Soup consumption is associated with a reduced risk of overweight and obesity but not metabolic syndrome in US adults: NHANES 2003-2006.
A limited number of studies have found that soup consumption is related to a lower risk of overweight and obesity in Asian and European populations, however, these studies do not provide a consistent picture regarding the association between soup consumption and markers of metabolic syndrome. To date, no study examining the relationship between soup and body weight or metabolic syndrome have been conducted in the US population. The present study used a sample of 4158 adults aged 19-64 who participated in the National Health and Nutrition Examination Survey between 2003 and 2006. The frequency of soup consumption was determined using a food frequency questionnaire. The weighted prevalence of soup consumption was 94%, with a seasonal variation in the frequency of soup consumption being found. Non-consumers of soup were at a higher risk of being overweight or obese (adjusted odds ratio = 1.381, P = 0.013), with a higher adjusted prevalence of reduced HDL cholesterol (adjusted odds ratio = 1.280, P = 0.045), but there was no association between soup consumption and metabolic syndrome (P = 0.520). The frequency of soup consumption was inversely associated with covariate-adjusted body mass index and waist circumference (P<0.05), but not with biomarkers of metabolic syndrome, except for a lower fasting insulin level in frequent soup consumers (P = 0.022). Results from the present study suggest soup consumption is not associated with metabolic syndrome. However, there is an inverse relationship between soup consumption and body weight status in US adults, which support laboratory studies showing a potential benefit of soup consumption for body weight management.


Immune alterations in subacute sclerosing panencephalitis reflect an incompetent response to eliminate the measles virus.
In subacute sclerosing panencephalitis (SSPE) the persistence of measles virus (MeV) may be related to the altered immune response. In this study, cytokine responses of lymphocytes and monocytes were evaluated in SSPE compared to controls with non-inflammatory (NICON) and inflammatory (ICON) diseases. Patients with SSPE (n = 120), 78 patients with ICON and 63 patients with NICON were included in this study. Phenotypes of peripheral blood mononuclear cells (PBMC) have been analyzed by flow cytometry. CD3 and CD28, and S. aureus Cowan strain I (SAC) stimulated and unstimulated cells were cultured and IL-2, IL-10, IFN-γ, IL-12p40, IL-12p70 and IL-23 were detected in supernatants by ELISA. MeV peptides were used for MeV-specific stimulation and IFN-γ secretion of PBMC was measured by ELISPOT. Spontaneous and stimulated secretions of IL-10 were lower in SSPE compared to both control groups. T cell stimulation induced lower IFN-γ production than ICON group, but higher IL-2 than NICON group in SSPE. Stimulated PBMC produced lower IL-12p70 in SSPE and had decreased CD46 on the cell surface, suggesting the interaction with the virus. IFN-γ responses against MeV peptides were not prominent and similar to NICON patients. The immune response did not reveal an inflammatory activity to eliminate the virus in SSPE patients. Even IL-10 production was diminished implicating that the response is self-limited in controlling the disease.


Measuring activity pacing in women with lower-extremity osteoarthritis: a pilot study.
We examined how women with osteoarthritis naturally use activity pacing and how pacing relates to symptoms and physical activity within daily routines. Thirty women with knee or hip osteoarthritis (mean age = 63.8 +/- 6.9) wore an actigraph accelerometer and repeatedly reported activity pacing, pain, and fatigue. Using the median split, symptom patterns were compared for low and high pacers. The relationship between activity pacing and physical activity was also examined. Activity pacing was low (1.4 +/- 0.9); pain and fatigue were mild (1.0 +/- 0.7 and 1.1 +/- 0.7, respectively). When compared with low pacers, high pacers had more severe, escalating symptoms. Activity pacing was related to lower physical activity (beta = -28.14, SE = 6.24), t(586) = -4.51, p = .0001. CONCLUSION. Pain, fatigue, and activity pacing use varied depending on average activity pacing level. High pacers may benefit from interventions to manage daily symptoms.


Magnetization transfer imaging in the detection of injury associated with mild head trauma.
Most traumatic brain injuries are classified as mild, yet in many instances cognitive deficits result. The purpose of this study was to investigate possible relationships between quantitative magnetization transfer imaging (MTI) and neurocognitive findings in a cohort of patients with mild head trauma but negative findings on conventional MR images. We examined 13 patients and 10 healthy volunteers with a standard MR protocol including fast spin-echo and gradient-echo imaging, to which was added quantitative MTI. MTI was performed with a modified gradient-echo sequence incorporating pulsed, off-resonance saturation. Both region-of-interest analysis and contour plots were obtained from the MTI data. A subgroup of nine patients was examined with a battery of neuropsychological tests, comprising 25 measures of neurocognitive ability. The magnetization transfer ratio (MTR) in the splenium of the corpus callosum was lower in the patient group as compared with the control group, but no significant reduction in MTR was found in the pons. Individual regional MTR values were significantly reduced in two cases, and contour plot analysis revealed focal areas of abnormality in the splenium of four patients. All the patients showed impairment on at least three measures of the neuropsychological test battery, and in two cases a significant correlation was found between regional MTR values and neuropsychological performance. Our results suggest that MTI and contour plot analysis may add sensitivity to the MR imaging examination of patients with traumatic brain injury.


