.0009, amp = 0.06 × 10(9)/L), lymphocytes (p < 0.0001, amp = 0.49 × 10(9)/L) oscillated significantly with gradually increasing mean levels through the day peaking at midnight. Iron, leukocytes and hemoglobin had the highest 24 hour oscillations in proportion to the reference intervals of the parameters for healthy young men. Biochemical screenings are biased by diurnal variations, which must be considered when blood concentrations of these parameters are interpreted in the clinical setting.


Comparative analysis between extra-short implants (≤6 mm) and 6 mm-longer implants: a meta-analysis of randomized controlled trial.
The goal of this systematic study was to compare the survival rate (SR), marginal bone loss (MBL) and clinical complications between extra-short implants (≤6 mm) and 6-mm-longer implants in randomized clinical trials. A systematic electronic and manual search was performed using the PubMed, Web of Science, Scopus and DOAJ databases. A meta-analysis was conducted to compare the SR and MBL between both groups. We have selected 17 studies out of 1016 articles for qualitative and quantitative analysis. The data from 956 patients and 1779 implants were used with an overall mean clinical follow-up of 3.88 years ranging from 1 to 8 years. Overall, the SR of extra-short implants (93.12%) was lower than the observed in 6-mm-longer implants (95.98%); however, there was no statistical significance on these findings (P > 0.10). MBL analysis showed that extra-short implants and the 6-mm-longer group presented an average of -0.71 and -0.92 mm after 1-year respectively. Three years follow-up showed MBL of -0.42 mm (≤6 mm) and -0.43 mm (>6 mm); 5 years follow-up showed an MBL of -0.69 mm (≤6 mm) and -0.46 mm (>6 mm); and after 8 years of follow-up, it was found an MBL of -1.58 mm (≤6 mm) and -2.46 mm (>6 mm). Within the limitation of this study, the results indicated that SR of extra-short implants was similar to 6-mm-longer implants. In contrast, MBL and the presence of clinical complications were observed at a lessened rate on extra-short implants.


Prognostic Value of Vimentin Is Associated With Immunosuppression in Metastatic Renal Cell Carcinoma.
Introduction: Vimentin, a classical marker of epithelial-mesenchymal transition, reflects the invasiveness of cancer cells. Its role in the genesis and progression of tumor has been reported in various cancers, including renal cell carcinoma. However, the impact of vimentin on tumor microenvironment, particularly its implication with tumor-infiltrating immune cells, is unknown. Methods: We conducted this study in 231 patients with metastatic renal cell carcinoma (mRCC) to determine the potential relationship between vimentin and immune status. Using immunohistochemical staining, expression of vimentin, CD8, FOXP3, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) were evaluated in resected tumor tissue. Kaplan-Meier analysis and Cox regression models were used for survival analysis. Chi-square test, Fisher exact test, and Mann-Whitney U-test were used for comparison between vimentin high and low groups. Results: High expression of vimentin, stroma PD-L1, and PD-1 indicated poor overall survival, whereas low regulatory T cell or high CD8+ T cell infiltration indicated long overall survival. Stroma PD-L1 (P = 0.030), vimentin (P = 0.026) expression, and CD8+ T cell infiltration (P < 0.001) were independent prognostic factors in mRCC. High vimentin expression was accompanied by high PD-1, PD-L1 expression, and increased regulatory T cell infiltration (all P < 0.001), indicating immunosuppression in the tumor microenvironment. Conclusions: We revealed that vimentin expression was associated with immunosuppression in mRCC, and the immune-suppressive status might be possibly posed by PD-1/PD-L1. Patients with high vimentin expression may acquire potential benefit from the recently approved PD-1/PD-L1 inhibitors. However, further clinical trials are needed to validate our findings.


Folic acid improves inner ear vascularization in hyperhomocysteinemic mice.
More than 29 million adults in the United States have been diagnosed with hearing loss. Interestingly, elevated homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), are also associated with impaired hearing. However, the associated mechanism remains obscure. The collagen receptor such as discoidin domain receptor 1 and matrix metalloproteinase (MMP) play a significant role in inner ear structure and function. We hypothesize that HHcy increases hearing thresholds by compromise in inner ear vasculature resulted from impaired Hcy metabolism, increased oxidative stress, collagen IVa and collagen Ia turnover. The treatment with folic acid (FA) protects elevated hearing thresholds and prevents reduction in vessel density by lowering abundant collagen deposition and oxidative stress in inner ear. To test this hypothesis we employed 8 weeks old male wild type (WT), cystathionine-beta-synthase heterozygote knockout (CBS+/-) mice, WT + FA (0.0057 μg/g/day, equivalent to a 400 μg/70 kg/day human dose in drinking water); and CBS(+/-) +FA. The mice were treated for four weeks. The hearing thresholds were determined by recording the auditory brainstem responses. Integrity of vessels was analyzed by perfusion of horseradish peroxidase (HRP) tracer. Endothelial permeability was assessed, which indicated restoration of HRP leakage by FA treatment. A total Hcy level was increased in stria vascularis (SV) and spiral ligament (SL) of CBS+/- mice which was lowered by FA. Interestingly, FA treatment lowered Col IVa Immunostaining by affecting its turnover. The levels of MMP-2, -9, methylenetetrahydrofolate reductase (MTHFR) and cystathione gamma lyase (CSE) were measured by Western blot analysis. The oxidative stress was high in SV and SL of CBS+/- compared to WT however the treatment with FA lowered oxidative stress in CBS+/- mice. These data suggested that hearing loss in CBS+/- mice was primarily due to leakage in inner ear circulation, also partly by induced collagen imbalance, increase in Hcy and oxidative stress in inner ear.


Astragalin-induced cell death is caspase-dependent and enhances the susceptibility of lung cancer cells to tumor necrosis factor by inhibiting the NF-кB pathway.
Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. Here, we demonstrate that the flavonoid astragalin (AG), also known as kaempferol-3-O-β-D-glucoside, induces cell death. This was prevented by the caspase inhibitors z-DEVD-FMK and z-LEHD-FMK. AG-induced cell death was associated with an increase in the Bax:Bcl-2 ratio and amplified by the inhibition of extracellular signal-regulated kinase (ERK)-1/2 and Akt signaling. Meanwhile, AG suppressed LPS-induced NF-κB activation. Additional studies revealed that AG inhibited tumor necrosis factor-alpha (TNFα)-induced NF-κB activity. AG also potentiated TNFα-induced apoptosis in A549 cells. Furthermore, using a mouse xenograft model, we demonstrated that AG suppressed tumor growth and induced cancer cell apoptosis in vivo. Taken together, these results suggest that AG may be a promising cancer therapeutic drug that warrants further investigation into its potential clinical applications.


Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease.
Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.


Cervical Cancer Screening Among Patients with Physical Disability.
Background: Pap smear has a central role in cervical cancer screening. Previous studies have found that female patients with disabilities are less likely to receive a Pap smear as recommended by guidelines. The aim of our study was to examine the association between physical disability and Pap smear receipt in Israel. Methods: This cross-sectional study was conducted using the electronic medical records of the second largest health care maintenance organization in Israel. All female patients during 2012-2017 aged 25-65 were identified. The exposure variable was physical disability, and the outcome variable was Pap smear receipt. We used logistic regression to control for covariates. Results: A total of 391,259 patients were eligible for this study, 6,720 (1.7%) with physical disability. 56.7% of patients with disabilities had received Pap smear compared to 63.3% of patients without disabilities, odds ratio (OR) 0.76, 95% confidence interval [CI] 0.72-0.80. When adjusting to sociodemographic and clinical covariates, patients with disabilities were less likely to receive Pap smear, adjusted OR 0.83, 95% CI 0.79-0.88. For all patients, older age, lower socioeconomic status, religious minorities, cardiovascular disease, type-2 diabetes mellitus, hypertension, smoking, and obesity were associated with lower odds of receipt of Pap smear. A history of nongynecologic oncologic disease was associated with increased odds of Pap smear receipt. Conclusion: Our study highlights the disparities between patients with and without physical disability with regard to screening for cervical cancer by receipt of Pap smear. Creating an appropriate practice with adequate access to patients with disability should be a focus for health care providers and policy makers.


CagA antibodies in Japanese children with nodular gastritis or peptic ulcer disease.
cagA(+) Helicobacter pylori strains have been linked to more severe gastric inflammation, peptic ulcer disease, and gastric cancer in adults, but there have been few studies of cagA in children. We examined the relationship between H. pylori cagA status and clinical status in Japanese children. Forty H. pylori-positive children were studied: 15 with nodular gastritis, 5 with gastric ulcers, and 20 with duodenal ulcers. H. pylori status was confirmed by biopsy-based tests and serum anti-H. pylori immunoglobulin G (IgG) antibody. As controls, 77 asymptomatic children with sera positive for anti-H. pylori IgG were enrolled. Levels of IgG antibodies to CagA in serum were measured by an antigen-specific enzyme-linked immunosorbent assay. In 16 patients with successful H. pylori eradication, posttreatment levels of CagA and H. pylori IgG antibodies also were studied. The CagA antibody seropositivities of asymptomatic controls (81.8%) and patients with nodular gastritis, gastric ulcers, and duodenal ulcers (80.0 to 95.0%) were not significantly different. Compared with pretreatment levels of CagA antibodies, posttreatment levels decreased progressively and significantly. We conclude that, as in Japanese adults, a high prevalence of cagA(+) H. pylori strains was found in Japanese children, and that there was no association with nodular gastritis or peptic ulcer disease. In the assessment of eradicative therapies, monitoring of serum anti-CagA antibodies does not appear to offer any direct benefit over monitoring of anti-H. pylori antibodies.


Nonsyndromic congenital retinal nonattachment gene maps to human chromosome band 10q21.
Nonsyndromic congenital retinal nonattachment (NCRNA) comprises congenital insensitivity to light, massive retrolental mass, shallow anterior chamber, microphthalmia, and nystagmus. We searched for the location of the gene responsible for an autosomal recessive form of NCRNA by using DNA samples from 36 individuals from a founding population. To this end we applied homozygosity mapping and a DNA pooling strategy using genomewide screen polymorphic microsatellite markers. We used two DNA pools, one pool contained DNA from 16 individuals affected with NCRNA. The second pool contained DNA from 20 normal carrier individuals, the parents of the patients. The polymorphic microsatellite markers were polymerase chain reaction (PCR)-amplified in each DNA pool; the PCR products were electrophoresed on polyacrylamide gels and visualized by silver staining. The banding patterns from DNA pools of affected and unaffected persons were compared, and linkage was detected between the NCRNA and D10S1225, a marker in 10q21. To confirm linkage of NCRNA to chromosome 10q21 by homozygosity mapping, the patients and their carrier parents were genotyped for a number of other microsatellite polymorphic markers in the 10q21region. Statistically significant linkage was observed with multiple polymorphic markers in the 10q21 region. At straight theta = 0 with markers D10S1225, D10S1428, D10S1422, and D10S1418 maximum LOD scores of 3.74, 3.58, 3. 79, and 3.48 were generated, respectively. TDT P values for markers D10S1225 and D10S1418 were 0.0000021 and 0.000021, respectively.


The variability and volatility of sleep: An ARCHetypal behavior.
Using 1975-2005 Dutch time-diary data covering over 10,000 respondents for 7 consecutive days each, we show that sleep time exhibits non-constant variability, or volatility, characterized by stationary autoregressive conditional heteroscedasticity: The absolute values of deviations from a person's average sleep on one day are positively correlated with those on adjacent days. Sleep is more variable on weekends and among younger people, those without young children, or with less education. Volatility is greater among parents with young children, slightly greater among men, but independent of other demographics. Economic incentives to minimize the dispersion of sleep imply higher-wage workers will exhibit less dispersion, which we observe. Sleep volatility spills over onto volatility in other personal activities, with no reverse causation onto sleep. The results illustrate a novel dimension of inequality among people and could be applied to a wide variety of human behavior and biological processes.


A framework for simulating gastric electrical propagation in confocal microscopy derived geometries.
Interstitial Cells of Cajal (ICC) initiate and actively propagate electrical events in the gastrointestinal tract known as slow-waves. The slow-waves coordinate the contraction of the gastrointestinal tract necessary for breakdown and mixing of ingested food. Degradation of the ICC numbers has been linked to several gastrointestinal motility disorders. However, limitations in imaging techniques and techniques for the quantification of ICC network structure have hindered our understanding of these disorders. We evaluated different machine learning techniques to segment ICC networks imaged using confocal microscopy. The accuracy the segmented networks were then quantified and compared using numerical metrics. Structurally realistic finite element meshes were constructed and used to simulate the propagation of electrical activation over the tissue blocks. The presented framework provides a system to quantify the structure and function of an ICC tissue sample. These methods are also applicable to other biological tissues and networks.


Clinical evaluation of propofol as sedative for endotracheal intubation in neonates.
To determine the effects of propofol for endotracheal intubation in neonates in daily clinical practice. We prospectively studied the pharmacodynamic effects of intravenous propofol administration in neonates who needed endotracheal intubation at the neonatal intensive care unit. Propofol was used for 62 intubations in neonates with postmenstrual ages ranging from 24 + 3 weeks to 44 + 5 weeks and bodyweights ranging from 520 to 4380 g. A 2 mg/kg bodyweight propofol starting dose was sufficient in 37% of patients; additional propofol was needed less often on the first postnatal day. The mean amount of propofol used was 3.3 (±1.2) mg/kg. The success rate of intubation depended on the experience of the physician and was related to the total administered amount of propofol. Hypotension occurred in 39% of patients and occurred more often at the first postnatal day. In 15% of procedures, propofol mono therapy was insufficient. This study shows that high doses of propofol are needed to reach effective sedation in neonates for intubation, with hypotension as a side effect in a considerable percentage of patients. Further research in newborn patients needs to identify optimal propofol doses and risk factors for hypotension.


Age-related changes in the proteoglycans of human skin.
Skin undergoes dramatic age-related changes in its mechanical properties, including changes in tissue hydration and resiliency. Proteoglycans are macromolecular conjugates of protein and carbohydrate (glycosaminoglycan) which are involved in these tissue properties. In order to examine whether age-related changes in skin proteoglycans may contribute to the age-related changes in the mechanical properties of skin, proteoglycans from human skin of various ages were extracted and analyzed. Samples were obtained from two different fetal ages, from mature skin, and from senescent skin. As a function of age, there is a decrease in the proportion of large chondroitin sulfate proteoglycans (versican) and a concomitant increase in the proportion of small dermatan sulfate proteoglycans (decorin). Based on reactivity with antibodies to various chondroitin sulfate epitopes, fetal versican differs from the versican found in older skin with respect to the chondroitin sulfate chains. Also, the decorin of fetal skin is slightly larger, while the decorin of older skin shows greater polydispersity in both its size and its charge to mass ratio. There are also age-related differences in the size and polydispersity of the core proteins of decorin. The most pronounced change in skin proteoglycans is the appearance in mature skin of a proteoglycan which is smaller than decorin, but which has the same amino terminal amino acid sequence as decorin. This small proteoglycan is abundant in mature skin and may be a catabolic fragment of decorin or an alternatively spliced form of decorin. In light of the known ability of decorin to influence collagen fibrillogenesis and fibril diameter, the appearance of this small decorin-related proteoglycan may have a significant effect on skin elasticity. The observation that proteoglycans in skin show dramatic age-related differences suggests that these changes may be involved in the age-related changes in the physical properties of skin.


[Foodborne illness caused by bacteria].
Despite the increasing level of food hygiene in the Czech Republic and other European Union member states, agents causing diseases transmitted from animals to human remain a serious problem in both human and veterinary medicine of the 21st century. The article is concerned with selected bacterial foodborne zoonoses in the Czech Republic and EU member states, including antibiotic resistance of the pathogens. Some preliminary results on the prevalence of pathogens in the human food chain in the Czech region of Moravia in 2007-2008 are presented.


4-(1-benzoylindol-3-yl)butyric acids and FK143: novel nonsteroidal inhibitors of steroid 5 alpha-reductase (II).
A novel series of indolebutyric acids with varying benzoyl substituents were synthesized to develop nonsteroidal inhibitors of steroid 5 alpha-reductase. We previously reported the discovery of a novel nonsteroidal 5 alpha-reductase inhibitor, FR119680, which had an IC50 value of 5.0 nM against the rat prostatic enzyme. However, this compound was not strongly active against the human prostatic enzyme. By further study of the structure-activity relationships we succeeded in producing the strongly active compound, FK143, 4-[3-[3-[bis(4-isobutylphenyl)-methylamino]benzoyl]-1H-indol-1-yl] butyric acid, with an IC50 value of 1.9 nM against the human enzyme. FK143 also has in vivo inhibitory activity against the castrated young rat model and it should therefore be an extremely useful agent for the treatment of benign prostatic hyperplasia.


Primary Cutaneous Gamma-Delta T Cell Lymphomas: A Case Series and Overview of the Literature.
Primary cutaneous gamma-delta T cell lymphomas (PCGDTCLs) are rare and aggressive cutaneous malignancies that have been diagnostically challenging for dermopathologists and clinicians since their first published descriptions in 1991. Since then, the availability of immunostaining for T cell receptors γ and δ in formalin-fixed paraffin-embedded samples has greatly increased our knowledge of the gamma-delta phenotype by showing that it may also be present in the context of indolent entities, such as mycosis fungoides (MFs) and lymphomatoid papulosis, and this has raised questions concerning its diagnostic and prognostic implications. We here describe the histological and clinical differences between the dermo-epidermal and subcutaneous sub-groups of PCGDTCL observed in a cohort of 20 patients attending a single experienced centre, with particular focus on cases with an MF-like presentation, which are still less well defined than those of classic MF.


Quantum Hall effect in kagomé lattices under staggered magnetic field.
The interplay of staggered magnetic field (SMF) and uniform magnetic field (UMF) on the quantum Hall effect (QHE) in kagomé lattices is investigated in the weak UMF limit. The topological band gaps coming from SMF are robust against UMF although the extended bands split into a series of Landau levels. With SMF applied, in the unconventional QHE region, one plateau of Hall conductance becomes wider and the others are compressed. Meanwhile, one of the two series of integer Hall plateaus splits and the resulting two series of Hall plateaus still exhibit the integer behavior. The Hall conductance varies with SMF step by step with the step height being e(2)/h or 2e(2)/h according to the QHE being conventional or unconventional. In the transitional regions, redistribution of Chern numbers happens even in the weak UMF limit.