Antibiotic prophylaxis in clean surgery: clean non-implant wounds.
Wound infection after clean surgery (the majority being hernia, varicose vein and breast surgery) is often greatly underestimated. If a trained and blinded observer is involved using close and prolonged surveillance to at least 30 days postoperatively with appropriate definitions or wound scores, an infection rate of up to 15% or more may be found. Equally controversial is the value of prophylactic antibiotics in preventing postoperative wound infection; there is no clear cut evidence of efficacy and some random controlled trials (RCTs) have shown no differences at all. There is a need for guidelines to be drawn up but further RCTs may be needed. An alternative to antibiotics is the systemic warming of patients or the local warming of the operative site prior to surgery. In day case surgery in particular, patients may have been deprived of fluids for 12h prior to surgery; they may become cold whilst waiting for surgery dressed in a theatre gown; and their apprehension may not be controlled with anxiolytics. The inflammatory response may be obtunded with an increased risk of superadded infection or poor healing in cutaneous tissue resulting in wound separation and fat necrosis. Only a third of sampled purulent discharges grow skin organisms such as Staphylococcus aureus or epidermidis. In a study of 421 patients the 138 randomly assigned to local warming (Warm Up, Augustine Medical) had a wound infection rate of 3.6% compared with another group of 139 randomly assigned to systemic warming (Bair Hugger, Augustine Medical) of 5.8%. A standard-treated third group of 139 had a wound infection rate of 13.7% (P<0.001). The warmed patients also had significantly lower wound scores based on 4 systems, had higher skin temperatures and capillary flow prior to surgery and were prescribed fewer postoperative antibiotics by their family doctors in the 6 postoperative weeks (15.9% vs 6.5%; P=0.002). Wound infections are more common than generally accepted if they are looked for by close surveillance. Antibiotics may be avoided by the use of warming with the lessening of the risks of allergy, resistance and emergence. It is uncertain whether antibiotic prophylaxis has a role in clean wound surgery. Breast surgery carries the highest risk of wound infection and this may risk delay in receiving planned adjuvant chemotherapy or radiotherapy. Perioperative warming of the operative site may be of greatest value in this group of patients.


Base and Nucleotide Excision Repair Pathways in DNA Plasmids Harboring Oxidatively Generated Guanine Lesions.
The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. We have demonstrated earlier that the oxidatively generated guanine lesions spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) are excised from double-stranded DNA by competing BER and NER in whole-cell extracts [Shafirovich, V., et al. (2016) J. Biol. Chem. 321, 5309-5319]. In this work we compared the NER and BER yields with single Gh or Sp lesions embedded at the same sites in covalently closed circular pUC19NN plasmid DNA (cccDNA) and in the same but linearized form (linDNA) of this plasmid. The kinetics of the Sp and Gh BER and NER incisions were monitored in HeLa cell extracts. The yield of NER products is ∼5 times greater in covalently closed circular DNA than in the linearized form, while the BER yield is smaller by ∼20-30% depending on the guanine lesion. Control BER experiments with 8-oxo-7,8-dihydroguanine (8-oxoG) show that the BER yield is increased by a factor of only 1.4 ± 0.2 in cccDNA relative to linDNA. These surprising differences in BER and NER activities are discussed in terms of the lack of termini in covalently closed circular DNA and the DNA lesion search dynamics of the NER DNA damage sensor XPC-RAD23B and the BER enzyme OGG1 that recognizes and excises 8-oxoG.


Burden of disease. Methods of calculating disability from mental disorder.
The Global Burden of Disease studies are important because they encompass morbidity as well as mortality. Burden due to morbidity is calculated from incidence, duration and disability. There is a dearth of epidemiological measurements of disability. Data from a quasi-community sample (n = 1364) were analysed. Diagnoses of mental and physical disorders, and reports of disability, were based on established methods. The disabilities reported in mental and physical disorders were comparable. Disability was correlated with comorbidity. The disability in mental disorders was examined by three methods: pure disorders, main problem and regression. It appears that major depression and substance disorder weights were overestimated, and anxiety disorder weights were underestimated in the Global Burden of Disease studies. A method for disentangling the effects of concurrent comorbidity is presented. The size of burden attributed to mental disorders is of potential benefit for funding mental health services, It is important that we get the estimates right.


Toxoplasmosis of the central nervous system in patients with AIDS in Mexico.
Toxoplasmosis of the central nervous system (CNS) is the most common cause of intracerebral lesions in patients with AIDS. It is now standard clinical practice to treat empirically, based on clinical and radiographic findings, and to perform a biopsy of the lesion only in those patients who fail to have a clinical and radiographic response after two weeks of therapy. This study describes the presentation and response to therapy of central nervous system toxoplasmosis in patients with AIDS at a private practice in Mexico City. A retrospective chart and radiology review of all patients with AIDS treated empirically for toxoplasmosis between 1988 and 1993 was performed. A total of 177 patients with AIDS were seen, nine (5.1%) had toxoplasmosis. Patients with toxoplasmosis were males with a median age of 39 years (range 26 - 65). In two patients, toxoplamosis of the CNS was the initial manifestation of HIV infection, all others had a prior diagnosis of AIDS with a mean of 10 months between their first AIDS defining event and the diagnosis of toxoplasmosis. The median CD4+ T-cell count at the time of the diagnosis of toxoplamsosis was 78 cells/microL. Most patients had headache associated with other focal neurological symptoms such as hemiplegia (2), hemiparesis (2) or seizures (4). Only 4 out of 9 patients had fever as part of their initial clinical presentation. Serum IgG antibodies against Toxoplasma gondii were positive in 6 out of 7 patients tested, while IgM antibodies were negative in all patients. On imaging studies (Computerized Tomography or Magnetic Resonance Imaging), 4 patients had a single lesion while the rest had two or more lesions. Two patients were initially treated with pyrimethamine/sulfadiazine and were later changed to pyrimethamine/clindamycin, which was the treatment given from the beginning to all other patients. One patient died of an intralesional hemorrhage two weeks after the diagnosis despite adequate therapy. The probability of surviving 6 months after the diagnosis of toxoplasmosis was 60%. The findings of these authors are similar to those reported in other series where toxoplasmosis of the CNS is a late complication of HIV infection associated with a CD4+ cell count of < 100 cells/microL. However, survival was short in spite of a good response to therapy.


Phylogenetic investigations of the stephanoberyciformes and beryciformes, particularly whalefishes (Euteleostei: Cetomimidae), based on partial 12S rDNA and 16S rDNA sequences.
DNA data were collected from a number of acanthomorph fishes for 12S rDNA (30 sequences) and 16S rDNA (39 sequences) to investigate the phylogenetic relationships of genera within Cetomimidae (whalefishes) and of this family within the Stephanoberyciformes/Beryciformes assemblage. The Cetomimidae are apparently monophyletic. Within the family, species of Gyrinomimus and Cetomimus form a clade but the former genus is paraphyletic with respect to the latter. Cetostoma is sister to Ditropichthys rather than to Gyrinomimus plus Cetomimus as suggested by morphological analyses. Rondeletiidae + Cetomimidae + Barbourisiidae are shown, as expected from morphological analyses, as a monophyletic group in the 12S rDNA analyses, but not in the 16S rDNA or combined analyses, although the shortest trees showing the group require only one extra step in each case. These three families plus Melamphaidae (our sample of Stephanoberyciformes) are not shown as a group in any analysis, with Melamphaidae being sister to Berycidae in the 16S and combined analyses, but dispersed in the 12S analyses. Maximum-parsimony trees without imposed constraints are notably shorter than trees constrained to show ordinal groupings or either of the two main current hypotheses of Stephanoberyciformes/Beryciformes relationships. The length difference is highly significant for most comparisons using either 12S or 16S rDNA sets or their combination, and significant or nearly so for all comparisons. In particular, the Beryciformes is unlikely to be monophyletic. The Holocentridae are included, with high bootstrap and Bremer support, in a clade of non-beryciforms comprising the Gempylidae, Zeidae, and Atheriniformes (the only higher acanthomorphs sampled) and not with other Beryciform families. In these data, the Berycidae are the sister to the Melamphaidae, a stephanoberyciform family.


Sexual selection drives rapid divergence in bowerbird display traits.
Sexual selection driving display trait divergence has been suggested as a cause of rapid speciation, but there is limited supporting evidence for this from natural populations. Where speciation by sexual selection has occurred in newly diverged populations, we expect that there will be significant differences in female preferences and corresponding male display traits in the absence of substantial genetic and other morphological differentiation. Two allopatric populations of the Vogelkop bowerbird, Amblyornis inornatus, show large, qualitative differences in a suite of display traits including bower structure and decorations. We experimentally demonstrate distinct male decoration color preferences within each population, provide direct evidence of female preferences for divergent decoration and bower traits in the population with more elaborate display, and show that there is minimal genetic differentiation between these populations. These results support the speciation by sexual selection hypothesis and are most consistent with the hypothesis that changes in male display have been driven by divergent female choice.