Potato Consumption and Risk of Cardiovascular Mortality and Type 2 Diabetes After Myocardial Infarction: A Prospective Analysis in the Alpha Omega Cohort.
Higher potato intake, especially French fries, was unfavorably associated with cardiometabolic endpoints in population-based studies. Little is known about this in patients with ischemic heart disease (IHD). Total and boiled potatoes and French fries intake were examined in relation to cardiovascular disease (CVD) mortality, all-cause mortality, and type 2 diabetes mellitus (T2DM) risk in Dutch post-myocardial infarction (MI) patients of the Alpha Omega Cohort. We analyzed 3,401 patients (60-80 years, 78% male), free from T2DM at baseline, with an MI ≤ 10 years before enrolment. Diet was assessed at baseline (2002-2006) using a 203-item validated Food Frequency Questionnaire (FFQ) that includes potato preparation methods. Cause-specific mortality was monitored through December 2018, and T2DM incidence (self-reported physician diagnosis and/or prescribed anti-diabetes medication) was monitored during the first 40 months of follow-up. Multivariable Cox models were used to obtain hazard ratios (HRs) for fatal endpoints and incident T2DM in tertiles of potato intake. Patients had a median total potato intake (mainly boiled) of 111 g/d, 96% consumed >1 serving (200 g) per week. French fries were consumed by 48% of the patients (median of 6 g/d among consumers). During >12 years of follow-up (38,987 person-years), 1,476 deaths occurred of which 641 were from CVD, 394 were from IHD, and 119 were from a stroke. Total and boiled potatoes were not associated with CVD mortality, but a higher risk of all-cause mortality was observed (HR: 1.07; 95% CI: 1.01, 1.14; per 50 g/d). Potato consumption tended to be positively associated with incident T2DM (186 cases; HR: 1.11, 95% CI: 0.94, 1.32; per 50 g/d). Results for French fries were inconsistent for all outcomes. In Dutch post-MI patients, potatoes (mainly boiled) were not associated with CVD mortality but possibly adversely associated with all-cause mortality and T2DM risk. These findings warrant confirmation in other IHD patient cohorts. The Alpha Omega Cohort is registered at ClinicalTrials.gov as NCT03192410.


Determining the resistance of carbapenem-resistant Klebsiella pneumoniae to common disinfectants and elucidating the underlying resistance mechanisms.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is a serious problem in hospitals worldwide, posing a particular risk to immunocompromised patients. Elimination strategies may prevent these drug-resistant bacteria from spreading within hospital environments. Here, the susceptibility of patient-derived CRKP strains to common chemical disinfectants and possible correlations between the presence of drug-resistance genes and increased resistance to disinfectants were investigated. The minimum inhibitory (MIC) and the minimum bactericidal concentrations (MBC) of common chemical disinfectants against each CRKP strain were determined using agar dilution; K. pneumoniae ATCC700603 served as a standard. The presence of the drug-resistance genes qacΔE, qacA, acrA and qacE was determined using PCR. A total of 27 clinically isolated CRKP strains collected in our hospital from 2011 to 2013 exhibited sensitivity to the following common chemical disinfectants in decreasing order of sensitivity: 75% ethyl alcohol > 2% glutaraldehyde > "84" disinfectant > 0.2% benzalkonium bromide > 2% iodine tincture > 1% iodophor > 0.1% chlorhexidine acetate. Of the 27 strains, 59, 41, 19 and 15% contained qacΔE, qacA, acrA and qacE resistance genes; 15% carried acrA, qacΔE and qacA, and 26% carried both qacA and qacΔE. Comparative analysis indicated that drug-resistance genes were correlated with higher MIC values. These pan-resistant pathogenic CRKP strains contained various drug-resistance genes and exhibited relatively high resistance to ethyl alcohol, chlorhexidine acetate and iodophor. Monitoring the drug-resistance rates of CRKP strains displaying disinfectant resistance may facilitate appropriate and effective sterilisation and thus preventing the spread of these pan-resistant strains.


Urethral and vaginal infections, age of patients and state of the pelvic floor in the aetiology of the irritative symptoms of the lower urinary tract in women.
The aim of this study was to evaluate the importance of a) urethral and/or vaginal infections caused by common germs or Mycoplasmas, Chlamydia, Candida; b) age of patients; c) pelvic floor disorders in the development of irritative urinary symptoms in women. 77 consecutive abacteriuric symptomatic female patients were compared with 55 asymptomatic women. A detailed micturition history and a genitourinary physical examination were performed. Urine samples as well as vaginal and urethral swabs were taken for cultures. No statistical difference was found between the two groups regarding both urethral and/or vaginal infections and pelvic floor disorders. Whereas a significant statistical difference was found in the age of the patients. In the symptomatic group the women were older than in the asymptomatic group. The results of this study confirm that ageing is a very important cause in the development of the lower urinary tract symptoms in women.


Thoracic gamma irradiation-induced obesity in C57BL/6 female mice.
To investigate the late effects of thoracic region irradiation (TRI) on mouse body weight. Female C57BL/6 mice were divided into nonirradiated, 5 Gy total body irradiation, 9 Gy sub-total body irradiation, and 12.5 Gy thoracic region irradiation (TRI) groups. Changes in mouse weight were monitored every other week at similar time points for 12 months. The anatomical characteristics of abdominal visceral fat distribution were recorded, and mitochondrial DNA copy number in the hearts and livers and lipid metabolic signaling in the liver were analyzed. Data were analyzed by one-way analysis of variance and a student's t-test. TRI led to a significant increase (p < .001) in body weight that was dependent on time and individuals [42.1% of mice were overweight (50% increase in body weight) 4 months post-TRI and 100% of mice were overweight at 10 months post-TRI]. Gross anatomical features of abdominal visceral fat distribution and storage in radiation-induced overweight/severely overweight mice were similar to those of high fat diet-induced overweight/severely overweight mice. The mitochondrial genome of heart and liver tissues from overweight/severely overweight mice had significantly (p < .05) decreased functional mitochondrial DNA copy number (ratios decreased from 1 to 0.71 or 0.49, respectively) and significantly (p < .05) increased mitochondrial DNA mutations (ratios increased from 1 to 3.21 or 1.83, respectively). CPT1 and IRS2 lipid metabolic signaling was significantly (p < .05-.01) decreased for both mRNA (fold decrease from 1 to 0.60 or 0.55, respectively) and protein (fold decrease from 1 to 0.62 or 0.19, respectively). TRI can cause mice to gain weight. These findings indicate that TRI can result in lipid metabolic abnormalities and provide a model to study the factors that result in these abnormalities.


Cell-specific peptide binding by human neutrophils.
Analysis of peptide binding to human neutrophils (PMN) using phage display techniques has revealed cell-specific motifs reactive with the PMN surface. Phage libraries displaying either linear 9-mer or cyclic 10-mer and 6-mer peptides were incubated with normal human neutrophils followed by elution of bound phage with low pH (pH 2.2) and non-ionic detergent. Three rounds of selection generated several related peptide sequences that bound with high avidity to PMN. Using the linear 9-mer library, PMN-binding phage expressed peptides with the motif (G/A)PNLTGRW. The binding of phage bearing this motif was highly specific since no binding was observed on lymphocytes, fibroblasts, epithelial, or endothelial cells. Functional assays revealed that phage bearing the sequence FGPNLTGRW induced a pertussis toxin-sensitive increase in PMN cytosolic calcium analogous to that observed with Galphai coupled receptors. Other prominent motifs identified included phage bearing the consensus DLXTSK(M/L)X(V/I/L), where X represents a non-conserved position. Phage with this motif bound exclusively to a sub population of human PMN that comprised approximately 50% of the total and did not elicit a calcium response. The binding of such phage to PMN was prevented by co-incubation with competing peptides displaying identical or similar sequences (IC50 range from 0.6 micromol/L to 50 micromol/L for DLXTSK and GPNLTG, respectively). We speculate that these techniques will be useful in identifying functional cell-specific binding motifs and contribute to the development of new therapeutic and diagnostic strategies in human disease.


The effects of capsaicin topical therapy in dogs with atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over clinical trial.
The efficacy of twice daily topical application of capsaicin (0.025%) for the management of pruritus in dogs with atopic dermatitis (AD) was evaluated in double-blinded, placebo-controlled study. Twelve dogs with AD were randomly assigned to either 0.025% capsaicin or vehicle lotion applied twice daily for 6 weeks. After a 4-week wash-out period, treatments were switched. Significant improvement was reported by owners (P = 0.0006), but not by investigators. Owners noted temporary worsening of pruritus after the first week of capsaicin therapy. Overall capsaicin was well tolerated. Substance P (SP) concentrations in the skin did not correlate with the severity of the pruritus and did not change significantly over time and between treatments. Lesional skin had less SP than nonlesional skin (P = 0.03). These observations suggest that topical capsaicin should be further evaluated as an adjunctive antipruritic agent in dogs with AD.


[Effect of urea on proteolysis of histone H2A in calf thymus nuclei].
The 1 hour incubation of calf thymus nuclei at 37 degrees C leads to a proteolysis of the histones H1, H3 and H2B. Urea does not influence the histone degradation while 1.5 and 2.0 M NaCl lead to the proteolysis of the H2A histone. On this background, 2 M urea restrains the degradation of the H2A histone. It is assumed that hydrogen bonds are very important for the activity of the proteinases and its interaction with the H2A histone.


Chromosome Segregation in the Oocyte: What Goes Wrong during Aging.
Human female fertility and reproductive lifespan decrease significantly with age, resulting in an extended post-reproductive period. The central dogma in human female reproduction contains two important aspects. One is the pool of oocytes in the human ovary (the ovarian reserve; approximately 106 at birth), which diminishes throughout life until menopause around the age of 50 (approximately 103 oocytes) in women. The second is the quality of oocytes, including the correctness of meiotic divisions, among other factors. Notably, the increased rate of sub- and infertility, aneuploidy, miscarriages, and birth defects are associated with advanced maternal age, especially in women above 35 years of age. This postponement is also relevant for human evolution; decades ago, the female aging-related fertility drop was not as important as it is today because women were having their children at a younger age. Spindle assembly is crucial for chromosome segregation during each cell division and oocyte maturation, making it an important event for euploidy. Consequently, aberrations in this segregation process, especially during the first meiotic division in human eggs, can lead to implantation failure or spontaneous abortion. Today, human reproductive medicine is also facing a high prevalence of aneuploidy, even in young females. However, the shift in the reproductive phase of humans and the strong increase in errors make the problem much more dramatic at later stages of the female reproductive phase. Aneuploidy in human eggs could be the result of the non-disjunction of entire chromosomes or sister chromatids during oocyte meiosis, but partial or segmental aneuploidies are also relevant. In this review, we intend to describe the relevance of the spindle apparatus during oocyte maturation for proper chromosome segregation in the context of maternal aging and the female reproductive lifespan.


CircNet 2.0: an updated database for exploring circular RNA regulatory networks in cancers.
Circular RNAs (circRNAs), which are single-stranded RNA molecules that have individually formed into a covalently closed continuous loop, act as sponges of microRNAs to regulate transcription and translation. CircRNAs are important molecules in the field of cancer diagnosis, as growing evidence suggests that they are closely related to pathological cancer features. Therefore, they have high potential for clinical use as novel cancer biomarkers. In this article, we present our updates to CircNet (version 2.0), into which circRNAs from circAtlas and MiOncoCirc, and novel circRNAs from The Cancer Genome Atlas database have been integrated. In total, 2732 samples from 37 types of cancers were integrated into CircNet 2.0 and analyzed using several of the most reliable circRNA detection algorithms. Furthermore, target miRNAs were predicted from the full-length circRNA sequence using three reliable tools (PITA, miRanda and TargetScan). Additionally, 384 897 experimentally verified miRNA-target interactions from miRTarBase were integrated into our database to facilitate the construction of high-quality circRNA-miRNA-gene regulatory networks. These improvements, along with the user-friendly interactive web interface for data presentation, search, and visualization, showcase the updated CircNet database as a powerful, experimentally validated resource, for providing strong data support in the biomedical fields. CircNet 2.0 is currently accessible at https://awi.cuhk.edu.cn/∼CircNet.


[Intraoperative radiotherapy in gastrointestinal tumors].
Intraoperative radiotherapy has proved its worth for curative and palliative treatment of gastrointestinal tumors. IORT indications comprise cancer of the stomach, of the pancreas and colorectal carcinomas. Most authors are cautious to apply it to carcinoma of the esophagus, of the small intestine and of the hepatobiliary system. IORT is applied as adjuvant treatment alone or in combination with postoperative external-beam photon irradiation +/- chemotherapy. There is evidence of an improved local control rate. Pain can be relieved in symptomatic patients by an IORT dose of > or = 20 Gy. Until now, however, there is no evidence of a prolonged relapse-free and overall survival.


Nedocromil sodium in obstructive airways disease: effect on symptoms and plasma protein leakage in sputum.
In patients with asthma or chronic obstructive pulmonary disease, there is chronic airway inflammation with increased leakage of plasma proteins into the airway lumen, which can be reduced by inhaled glucocorticosteroids. Nedocromil sodium is an anti-inflammatory drug, and we questioned whether it also affects the leakage of plasma proteins. In a double-blind placebo-controlled study we investigated the effect of 12 weeks of treatment with nedocromil on forced expiratory volume in one second (FEV1), provocative concentration of histamine causing a 20% fall in FEV1 (PC20), peak flow, symptom scores, and plasma protein leakage in sputum, in 31 patients with obstructive airways disease and sputum production (mean (range) FEV1 61% of predicted (42-87%); geometric mean (range) PC20 0.39 (0.04-2.9) mg x mL(-1)). As a measure for plasma protein leakage we calculated the relative coefficients of excretion (RCE) of proteins from serum to the soluble phase of sputum. There was a small increase in morning and evening peak flow (p<0.05) and a decrease in night-time bronchodilator use (p<0.02) in favour of nedocromil. The RCE of alpha2-macroglobulin to albumin significantly decreased after treatment with nedocromil (p=0.03). The results show limited clinical efficacy of nedocromil in our study group. They further suggest that the anti-inflammatory properties of nedocromil extend to inhibition of plasma protein leakage into the airways.


Comparison of Mental Health Service Utilization by Asian Americans and Non-Hispanic Whites versus Their Cardiovascular Care Utilization.
This study will determine whether racial/ethnic disparities persist in various psychiatric disorders among Asian Americans. Secondary analyses of data from the second largest public health system in the US (total N=22294) were performed. Chi-squared statistics were used to compare the race for mental health service utilization for five psychiatric diagnoses. Cardiovascular care utilization by Asian Americans and non-Hispanic whites was used as a proxy for overall healthcare utilization rates between the two racial groups and constituted the expected values for the analysis. Asian Americans were less likely to utilize mental health services for bipolar disorder, schizophrenia, anxiety, depression, and intellectual disabilities. The results of this study call for ways to increase mental health service utilization on par with cardiovascular healthcare utilization among Asian Americans.


Low molecular mass protein patterns in mycobacterial culture filtrates and purified protein derivatives.
Mycobacterial polypeptides from 2 kDa to 14 kDa may be involved in host response to infection and be useful for new diagnostics and vaccines. Tris-tricine SDS-polyacrylamide gel electrophoresis separation of proteins in tuberculin purified protein derivative (PPD) and in 6-8-week culture filtrates of Mycobacterium tuberculosis, Mycobacterium bovis BCG, and other Mycobacterium species demonstrated as many as 10 low molecular mass bands. Common and distinct bands were observed among different species and PPD. These low molecular mass culture filtrate proteins may represent potential diagnostic reagents and vaccines for Mycobacterium tuberculosis.


Recent advances in drug delivery and targeting to the brain.
Our body keeps separating the toxic chemicals in the blood from the brain. A significant number of drugs do not enter the central nervous system (CNS) due to the blood-brain barrier (BBB). Certain diseases, such as tumor growth and stroke, are known to increase the permeability of the BBB. However, the heterogeneity of this permeation makes it difficult and unpredictable to transport drugs to the brain. In recent years, research has been directed toward increasing drug penetration inside the brain, and nanomedicine has emerged as a promising approach. Active targeting requires one or more specific ligands on the surface of nanoparticles (NPs), which brain endothelial cells (ECs) recognize, allowing controlled drug delivery compared to conventional targeting strategies. This review highlights the mechanistic insights about different cell types contributing to the development and maintenance of the BBB and summarizes the recent advancement in brain-specific NPs for different pathological conditions. Furthermore, fundamental properties of brain-targeted NPs will be discussed, and the standard lesion features classified by neurological pathology are summarized.


Transcriptional regulation of rat insulin-like growth factor-binding protein-1 expression by growth hormone.
The low mol wt insulin-like growth factor-binding protein (IGFBP-1) originally isolated from amniotic fluid has been considered to be GH independent. In this report we have examined the effect of GH on hepatic IGFBP-1 expression in the hypophysectomized rat. Using a rat IGFBP-1 cDNA probe we now demonstrated that hepatic IGFBP-1 expression is up-regulated in the GH-deficient rat. In addition, using ligand blotting, an increase in the abundance of a 30-kDa [125I]IGF-I-BP was detected in both hepatic extracts and serum from hypophysectomized rats. After a single ip injection of GH, the IGFBP-1 transcription rate was reduced within 30 min to the levels seen in the sham-operated control rats. Similarly, hepatic IGFBP-1 mRNA abundance was reduced after both acute GH injection and chronic GH treatment for 8 days. These data demonstrate that IGFBP-1 expression is inversely regulated by GH.


Trends in chronic maxillary sinusitis that require surgical treatment in northern Finland.
To examine trends in the incidence of chronic maxillary sinusitis that require surgical treatment in northern Finland, a retrospective population-based survey from 1974 through 1995 was conducted. Data on surgical cases and on various demographic factors and on variables describing medical care in the area were collected for every third year. The overall crude incidence rate (per 100,000 person-years) of chronic maxillary sinusitis requiring surgical therapy was 44 for children and 76 for adults. The age-standardized incidence rate dropped by 78% in children, and by 66% in adults during the period. The changes found to have taken place in the population and in medical care and which could have promoted the decrease were higher educational level and mean income, smaller families, improved level of hygiene, a higher number of physicians and an expanded use of broader-spectrum antibiotics. In conclusion, the most serious forms of chronic maxillary sinusitis, that require operative treatment, are decreasing in both children and adults in northern Finland.


A highly efficient "metalloligand" strategy for the synthesis of ternary Ln-Ru-W hybrids.
A series of novel ternary Ln-Ru-W hybrids constructed by metalloligands ([Ru(II)(bpy)2(4,4'-dcbpy)](PF6)2, m-H2LRu) and high-nuclear lanthanide clusters have been successfully synthesized using an efficient "metalloligand" strategy for the first time. Slow magnetic relaxation has been observed within the Dy-based hybrid.


Key.Net: Keypoint Detection by Handcrafted and Learned CNN Filters Revisited.
We introduce a novel approach for keypoint detection that combines handcrafted and learned CNN filters within a shallow multi-scale architecture. Handcrafted filters provide anchor structures for learned filters, which localize, score, and rank repeatable features. Scale-space representation is used within the network to extract keypoints at different levels. We design a loss function to detect robust features that exist across a range of scales and to maximize the repeatability score. Our Key.Net model is trained on data synthetically created from ImageNet and evaluated on HPatches and other benchmarks. Results show that our approach outperforms state-of-the-art detectors in terms of repeatability, matching performance, and complexity. Key.Net implementations in TensorFlow and PyTorch are available online.


The accuracy of pleural ultrasonography in diagnosing complicated parapneumonic pleural effusions.
We compared the accuracy of pleural ultrasound versus chest CT versus chest radiograph (CXR) to determine radiographic complexity in predicting a complicated parapneumonic effusion (CPPE) defined by pleural fluid analysis. 66 patients with parapneumonic effusions were identified with complete data. Pleural ultrasound had a sensitivity of 69.2% (95% CI 48.2% to 85.7%) and specificity of 90.0% (95% CI 76.3% to 97.2%). Chest CT had a sensitivity of 76.9% (95% CI 56.3% to 91.0%) and specificity of 65.0% (95% CI 48.3% to 79.4%). CXR had a sensitivity of 61.5% (95% CI 40.6% to 79.8%) and specificity of 60.0% (95% CI 43.3% to 75.1%). Pleural ultrasound appears to be a superior modality to rule in a CPPE when compared with chest CT and CXR.