Microarrays for the detection of HBV and HDV.
The increasing pace of development in molecular biology during the last decade has had a direct effect on mass testing and diagnostic applications, including blood screening. We report the model Microarray that has been developed for Hepatitis B virus (HBV) and Hepatitis D virus (HDV) detection. The specific primer pairs of PCR were designed using the Primer Premier 5.00 program according to the conserved regions of HBV and HDV. PCR fragments were purified and cloned into pMD18-T vectors. The recombinant plasmids were extracted from positive clones and the target gene fragments were sequenced. The DNA microarray was prepared by robotically spotting PCR products onto the surface of glass slides. Sequences were aligned, and the results obtained showed that the products of PCR amplification were the required specific gene fragments of HBV, and HDV. Samples were labeled by Restriction Display PCR (RD-PCR). Gene chip hybridizing signals showed that the specificity and sensitivity required for HBV and HDV detection were satisfied. Using PCR amplified products to construct gene chips for the simultaneous clinical diagnosis of HBV and HDV resulted in a quick, simple, and effective method. We conclude that the DNA microarray assay system might be useful as a diagnostic technique in the clinical laboratory. Further applications of RD-PCR for the sample labeling could speed up microarray multi-virus detection.


Discovery of Lead 2-Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity.
Opportunistic fungal infections represent a global health problem, mainly for immunocompromised individuals. New therapeutical options are needed since several fungal strains show resistance to clinically available antifungal agents. 2-Thiazolylhydrazones are well-known as potent compounds against Candida and Cryptococcus species. A scaffold-focused drug design using machine-learning models was established to optimize the 2-thiazolylhydrazone skeleton and obtain novel compounds with higher potency, better solubility in water, and enhanced absorption. Twenty-nine novel compounds were obtained and most showed low micromolar MIC values against different species of Candida and Cryptococcus spp., including Candida auris, an emerging multidrug-resistant yeast. Among the synthesized compounds, 2-thiazolylhydrazone 28 (MIC value ranging from 0.8 to 52.17 μM) was selected for further studies: cytotoxicity evaluation, permeability study in Caco-2 cell model, and in vivo efficacy against Cryptococcus neoformans in an invertebrate infection model. All results obtained indicate the great potential of 28 as a novel antifungal agent.


Development of an In Vitro Release Assay for Low-Density Cannabidiol Nanoparticles Prepared by Flash NanoPrecipitation.
Nanoparticle encapsulation is an attractive approach to improve the oral bioavailability of hydrophobic therapeutics. The high specific surface area of nanoparticle formulations, combined with the thermodynamically driven increased solubility of an amorphous drug core, promotes rapid drug dissolution. However, the physicochemical properties of the hydrophobic therapeutic can present obstacles to in vitro characterization of nanoparticle formulations. Namely, drugs with low density and high membrane binding affinity frustrate traditional analytical methods to monitor release kinetics from nanoparticles. In this work, cannabidiol (CBD) was encapsulated into nanoparticles with low polydispersity and high drug loading via Flash NanoPrecipitation (FNP), a scalable self-assembly process. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) and lecithin were employed as amphiphilic particle stabilizers during the FNP process. However, the low density and high membrane binding affinity of the amorphous CBD nanoparticle core prevented the characterization of in vitro release kinetics by conventional methods. Released CBD could not be separated from intact nanoparticles by filtration or centrifugation. To address this challenge, an alternative approach is described to coencapsulate 6 nm hydrophobic Fe3O4 colloids with CBD during FNP. The Fe3O4 colloids were added at 33% by mass (approximately 20% by volume) to increase the density of the nanoparticles, resulting in particles with an average diameter of 160 nm (CBD-lecithin-Fe3O4) or 280 nm (CBD-HPMCAS-Fe3O4). This densification enabled the centrifugal separation of dissolved (released) CBD from unreleased CBD during the in vitro assay while avoiding the losses associated with a filtration step. The resulting nanoparticle formulations provided more rapid and complete in vitro dissolution kinetics than bulk CBD, representing a 6-fold improvement in dissolution compared to crystalline CBD. The coencapsulation of high-density Fe3O4 colloids to enable the separation of nanoparticles from release media is a novel approach to measuring in vitro release kinetics of nanoencapsulated low-density, hydrophobic drug molecules.