Increase of maternal plasma leptin concentrations during pregnancy: comparison with nonpregnant women.
To investigate the physiological changes of leptin levels and whether placenta is linked to its production during pregnancy, plasma of 65 pregnant women at various gestational weeks were compared with those of 34 age- and body mass index (BMI)-matched nonpregnant women in the study. The leptin levels showed a gradual increase from 7-13 gestational week, then continuously elevated during weeks 14-20, 21-27, 28-34, virtually reaching a peak at 35-41 weeks' gestation. When they were compared to those of age- and BMI-matched nonpregnant women, a significant (P < 0.0001) increase was found with every gestational week. There were positive correlations between maternal leptin and BMI of first (7-13th week), second (14-27th week) and third (28-41st week) trimesters, with the correlation coefficients of 0.40 (P < 0.05), 0.54 (P < 0.001), and 0.49 (P < 0.001), respectively. No correlation (r = -0.17, P > 0.05, n = 31) was found between maternal leptin level and the neonatal birth weight. These data suggest that placental production of leptin is one major source of higher levels in maternal circulating leptin other than maternal gain of fat mass and that maternal leptin level is not related to fetal birth weight during pregnancy.


Eosinophilic gastritis--an unusual cause of gastric outlet obstruction.
Eosinophilic gastroenteritis is a rare entity. We report a 41-year-old man who presented with features of gastric outlet obstruction due to a submucosal lesion in the distal end of the stomach. Distal gastrectomy with Billroth II reconstruction was done. Histology showed eosinophilic gastritis infiltrating the muscular and serosal layers of the pylorus and antrum.


[Experimental study of a biological micro-arterial prosthesis].
An arterial prosthesis prepared from human placental arteries, diameter 1.0 mm, length 20 mm, was evaluated after implantation into the infrarenal region of the aorta of the rat. The permeability rate after one year (70%) compares favorably with results after fresh arterial autografts. Histology showed that the prosthesis acted as a matrix colonizable by the tissues of the recipient. The internal surface of the tube was covered by a tissular layer in which fibrillary elements suggestive of elastic fibers were developing.


Angiotensin II receptors in rabbit vascular grafts.
New Zealand White rabbits were used as a model of autologous venous bypass grafting. A section of jugular vein was sutured into the divided common carotid artery. The animals were euthanized one month after surgery. At that time histopathology showed myointimal thickening of the graft segments. Angiotensin II receptor assays showed that the AT1 receptor was present in the grafts, concentrated in the intima. These localized receptors were shown to be similar to the prototypic vascular AT1 receptor through the use of the specific antagonist DuP 753.


[Study on testing methods of Al content of polyimide hybrid films with Al2O3].
The inorganic particles hybrid polyimide films are newly emerging advanced materials with excellent corona-resistant and have been widely used in frequency control motor. The Al2O3/PI hybrid films with different Al2O3 contents were prepared by superfine aluminum power treated by coupling agent and polyamide acid (PAA). Qualitative analysis and quantitative analysis on the inorganic content to it were conducted using Fourier Transform Infrared Spectroscope (FTIR), X-ray photoelectron spectroscopy (XPS), Inductively coupled plasma spectrometry (ICP), Gravimetric method, Thermogravimetric Analysis (TG/air atmosphere). It was found that FTIR and XPS are good qualitative analysis methods. FTIR is used to inference possible components by analyzing the structure of material. The method has a lot of advantages such as easily operational, good repeatability, high accuracy and so on. XPS is mainly used to get information of elements contained in the material, it provides information about the core level binding energies and oxidation states of complexes. It can be used to identify the species and valence states of elements, measure the relative content of elements. The relative standard deviations (RSDs) of XPS and TG are too great to perform quantitative analysis, the RSDs of XPS are all above 5.0%, and TG's RSDs are also above 2.0%. So they can be only used as semiquantitative analysis methods. On the contrary, ICP and Gravimetric method are two excellent quantitative analysis methods, their RSDs are all below 1.0%. Moreover Gravimetric method only can be used to analyze single inorganic constituent complex material, although its measured value is closest approach to theoretical value. ICP is the most accurate method and it can be used to analyze multi inorganic components in complex material, this method proved to be easily operational, rapid, highly sensitive, and accurate, and can be adopted as the method of determining many elements simultaneously. So a method was got to analysis of inorganic constituent in complex material from the conclusion upward. Firstly, components in complex material are defined by using FTIR and XPS as qualitative analysis methods and then using the result of XPS as a reference, exactly quantitative analysis of inorganic constituent in complex material was performed by using Gravimetric method and ICP.


Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis.
Enterocytes of the small intestine (SI) play an important role in maintaining systemic lipid levels by regulating dietary lipid absorption and postprandial lipoprotein secretion. An excessive amount of dietary-derived triglycerides (TGs) taken up by the apical side of enterocytes or basolaterally internalized lipoprotein remnants can be transiently stored in cytosolic lipid droplets (cLDs). As mice lacking adipose TG lipase (ATGL) in the SI display massive accumulation of cLDs but also delayed cholesterol absorption, we hypothesized that SI-specific overexpression of ATGL (Atgl iTg) might have beneficial effects on lipid homeostasis in the gut and possibly throughout the body. Here, we demonstrate that Atgl iTg mice had only modestly increased enzymatic activity despite drastically elevated Atgl mRNA levels (up to 120-fold) on chow diet, and was highly induced upon high-fat/high-cholesterol diet (HF/HCD) feeding. Atgl iTg mice showed markedly reduced intestinal TG concentrations after acute and chronic lipid challenge without affecting chylomicron TG secretion. Circulating plasma cholesterol levels were significantly lower in Atgl iTg mice under different feeding conditions, contrasting the accelerated uptake of dietary cholesterol into the circulation after HF/HCD feeding. In the fasted state, gene expression analysis revealed modulation of PPARα and liver X receptor (LXR) target genes by an increased fatty acid release, whereas the decreased plasma cholesterol concentrations in refed mice were more likely due to changes in HDL synthesis and secretion. We conclude that ATGL, in addition to its role in TG catabolism, plays a critical role in whole-body cholesterol homeostasis by modulating PPARα and LXR signaling in intestinal enterocytes.


Visual mental imagery interferes with allocentric orientation judgements.
The subjective visual vertical is determined when a subject judges the orientation of an indicator (e.g. a short line segment) as apparently vertical. The mechanisms that underlie this perceptual performance are usually assumed to be based predominantly on bottom-up processing of primarily vestibular and visual information. However, it is also possible that top-down processes play a role in such abilities. We used an interference paradigm in order to investigate the effects of mental images on the perception of the visual vertical. The results demonstrate for the first time that visual mental imagery can exert the same directional influence on the subjective visual vertical as a perception of the corresponding stimulus.


Reversal of intestinal failure-associated liver disease in infants and children on parenteral nutrition: experience with 93 patients at a referral center for intestinal rehabilitation.
Intestinal failure (IF)-associated liver disease (IFALD) complicates the treatment of children with IF receiving parenteral nutrition (PN). We hypothesized that prevention or resolution of IFALD was possible in most children and that this would result in improved outcomes. We reviewed prospectively gathered data on all children referred to the intestinal rehabilitation and transplantation center at our institution. Total bilirubin level (TB) was used as the marker for IFALD. Patients were grouped based on TB at referral and at subsequent inpatient stays and outpatient visits. Standard treatment consisted of cycling of PN, limiting lipid infusion, enteral stimulation, use of ursodeoxycholic acid, and surgical intervention when necessary. Outcomes such as mortality, dependence on PN, and need for transplantation were assessed. Statistical analyses were performed using Fisher's exact, Mann-Whitney U, and Wilcoxon signed rank tests. Ninety-three patients with intestinal failure and on PN were treated at our center from 2003 to 2009. Median age at referral was 5 months (0.5-264 months). Prematurity was a complicating factor in 63 patients and necrotizing enterocolitis was the most common diagnosis. Eighty-two children had short bowel syndrome, whereas the remaining 11 had extensive motility disorders. 97% of children required significant alteration of their PN administration. At referral, 76 of 93 children had TB 2.0 mg/dL or higher, and 17 had TB below 2.0 mg/dL. TB normalized in 57 of 76 children with elevated TB at referral, and TB remained elevated in 19. Normalization of TB was associated with a mortality of 5.2%, and transplantation was needed in 5.2%. Conversely, when TB remained elevated, mortality was 58% (P = .0002 vs TB normalized), and transplantation occurred in 58% owing to failure of surgical and medical rehabilitation. Most children referred for treatment of IF have IFALD. A dedicated IF rehabilitation program can reverse IFALD in many children, and this is associated with improved outcome.


Hard contact lens-induced corneal neovascularization treated by oxygenation.
A 39-year-old man suffered from corneal neovascularization, through to result from hypoxia caused by improper use of polymethylmethacrylate (PMMA) hard contact lenses. The condition was successfully treated by oxygenation of the corneas under swimming goggles.


Involvement of lysosomes in the pathogenesis of CAG repeat diseases.
In CAG repeat diseases, affected neurons possess many cytoplasmic granules immunopositive for expanded polyglutamine stretches. Electron microscopic immunohistochemistry showed that the granules corresponded to lysosomes of primitive type. The results suggest that, in addition to the ubiquitin/proteasome pathway, mutant proteins with expanded polyglutamine stretches are involved in the lysosomal pathway for protein degradation and that this processing mechanism may serve as a target for a new therapeutic approach to CAG repeat diseases.


Energetic state is a strong regulator of sarcoplasmic reticulum Ca2+ loss in cardiac muscle: different efficiencies of different energy sources.
Increased diastolic sarcoplasmic reticulum (SR) Ca(2+) loss could depress contractility in heart failure. Since the failing myocardium has impaired energetics, we investigated whether Ca(2+) loss is linked to changes in energetic pathways. Leakage from SR in mouse permeabilized preparations was assessed using exogenous ATP, ATP + phosphocreatine (activation of bound creatine kinase, CK), ATP + mitochondrial substrates (mitochondrial activation), or with all of these together (optimal energetic conditions) in Ca(2+)-free solution. In ventricular fibres caffeine-induced tension transients under optimal energetic conditions were used to estimate SR [Ca(2+)]. In cardiomyocytes, intra-SR Ca(2+) was monitored by use of the fluorescent marker Mag-fluo 4. In fibres, SR Ca(2+) content after 5 min incubation strongly depended on energy supply (100%-optimal energetic conditions; 27 +/- 5%-exogenous ATP only, 52 +/- 5%-endogenous CK activation; 88 +/- 8%-mitochondrial activation, P < 0.01 vs. CK system). The significant loss with only exogenous ATP was not inhibited by the ryanodine receptor blockers tetracaine or ruthenium red. However, the SR Ca(2+)-ATPase (SERCA) inhibitors cyclopiazonic acid or 2,5-di(tert-butyl)-1,4-benzohydroquinone significantly decreased Ca(2+) loss. At 100 nM external [Ca(2+)], the SR Ca(2+) loss was also energy dependent and was not significantly inhibited by tetracaine. In cardiomyocytes, the decline in SR [Ca(2+)] at zero external [Ca(2+)] was almost two times slower under optimal energetic conditions than in the presence of exogenous ATP only. At low extra-reticular [Ca(2+)], the main leak pathway is an energy-sensitive backward Ca(2+) pump, and direct mitochondrial-SERCA ATP channelling is more effective in leak prevention than local ATP generation by bound CK.


A 13-Mer peptide of a brain injury-derived protein supports neuronal survival and rescues neurons from injury caused by glutamate.
Neuronal survival is mediated by several kinds of proteins. Among these, neurotrophic factors play important roles in the nervous system by supporting neuronal activity and survival. It has been suggested recently that certain factors promote neuronal survival in the case of brain injury. To examine this possibility, we purified a novel neurotrophic factor from Gelfoam that was implanted at the site of injury caused in neonatal rats. During amino acid sequence analysis, we found that a fragmental peptide of this neurotrophic protein consisting of 13 amino acids showed neurotrophic activity. This 13-mer peptide promoted survival of septal cholinergic and mesencephalic dopaminergic neurons in culture and rescued hippocampal neurons from injury caused by glutamate in culture. This peptide rescued neurons from cell death caused by glutamate, even when added 4.5 h after glutamate exposure.


Patterning cascades in the neural tube. Neural development.
The vertebrate central nervous system comprises an intricate array of neurons generated in a highly organized way. Examination of the genes expressed and required at early stages of neural differentiation reveals that a coordinated signalling cascade transforms progenitor cells into discrete neuronal subsets.


Socioeconomic indices as independent correlates of C-reactive protein in the National Longitudinal Study of Adolescent Health.
To examine the association between socioeconomic status (SES) and C-reactive protein (CRP) to understand how SES may increase the risk of cardiovascular disease and thus identify targets for prevention measures. Path models were used to examine direct and indirect associations of four indices of SES (objective early life built environment ratings, parental and participant education, and income) with CRP measured during early adulthood using data from the National Longitudinal Adolescent Health Study (n = 11,371; mean age = 29 years, range = 24-32 years; 53.8% women, 28.0% black participants). The present study examined potential mediation of the association of SES with CRP by way of body mass index (BMI), smoking, and alcohol consumption within white and black men and women. BMI was a mediator of the relation between parent education and CRP for white men (path coefficient [γ] = -0.05, p < .001) and women (γ = -0.05, p < .001). Smoking mediated the income-CRP (γ = -0.01, p < .01) and the education-CRP (γ = -0.07, p < .001) relation for white men. BMI mediated the relation between all measures of SES and CRP for white women (γ values between -0.02 and -0.05; p values < .01). None of the risk factors mediated the SES-CRP relation in black participants. These findings indicate that the association of SES with CRP is influenced by both the timing and type of SES measure examined. In addition, race and sex play a role in how potential mediators are involved with the SES-CRP relationship, such that BMI and smoking were mediators in white men, whereas BMI was the sole mediator in white women.


Optimization of the Close-to-Carrier Phase Noise in a CMOS-MEMS Oscillator Using a Phase Tunable Sustaining-Amplifier.
In this paper, the phase noise of a 24-MHz complimentary metal-oxide-semiconductor microelectromechanical systems (CMOS-MEMS) oscillator with zero-level vacuum package is studied. We characterize and analyze the nonlinear regime of each one of the modules that compose the oscillator (CMOS sustaining-amplifier and MEMS resonator). As we show, the presented resonator exhibits a high nonlinear behavior. Such a fact is exploited as a mechanism to stabilize the oscillation amplitude, allowing us to maintain the sustaining-amplifier working in the linear regime. Consequently, the nonlinear resonator becomes the main close-to-carrier phase noise source. The sustaining amplifier, which functions as a phase shifter, was developed such that MEMS operation point optimization could be achieved without an increase in circuitry modules. Therefore, the system saves on area and power, and is able to improve the phase noise 26 dBc/Hz (at 1-kHz carrier frequency offset).


Is there logic behind fetal monitoring?
Practitioners of biomedicine pride themselves on making logical decisions based on scientific fact and research evidence. However, continuous electronic fetal monitoring, as it is applied in contemporary North American obstetric practice, does not stand up to the rules of logic or the application of empirical evidence. In the face of growing evidence against the efficacy of continuous electronic fetal monitoring for improving birth outcomes, perinatal health care providers need to critically evaluate the arguments that supported its inception and consider whether its continued application can be defended.


[Therapy of stromal herpetic keratitis with a new immunomodulator likopide].
Likopide (N-acetylglucosamine-(beta 1-4)-N-acetylmuramyl-alanyl-D-isoglutamine) is a synthetic analog of muramylpeptides, characterized by immunomodulating properties and increasing the nonspecific resistance to infections. Seventy patients with ophthalmic herpes were examined, 35 of these were treated with likopide and 35 were administered placebo. Fifty-two of these suffered from stromal keratitis with ulceration and 18 had no ulcers. The trials were carried out by the double blind test with placebo. Likopide was administered orally in 10 mg tablets twice daily according to the following protocol: 3 days of treatment, 3-day interval, and 3-day treatment. All the patients were administered local specific (acyclovir ointment) and general symptomatic therapy. Immunological studies were carried out before and after therapy. Clinical assessment showed a reliably high therapeutic efficacy of likopide, its total value (excellent and good results) being as high as 88.5%. The mean duration of therapy with likopide was 11.4 +/- 0.4 days versus 15.2 +/- 0.9 days in the placebo group. Judging by the recovery criteria (arrest of inflammation, epithelization of the cornea, resorption of corneal infiltration and edema, resorption of iritis) likopide reliably accelerated healing and ensured a higher increase of vision acuity. Likopide reliably decreased the rate of detection of herpes simplex virus antigen in the involved eye conjunctiva in comparison with the placebo group patients (97.1% of negative cases versus 60%). The drug was well tolerated by the patients, no side effects were observed. Skin allergic tests with likopide showed no drug allergies.


[Medical and psycho-social screening of ageing patients in dental office].
The demographic changes cause an increasing number of ageing persons laying claim to medical and dental care. They are trying to maintain their habit of regular dental controls. Therefore, the dental care team should be able to recognize early medical and psycho-social deficiencies relevant for oral health. In this way, health status and ressources of elderly persons could be estimated better and failures in oral diagnosis as well as in treatment due to monodisciplinary case analysis could be avoided. This paper presents a systematic medical and psychosocial screening concept for oral care of elderly patients.


Management of the preauricular sinus.
The preauricular sinus is a relatively common physical finding especially in the pediatric population. It is defined as a congenital lesion in which a small skin opening located in front of the external ear communicates with a subcutaneous network of cysts. The vast majority are benign in nature and require no intervention. Draining sinus tracts are prone to infection and should be excised. Complete excision of the pit and sinus tract provides the only definitive cure. To prevent problematic recurrence, we recommend wide exposure of the lesion by the technique described.


A rare presentation of isolated carpal bone tuberculous osteomyelitis mimicking gouty arthritis.
Tuberculosis (TB) is the most prevalent infectious disease in Southeast Asia. It causes both pulmonary and extrapulmonary diseases. TB of the wrist is rare and presents as osteomyelitis or tenosynovitis. We report a middle-aged male with carpal bone tuberculous osteomyelitis. He presented with left wrist pain initially treated as gouty arthritis. Within 2 weeks, he developed seropurulent discharge with osteomyelitic changes on imaging. He underwent debridement, and intraoperatively, there was destruction of most carpal bones. Histopathological examination revealed chronic granulomatous inflammation with abscess formation. Anti-TB medication was initiated, and he made a complete recovery with almost full range of wrist movement after 9 months of treatment. This case serves as a reminder that TB is a great mimicker, and a high index of suspicion is required to make a diagnosis of TB of the wrist. Early initiation of anti-TB is pivotal to prevent complications and deterioration of joint functions.


Emergency department stat test turnaround times. A College of American Pathologists' Q-Probes study for potassium and hemoglobin.
We report aggregate turnaround times (TATs) from phlebotomy to result reporting of emergency department patients' hemoglobin and potassium results for 722 subscribers to the College of American Pathologists Q-Probes program. Approximately 40,000 specimens were obtained for each analyte. Median interinstitutional TAT time of 25 minutes for hemoglobin and 36 minutes for potassium varied little by shift, weekdays, or weekends. The type of personnel collecting the specimen and the method of specimen transport were the most important factors affecting TATs. Specimen transit times accounted for approximately one third of the total TATs, but when couriers transported hemoglobin specimens, the median transit time was equivalent to the median intralaboratory test TAT. The influence of various measures used to improve test transit and TATs is presented.


Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism.
Extracellular signal-regulated kinases (ERKs) are key regulatory proteins that mediate cell survival, proliferation, and differentiation. Reactive oxygen species (ROS) may play a role in activation of the ERK pathway. Because mitochondria are a major source of ROS, we investigated whether mitochondria-derived ROS play a role in ERK activation. Diazoxide, a potent mitochondrial ATP-sensitive K+ (K(ATP)) channel opener, is known to depolarize the mitochondrial membrane potential and cause a reversible oxidation of respiratory chain flavoproteins, thus increasing mitochondrial ROS production. Using THP-1 cells as a model, we postulated that opening mitochondrial K(ATP) channels would increase production of ROS and, thereby, regulate the activity of the ERK kinase. We found that opening mitochondrial K(ATP) channels by diazoxide induced production of ROS as determined by an increased rate of dihydroethidium and dichlorofluorescein fluorescence. This increased production of ROS was associated with increased phosphorylation of ERK kinase in a time-dependent fashion. The MEK inhibitors PD-98059 and U-0126 blocked ERK activation mediated by diazoxide. N-acetylcysteine, but not diphenyleneiodonium, attenuated ERK activation mediated by diazoxide. Adenovirus-mediated overexpression of manganese superoxide dismutase, which is expressed in mitochondria, decreased the rate of dihydroethidium oxidation as well as ERK activation. We conclude that mitochondrial K(ATP) channel openers trigger ERK activation via mitochondria-derived ROS.


Anti-SARS-CoV-2 antibodies persistence after natural infection: a repeated serosurvey in Northern Italy.
To evaluate the decline of antibodies induced by SARS-CoV-2 infection, the individuals resident in 5 municipalities of the Autonomous Province of Trento, Northern Italy, who resulted IgG positive for anti-SARS-CoV-2 nucleocapsid (NC) in May 2020, were tested four months later. Anti-SARS-CoV-2 NC antibodies were detected using the Abbott SARS-CoV-2 IgG assay. Samples that gave a negative result were re-tested using the Liaison SARS-CoV-2 IgG assay to assess anti-spike (S) S1/S2 antibodies. The fifty-percent tissue culture infective dose (TCID50) neutralizing assay was performed on a subgroup of formerly positive sera. Statistical analysis was performed by STATA version 16.1 (STATA Corp., College Station, Texas, USA). Overall, 480 out of 1159 participants became seronegative for anti-NC IgG antibodies. Age above 70 years and cough were associated with persistent anti-NC IgG levels. Most anti-NC IgG negative sera were positive for anti-S IgG (77.9%). The neutralization assay showed high concordance with anti-S antibodies positivity. In conclusion, a decline of anti-NC IgG values was recorded four months after the first evaluation. A high proportion of anti-NC seronegative individuals were positive for anti-spike IgG antibodies, which appear to persist longer and to better correlate with neutralization activity.


Polarographic study on poly alpha-L-glutamic acid-Cd2+,Co2+ complexes in the helix-coil pH region.
Interactions between poly alpha- L-glutamic acid (PGA) and metal ions Cd(2+), Co(2+) were studied by direct current polarography. The diffusion currents of these ions decreased sharply in the presence of PGA in the pH region from 5.0 through neutral. A corresponding increase in the helix content of the PGA-metal ion complex was revealed by CD measurements on the same solutions. Helix contents determined by polarography were in good agreement with those by CD in the neutral pH region. On the contrary, the decrease of current in lower acidic pH regions was independent of helix formation and suggested that metal ions coordinate to sporadically-dissociated carboxylate groups to cause aggregation of the intra and/or inter polymer chains. The diffusion current of the ions, therefore, is a parameter sensitive to the conformational changes of PGA from acidic through neutral pH region.


Multi-copy alpha-amylase genes are crucial for Ditylenchus destructor to parasitize the plant host.
Ditylenchus destructor is a migratory plant-parasitic nematode that causes huge damage to global root and tuber production annually. The main plant hosts of D. destructor contain plenty of starch, which makes the parasitic environment of D. destructor to be different from those of most other plant-parasitic nematodes. It is speculated that D. destructor may harbor some unique pathogenesis-related genes to parasitize the starch-rich hosts. Herein, we focused on the multi-copy alpha-amylase genes in D. destructor, which encode a key starch-catalyzing enzyme. Our previously published D. destructor genome showed that it has three alpha-amylase encoding genes, Dd_02440, Dd_11154, and Dd_13225. Comparative analysis of alpha-amylases from different species demonstrated that the other plant-parasitic nematodes, even Ditylenchus dipsaci in the same genus, harbor only one or no alpha-amylase gene, and the three genes from D. destructor were closely clustered in the phylogenetic tree, indicating that there was a unique expansion of the alpha-amylase gene in D. destructor. The enzymatic activity of the three alpha-amylase proteins was verified by an enzyme assay. Quantitative real-time PCR assay showed that the expression of the three alpha-amylase genes in the post-hatching stage of D. destructor was found to be significantly higher than that in eggs. In the in situ hybridization assay, the expression of the genes was localized to the intestine, implying the association of these genes with nematode digestion. An infection assay in sweet potato demonstrated that RNA interference of any one alpha-amylase gene had no influence on the infectivity of D. destructor. Using the multi-target dsRNA cocktail method, it was found that silencing of two of the three genes inhibited nematode infection, and the infectivity of worms treated with three dsRNA simultaneously changed the most, which decreased by 76.6%. Thus, the multi-copy alpha-amylase genes in D. destructor are compensatory and crucial for nematodes to parasitize the plant host.


Differential effects of selective and non-selective NOS inhibition on renal arginine and protein metabolism during endotoxemia in rats.
The kidney is the main endogenous producer of circulating arginine. Renal arginine disposal is directed to protein synthesis, urea production and nitric oxide synthesis. The administration of nitric oxide synthase inhibitors during sepsis may be beneficial or detrimental depending on the specificity of the inhibitor. We aimed to measure the effects of two NOS inhibitors, with different specificity, on renal arginine and protein turnover in a rat model of sepsis. Rats were subject to double hit endotoxemia and either L-NAME (non-specific), SMT (iNOS specific) or saline. Under anesthesia, vessels supplying and draining the kidney were catheterized. Systemic and intra-renal arginine and protein metabolism were measured using a primed continuous infusion of L-[2,3-(3)H]arginine and L-[2,6-(3)H]phenylalanine. Non-specific NOS reduced systemic protein and arginine turnover, whereas selective iNOS inhibition did not. In the kidney, blood flow was reduced by L-NAME, but not by SMT. In conjunction with this, non-selective NOS inhibition increased renal protein breakdown, whereas selective iNOS inhibition increased renal arginine production. This study shows that non-selective NOS inhibition using L-NAME is detrimental for systemic and renal protein metabolism. Selective NOS inhibition stimulates renal arginine synthesis, without changing circulating arginine levels.


[Investigation of a novel VP4 subgenotype of rotavirus in children with diarrhea in Beijing during 2009-2010].
P[8]b is a newly discovered sub-genotype for VP4 gene of group A human rotaviruses (HRV) worldwide. This study was to develop an effective method to identify P[8]a, P[8]b, P[4] and P[6] (sub) genotypes of VP4 genes of HRV and to investigate the prevalence of P[8]b sub-genotype and its G/P combinations of HRV in outpatient and inpatient children with diarrhea in Children's Hospital affiliated to Capital Institute of Pediatrics from 2009 to 2010. By analyzing the collected nucleotide sequences of VP4 gene for all known P genotypes of HRV including P[8]b subtype from GenBank and using softwares of DNAS-tar and MegAlign to align and analyze multiple sequences, probes for P[8]a, P[8]b, P[4] and P[6] (sub) genotypes in the corresponding regions which are highly divergent among genes from different genotypes and conserved within genes of VP4s in same genotypes were designed. Then four sets of primers for PCR amplified DIG labeled probes were designed and corresponding DIG-labeled specific P genotype probes were synthesized with PCR by using VP8* genes of Beijing field HRV strains representing P-genotypes P[8]a, P[8]b, P[4] and P[6], respectively, as templates. Dot-blot hybridization was developed based on cDNA of VP4 genes. The dot-blot hybridization assay for P genotyping was reliable which was confirmed by sequencing of RT-PCR products of VP4 genes amplified from corresponding clinical samples. P genotyping for VP4 genes from 88 HRV positive specimens from the Outpatient Department (55%, 88/160) and 79 HRV positive specimens from the hospitalized (70.5%, 79/112) children with diarrhea indicated that P[8] a subtype was still the most prevalent sub-genotype, which was 96.6% (85/88) and 62.0% (49/79) respectively. The positive rate for P[8]b subtypes in hospitalized children with HRV diarrhea was higher (27.9%, 22/79) than that of in outpatient (2.3%, 2/88) HRV infected children. HRV with P[4] genotype was only found in one of the hospitalized children (1.3%, 1/79), and HRV with P[6] genotype was not detected from specimens either from outpatient or inpatient. G9P[8]b was the predominant combination among the P[8]b subtype of HRV positive specimens in this study. The results in this study indicated that G9P[8]b HRV circulated in children with diarrhea in Beijing.


Emotional intelligence and the Occupational Personality Questionnaire (OPQ).
This study explores the relationship between the Bar-on EQ-I and the Occupational Personality Questionnaire OPQ32i to determine if there is a link between self- and other-reported Emotional Intelligence and personality traits. Data was obtained from 329 managers working in the IT and Finance sectors and included multi-source (360°) measures of Emotional Intelligence. Results indicated construct overlap and correlations between some elements of Emotional Intelligence and the OPQ32i with a stronger relationship between 360 measures of Emotional Intelligence and personality. On both the self-report measure of EQ-I and the 360 measure the mood scale showed a strongest link with personality factors. Measures of Emotional Intelligence which include a 360 component may thus provide a more useful indicator of an individual's ability to manage their own feelings and those of others.