Identification of Loci Associated with Enhanced Virulence in Spodoptera litura Nucleopolyhedrovirus Isolates Using Deep Sequencing.
Spodoptera litura is an emerging pest insect in cotton and arable crops in Central Asia. To explore the possibility of using baculoviruses as biological control agents instead of chemical pesticides, in a previous study we characterized a number of S. litura nucleopolyhedrovirus (SpltNPV) isolates from Pakistan. We found significant differences in speed of kill, an important property of a biological control agent. Here we set out to understand the genetic basis of these differences in speed of kill, by comparing the genome of the fast-killing SpltNPV-Pak-TAX1 isolate with that of the slow-killing SpltNPV-Pak-BNG isolate. These two isolates and the SpltNPV-G2 reference strain from China were deep sequenced with Illumina. As expected, the two Pakistani isolates were closely related with >99% sequence identity, whereas the Chinese isolate was more distantly related. We identified two loci that may be associated with the fast action of the SpltNPV-Pak-TAX1 isolate. First, an analysis of rates of synonymous and non-synonymous mutations identified neutral to positive selection on open reading frame (ORF) 122, encoding a viral fibroblast growth factor (vFGF) that is known to affect virulence in other baculoviruses. Second, the homologous repeat region hr17, a putative enhancer of transcription and origin of replication, is absent in SpltNPV-Pak-TAX1 suggesting it may also affect virulence. Additionally, we found there is little genetic variation within both Pakistani isolates, and we identified four genes under positive selection in both isolates that may have played a role in adaptation of SpltNPV to conditions in Central Asia. Our results contribute to the understanding of the enhanced activity of SpltNPV-Pak-TAX1, and may help to select better SpltNPV isolates for the control of S. litura in Pakistan and elsewhere.


Role of the angiotensin II type 2 receptor in arterial remodeling after wire injury in mice.
The angiotensin II type 2 (AT2) receptor promotes apoptosis and inhibits cell proliferation. In the present study, we investigated the role of the AT2 receptor in vascular repair and remodeling following severe vascular injury using AT2 knockout (AT2KO) mice. Left femoral arteries of AT2KO mice and wild-type (WT) control mice were injured by a 0.38 mm steel wire inserted from the lumen. Twenty-eight days after the injury, a concentric vascular wall thickening, composed largely of neointima, was noted both in AT2KO and WT mice. The area occupied by the neointima and the cell count within it were not different in the two mouse strains. However, the area of the medial layer and the cell count within it were significantly larger in AT2KO mice than in WT mice. A BrdU incorporation assay showed that the proliferative activity was high in the neointima but it was not different between the strains. On the other hand, apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was significantly inhibited in the neointima and the media of AT2KO mice compared to the levels in WT mice. However, the number of TUNEL-positive cell was much smaller in the neointima than in the medial layer in both strains. Taken together, these results indicate that AT2 receptors promote the apoptosis of vascular cells but have no net effect on the neointimal cell growth or luminal narrowing after wire injury. The AT2 receptor may be involved in the control of medial layer thickness, at least in part, through medial cell apoptosis.


Effects of the synthetic selectin inhibitor TBC1269 on tissue damage during acute Mannheimia haemolytica-induced pneumonia in neonatal calves.
To determine effects of the selectin inhibitor TBC1269 on neutrophil-mediated pulmonary damage during acute Mannheimia haemolytica-induced pneumonia in newborn calves. Eighteen 1- to 3-day-old colostrum-deprived calves. Mannheimia haemolytica or saline (0.9% NaCl) solution was inoculated in both cranial lung lobes of 12 and 6 calves, respectively. Calves were euthanatized 2 (saline, n = 3; M haemolytica, n = 4) or 6 hours (saline, n = 3; M haemolytica, n = 8) after inoculation. Four M haemolytica-inoculated calves euthanatized at 6 hours also received TBC1269 (25 mg/kg, IV) 30 minutes before and 2 hours after inoculation. Conjugated diene (CD) concentrations, inducible nitric oxide synthase (iNOS) expression, and apoptotic cell counts were determined in lung specimens collected during necropsy. Conjugated diene concentrations were significantly increased in all M haemolytica-inoculated groups, compared with saline-inoculated groups. Calves treated with TBC1269 had decreased concentrations of CD, compared with untreated calves, although the difference was not significant. Number of apoptotic neutrophils and macrophages increased significantly inTBC1269-treated calves, compared with untreated calves. Inducible nitric oxide synthase was expressed by epithelial cells and leukocytes. However, iNOS was less abundant in airway epithelial cells associated with inflammatory exudates. Degree of iNOS expression was similar between TBC1269-treated and untreated calves. Mannheimia haemolytica infection in neonatal calves resulted in pulmonary tissue damage and decreased epithelial cell iNOS expression. The selectin inhibitor TCB1269 altered, but did not completely inhibit, neutrophil-mediated pulmonary damage.