Big bacteria pass through very small holes.
Can normal-sized bacteria pass through small holes, and if so how? We have found that common, potentially pathogenic, bacteria (which are nominally larger than 0.2 microm) can cross a 0.2 microm nylon membrane. All of the bacteria crossed from the upper membrane surface to the solid medium below the membrane; this ability was highly repeatable and did not depend on the make of membrane used. Bacteria growing below the membrane exhibited normal size and morphology. We suggest that the ability of common bacteria to pass through small holes has important implications in relation to their role as pathogens.


Machine-Assisted Organic Synthesis.
In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies.


Investigating the Long-Term Effect of an Interdisciplinary Multimodal Rehabilitation Program on Levels of Bioactive Lipids and Telomerase Activity in Blood from Patients with Chronic Pain.
Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP.


Medicines Optimisation for Respiratory Patients: The Establishment of a New Consultant Respiratory Pharmacist Role in Northern Ireland.
Medicines optimisation for those with respiratory conditions can have a significant impact on clinical outcomes and substantial efficiency gains for health care. Consultant pharmacists are experts working at the top of their specialism in four main pillars of practice, namely clinical care, leadership, education and training, and research and development. A consultant respiratory pharmacist has recently been appointed at a large Health and Social Care Trust in Northern Ireland to provide expert care and clinical leadership for the medicines optimisation agenda with regards to respiratory care in Northern Ireland. Alongside clinical practice, leadership, and service development, emphasis will be placed on monitoring and evaluating the work of the consultant respiratory pharmacist with a view to gathering the necessary evidence to support the case for further investment in such consultant pharmacist posts in the region. This short communication article outlines some of the clinical and economic factors associated with the decisions to invest in the consultant pharmacist model of care in Northern Ireland.


Consensus of microbiology reporting of ear swab results to primary care clinicians in patients with otitis externa.
Otitis externa is a ubiquitous inflammatory disease; although it arises most commonly from an infection, there is no consensus in the UK for the reporting of ear swab culture results. This study aims to review current microbiology laboratory reporting of ear swab specimens to primary care and reach an evidence-based consensus for a reporting policy. Fifty consecutive ear swab reports were reviewed from each of 12 laboratories in the South West region to determine and discuss reporting practice. The Health Protection Agency (HPA) GP Microbiology Laboratory Use Group reviewed the underlying evidence and worked towards a consensus of expert microbiology opinion for laboratory reporting of ear swab results using a modified version of the Delphi technique. A total of 487 reports from primary care were reviewed (54% female; 46% male). Cultures most commonly yielded Pseudomonas species (36%), Staphylococcus species (21%), Streptococcus species (15%) and fungi (11%). Five reporting policies were agreed: Policy 1: Common pathogens such as group A beta-haemolytic streptococci, Streptococcus pneumoniae, Staphylococcus aureus - Always reported by name with antibiotic susceptibilities. Policy 2: Pseudomonas species - Always reported, but antibiotic susceptibilities only reported in severe disease. Policy 3: Aspergillus, Candida, coliforms and Proteus species, as well as non-group A streptococci and anaerobes - Only reported if moderate numbers of colonies and it is the predominant organism present; if appropriate report antibiotic susceptibilities. Policy 4: Coagulase-negative staphylococci, diphtheroids and enterococci - Not reported by name; generic terms used and antibiotic susceptibilities not reported. Policy 5: When antibiotic susceptibilities reported these must include susceptibility to a topical antibiotic. It is suggested that laboratories should consider adopting this evidence-based reporting consensus for ear swab culture results from primary care patients with otitis externa.


Simple Algorithms for Distributed Leader Election in Anonymous Synchronous Rings and Complete Networks Inspired by Neural Development in Fruit Flies.
Leader election in anonymous rings and complete networks is a very practical problem in distributed computing. Previous algorithms for this problem are generally designed for a classical message passing model where complex messages are exchanged. However, the need to send and receive complex messages makes such algorithms less practical for some real applications. We present some simple synchronous algorithms for distributed leader election in anonymous rings and complete networks that are inspired by the development of the neural system of the fruit fly. Our leader election algorithms all assume that only one-bit messages are broadcast by nodes in the network and processors are only able to distinguish between silence and the arrival of one or more messages. These restrictions allow implementations to use a simpler message-passing architecture. Even with these harsh restrictions our algorithms are shown to achieve good time and message complexity both analytically and experimentally.


MicroRNA Mediated Changes in Drug Metabolism and Target Gene Expression by Efavirenz and Rifampicin In Vitro: Clinical Implications.
Efavirenz (EFV) and rifampicin (RMP) are widely prescribed in Africa for treatment of HIV/AIDS and tuberculosis epidemics. Exposure to medicines can alter drug metabolism, for example, through changes in expression of microRNAs. We report, in this study, novel observations on the ways in which EFV and RMP change microRNA expression signatures in vitro in HepaRG cells. Additionally, we discuss the clinical implications of changes in expression of drug-metabolizing enzyme genes, such as CYP3A4, CYP3A5, UGT1A1, CYP2B6, and NR1I3. Differentiated HepaRG cells were treated with EFV (6.4 μM) or RMP (24.4 μM) for 24 h. Treatment of HepaRG cells with EFV resulted in a significant increase in messenger RNA (mRNA) expression for CYP3A4 (12.51-fold, p = 0.002), CYP3A5 (2.10-fold, p = 0.019), and UGT1A1 (2.52-fold, p = 0.005), whereas NR1I3 expression decreased (0.41-fold, p = 0.02). On the other hand, treatment of HepaRG cells with RMP resulted in a significant increase in mRNA expression for CYP2B6 (6.68-fold, p = 0.007) and CYP3A4 (111.96-fold, p = 0.001), whereas NR1I3 expression decreased (0.46-fold, p = 0.033). These data point to several important clinical implications through changes in drug/drug interaction risks and achieving optimal therapeutics. All in all, this study shows that differential expression of microRNAs after treatment with EFV and RMP adds another layer of complexity that should be incorporated in pharmacogenomic algorithms to render drug response more predictable.


Effects of diabetes insipidus mutations on neurophysin folding and function.
Mechanisms underlying the pathogenicity of diabetes insipidus mutations were probed by studying their effects on the properties of bovine oxytocin-related neurophysin. The mutations G17V, DeltaE47, G57S, G57R, and C67STOP were each shown to have structural consequences that would diminish the conformational stability and folding efficiency of the precursors in which they were incorporated, and factors contributing to the origins of these property changes were identified. Effects of the mutations on dimerization of the folded proteins were similarly analyzed. The projected relative impact of the above mutations on precursor folding properties qualitatively parallels the reported relative severity of their effects on the biological handling of the human vasopressin precursor, but quantitative differences between thermodynamic effects and biological impact are noted and explored. The sole mutation for which no clear thermodynamic basis was found for its pathogenicity was 87STOP, suggesting that the region of the precursor deleted by this mutation plays a role in targeting independent from effects on folding, or participates in stabilizing interactions unique to the human vasopressin precursor.


Transactivation activity and nucleocytoplasmic transport of β-catenin are independently regulated by its C-terminal end.
The key protein in the canonical Wnt pathway is β-catenin, which is phosphorylated both in absence and presence of Wnt signals by different kinases. Upon activation in the cytoplasm, β-catenin can enter into the nucleus to transactivate target gene expression, many of which are cancer-related genes. The mechanism governing β-catenin's nucleocytoplasmic transport has been recently unvealed, although phosphorylation at its C-terminal end and its functional consequences are not completely understood. Serine 646 of β-catenin is a putative CK2 phosphorylation site and lies in a region which has been proposed to be important for its nucleocytoplasmic transport and transactivation activity. This residue was mutated to aspartic acid mimicking CK2-phosphorylation and its effects on β-catenin activity as well as localization were explored. β-Catenin S6464D did not show significant differences in both transcriptional activity and nuclear localization compared to the wild-type form, but displayed a characteristic granular nuclear pattern. Three-dimensional models of nuclei were constructed which showed differences in number and volume of granules, being those from β-catenin S646D more and smaller than the wild-type form. FRAP microscopy was used to compare nuclear export of both proteins which showed a slightly higher but not significant retention of β-catenin S646D. Altogether, these results show that C-terminal phosphorylation of β-catenin seems to be related with its nucleocytoplasmic transport but not transactivation activity.


Occurrence of Temperature-Sensitive Phenotypic Plasticity in Chlorophyll-Deficient Mutants of Arabidopsis thaliana.
A collection of 75 putative mutants with alterations in leaf pigmentation was visually selected from Arabidopsis thaliana plants (M(2) generation) grown at 26 degrees C from seeds treated with the mutagen ethylmethanesulfonate. Fifty-eight of the plants were found to have chlorophyll contents decreased by at least 10% from the parental Columbia ecotype. These plants were screened for chlorophyll content and the ratio of chlorophyll b/a after growth at 20 or 26 degrees C. Relative to the parental type, a significant number of individuals in which the chlorophyll-deficient phenotype was exacerbated at one of the growth temperatures were identified. We conclude that temperature-sensitive phenotypic plasticity for chlorophyll content is relatively common in mutant populations of higher plants.


Beta-carotene generates thiobarbituric acid-reactive substances by interaction with nitrogen dioxide in air.
Generation of thiobarbituric acid-reactive substances (TBARS) from methyl linoleate in the exposure of nitrogen dioxide/air was inhibited by beta-carotene in a dose-dependent manner. However, introduction of nitrogen dioxide/air or oxygen into a solution of beta-carotene generated a significant amount of TBARS accompanying loss of its characteristic yellow color. Storing beta-carotene in a solid state at ambient temperatures in air generated a large amount of TBARS accompanying loss of its yellow color. TBARS from beta-carotene may interfere the measurement of TBARS from polyunsaturated fatty acids, and may give undesirable effects on biomaterials.