Characterization of the tyrosine phosphorylation of calpactin I (annexin II) induced by platelet-derived growth factor.
Stimulation in vivo of Swiss 3T3 fibroblasts with platelet-derived growth factor (PDGF) in the presence of orthovanadate induces the tyrosine phosphorylation of a 39 kDa protein, identified as the phosphorylated slow-migrating form of calpactin I (annexin II) heavy chain, p36. In fact, in PDGF-stimulated cells, anti-(calpactin I) antibodies recognize a doublet of bands, p36 and p39, and the latter disappears upon treatment with phosphatase. In many regards phosphorylation of p39 differs from the rapid and transient phosphorylation of the PDGF receptor and of other substrates: (a) it has slower kinetics but is then stable for longer periods of time; (b) it occurs at 37 degrees C but not at 4 degrees C; and (c) whereas most of the tyrosine-phosphorylated proteins are associated with membrane-enriched preparations, membrane association of p39 only occurs in the presence of Ca2+. Moreover, calpactin I leaks out of permeabilized cells at 0.1 microM free Ca2+, whereas it remains associated with the cells at concentrations of Ca2+ greater than or equal to 1 microM. PDGF does not stimulate phosphoinositide turnover (and thus Ca2+ mobilization) at 4 degrees C; thus it can be suggested that the Ca(2+)-dependent translocation of the protein to membrane/cytoskeletal structures is a necessary condition for its phosphorylation. In addition, calpactin I may not be a direct substrate for the PDGF receptor kinase, but rather the substrate of another tyrosine kinase activated by the receptor.


Insulin promotes glucose consumption via regulation of miR-99a/mTOR/PKM2 pathway.
Insulin is known to regulate multiple cellular functions and is used for the treatment of diabetes. MicroRNAs have been demonstrated to be involved in many human diseases, including Type 2 diabetes. In this study, we showed that insulin decreased miR-99a expression levels, but induced glucose consumption and lactate production, and increased the expression of mTOR, HIF-1α and PKM2 in HepG2 and HL7702 cells. Forced expression of miR-99a or rapamycin treatment blocked insulin-induced PKM2 and HIF-1α expression, and glucose consumption and lactate production. Meanwhile, knockdown of HIF-1α inhibited PKM2 expression and insulin-induced glucose consumption. Taken together, these findings will reveal the role and mechanism of insulin in regulating glycolytic activities via miR-99a/mTOR.


Visual fields of cats with cortical and tectal lesions.
When cats were tested for visual field perimetry, the field of vision for each eye separately was from 45 degrees contralateral to 90 degrees ipsilateral. After either bilateral occipitotemporal lesions (with a split of the tectal commissure) or bilateral area 17, 18, and 19 lesions, the cats could see with each eye only from the midline to 90 degrees ipsilateral. A cat that became nearly totally blind as a result of bilateral occipitotemporal decortication had a subsequent tectal split which enabled it to see with each eye from the midline to 90 degrees ipsilateral.


mirTools: microRNA profiling and discovery based on high-throughput sequencing.
miRNAs are small, non-coding RNA that negatively regulate gene expression at post-transcriptional level, which play crucial roles in various physiological and pathological processes, such as development and tumorigenesis. Although deep sequencing technologies have been applied to investigate various small RNA transcriptomes, their computational methods are far away from maturation as compared to microarray-based approaches. In this study, a comprehensive web server mirTools was developed to allow researchers to comprehensively characterize small RNA transcriptome. With the aid of mirTools, users can: (i) filter low-quality reads and 3/5' adapters from raw sequenced data; (ii) align large-scale short reads to the reference genome and explore their length distribution; (iii) classify small RNA candidates into known categories, such as known miRNAs, non-coding RNA, genomic repeats and coding sequences; (iv) provide detailed annotation information for known miRNAs, such as miRNA/miRNA*, absolute/relative reads count and the most abundant tag; (v) predict novel miRNAs that have not been characterized before; and (vi) identify differentially expressed miRNAs between samples based on two different counting strategies: total read tag counts and the most abundant tag counts. We believe that the integration of multiple computational approaches in mirTools will greatly facilitate current microRNA researches in multiple ways. mirTools can be accessed at http://centre.bioinformatics.zj.cn/mirtools/ and http://18.104.22.168/mirtools.


[Acid-base properties of the polyene antibiotic nystatin].
The acid-base properties and transformation of nystatin in water, methanol, 80 per cent ethanol, 70 per cent propanol and 70 per cent dimethylsulfoxide were studied. The data are indicative of a significant difference in the protolytic properties of the antibiotic in various solutions. Nonreversible conformative conversions of nystatin in water and methanol not connected with the loss of the antibiotic activity were observed. It is suggested that the molecule of nystatin in the above solutions could be in 3 main states, i. e. inert native and activated. The results of the study may be of use in development of the schemes for isolation of nystatin from the mycelium preparation of some of its water soluble forms.


CT densitometry of the cochlear capsule in otosclerosis.
Cochlear otosclerosis can be recognized in most cases by high-definition axial and coronal CT images. However, routine technique does not allow a quantitative measurement of the changes. Reported here is a study of cochlear CT densitometry. The densitometric profile of the cochlear capsule was obtained in 10 ears with normal hearing and 50 ears in 27 patients with known clinical otosclerosis and progressive mixed-type hearing loss. Patients with hearing loss had decreased absorption of as much as 60% in comparison to the normal range. In 42 ears with abnormal densitometric profiles, the changes were visibly apparent on the CT images, whereas in eight others, the densitometric profile alone demonstrated decreased absorption.


[Short-term predictability of influenza AH1N1 cases based on deterministic models].
Influenza AH1N1 severely affected the population of Chile. It has high transmissibility, which may stress the health system capacity. An adequate prediction of number of cases and frequency of complications is needed. Chilean and OMS dialy reports of cases from April to Jun 2009 were analyzed in this study. We developed a simple methodology for short-term forecast of case number, based on deterministic models. Predicted and observed values were compared with regression analyses and Bland-Altman diagrams. We found that the intrinsic rate of increase of the number of cases in the world and in Chile, after an initial high instability, decreases to stable valúes, allowing a relatively accurate forecasting the next day and for a serial period. The estimators obtained are over-estimators, which allow an adequate safety factor for the estimations. The method is easy to implement in software for routine use and can be useful in monitoring this epidemic and others in the future.


Influenza-associated invasive aspergillosis in patients admitted to the intensive care unit in Sweden: a prospective multicentre cohort study.
The purpose of this study was to prospectively investigate the incidence of influenza-associated pulmonary aspergillosis (IAPA) in influenza patients admitted to intensive care units in Sweden. The study included consecutive adult patients with PCR-verified influenza A or B in 12 Swedish intensive care units (ICUs) over four influenza seasons (2019-2023). Patients were screened using serum galactomannan and β-d-glucan tests and fungal culture of a respiratory sample at inclusion and weekly during the ICU stay. Bronchoalveolar lavage was performed if clinically feasible. IAPA was classified according to recently proposed case definitions. The cohort included 55 patients; 42% were female, and the median age was 59 (IQR 48-71) years. All patients had at least one galactomannan test, β-d-glucan test and respiratory culture performed. Bronchoalveolar lavage was performed in 24 (44%) of the patients. Five (9%, 95% CI 3.8% - 20.4%) patients were classified as probable IAPA, of which four lacked classical risk factors. The overall ICU mortality was significantly higher among IAPA patients than non-IAPA patients (60% vs 8%, p = 0.01). The study represents the first prospective investigation of IAPA incidence. The 9% incidence of IAPA confirms the increased risk of invasive pulmonary aspergillosis among influenza patients admitted to the ICU. Therefore, it appears reasonable to implement a screening protocol for the early diagnosis and treatment of IAPA in influenza patients receiving intensive care. ClinicalTrials.gov NCT04172610, registered November 21, 2019.


Anti-HIV antibody-dependent activation of NK cells impairs NKp46 expression.
There is much interest in the potential of Ab-dependent cellular cytotoxicity (ADCC) to slow disease progression following HIV infection. Despite several studies demonstrating a positive association between ADCC and slower disease progression, it is possible that continued stimulation of NK cells by ADCC during chronic HIV infection could render these cells dysfunctional. Indeed, activation of NK cells by ADCC results in matrix metalloproteinase-induced reductions in CD16 expression and activation refractory periods. In addition, ex vivo analyses of NK cells from HIV-infected individuals revealed other alterations in phenotype, such as decreased expression of the activating NKp46 receptor that is essential for NK-mediated antitumor responses and immunity from infection. Because NKp46 shares a signaling pathway with CD16, we hypothesized that activation-induced downregulation of both receptors could be controlled by a common mechanism. We found that activation of NK cells by anti-HIV or anti-CD16 Abs resulted in NKp46 downregulation. The addition of a matrix metalloproteinase inhibitor attenuated NKp46 downregulation following NK cell activation by anti-HIV Abs. Consequently, these results suggest that continued stimulation through CD16 has the potential to impair natural cytotoxicity via attenuation of NKp46-dependent signals.


Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome.
Patients coinfected with HIV and Mycobacterium tuberculosis frequently experience a paradoxical worsening of tuberculosis (TB) symptoms early after the initiation of combination antiretroviral therapy (cART). This immune reconstitution inflammatory syndrome (TB-IRIS) can lead to significant morbidity and needs to be distinguished from TB recurrence due to ineffective treatment. We investigated whether plasma biomarkers could predict the occurrence of TB-IRIS. ANRS 129 BKVIR is a single-arm multicentre trial that enrolled 69 cART-naïve HIV-1-infected patients treated for TB. The patients received once-daily tenofovir/emtricitabine/efavirenz first-line regimen. TB-IRIS cases (IRIS+) were validated by an Event Review Committee. A panel of 26 plasma biomarkers was monitored longitudinally for 24 weeks from cART initiation onward, using multiplexed assays and high-sensitivity ELISA. Statistical analyses of biomarkers were adjusted for test multiplicity. One-third of patients (n=23) experienced TB-IRIS. The inflammatory cytokines and chemokines interleukin (IL)-6, IL-8, interferon-gamma-induced protein 10 (IP-10), and tumour necrosis factor-alpha (TNF-α) showed increased plasma levels at week 4 in IRIS-positive (IRIS+) patients (P<0.05 for each biomarker). The soluble IL-2 receptor sCD25, which is released upon CD4 T-cell activation, was significantly increased at week 0 in IRIS+ patients (P<0.05), and remained elevated throughout follow-up. IL-7, a key homeostatic cytokine for CD4 T-cells, showed a trend for higher values in the TB-IRIS group. Both sCD25 and IL-7 baseline levels were independently associated with a shorter time to TB-IRIS occurrence (P=0.005 and P=0.02, respectively). These findings support a role for CD4 T-cell activation prior to massive inflammation in the development of TB-IRIS.


Greater trochanteric pain syndrome.
Pain around the greater trochanter is still a common clinical problem that may be secondary to a variety of either intra-articular or periarticular pathologies. Gluteal tendon pathologies are one of the primary causes of greater trochanteric pain, with attrition of the fasciae latae against the gluteus medius and minimus tendons, and the trochanteric bursa being possible causes. Key sonographic findings of gluteal tendinopathy, bursitis, and differential diagnosis are described in this overview. Clinical diagnosis and treatment of greater trochanteric pain syndrome is still challenging; therefore ultrasound is helpful to localize the origin of pain, determine underlying pathology, and, based on these findings, to guide local aspiration and/or injection in cases of tendinopathy and/or bursitis.


The impact of work rewards on radiographers' organizational commitment.
Organizational commitment is an affective work outcome that has been used to predict work-related behaviors such as turnover, absenteeism and intent-to-leave. There has been little research in organizational commitment for the allied health professions and no empirical studies in the radiologic sciences. The purpose of this study was to examine the predictive value of selected intrinsic and extrinsic work reward variables--involvement, significance, autonomy, general working conditions, supervision and salary--on staff radiographers' organizational commitment. In this study of 600 full-time staff radiographers in North and South Carolina, supervision (for ages 20-37 years) and involvement (for ages 38-66 years) were significant predictors of organizational commitment. The results of the study indicate that healthcare organizations should provide potential supervisors with managerial training, especially for radiographers who move to supervisory positions based on clinical skills and years of experience. In the long run, such programs are much less expensive than costs associated with replacing employees who leave the organization because of low organizational commitment. Also, management strategies and programs to redesign and enhance job tasks may help maintain or increase organizational commitment.


[30 Years of the Tragedy in Chernobyl. Clinical and Immunological Effects in Liquidators of Consequences of the Chernobyl Accident. Main Results of Long-Term Monitoring].
Results of long-term immunological monitoring of liquidators of consequences of the Chernobyl accident and the revealed regularities are presented. Earlier the unknown phenomenon of the activating influence of radiation at small doses on the T-cellular link of the immune status (IS), mainly on T-lymphocytes/helper was for the first time established. This phenomenon came to light among participants of LPA working in an extreme situation of 1986 in the zones of the CN PP and further was confirmed by inspection of the personnel of a 30-km zone of the CNPP in 1990; the personnel at radiation dangerous nuclear power plants and the population living near these objects, the population polluted by radionuclides on the territories of the Bryansk region. This effect in the presence of clinical symptoms which can be caused by influence of a radiation factor was most expressed. Prognostic value of the changes in the development of IS immune insufficiency (ID), cellular and humoral link in the near future after taking part in clean-up workers are established. These laws have a theoretical value for immunology and radiobiology, and practical health care as well, as the formation of a phenotype of IS defines approaches to immunoprophylactics and immunocorrection, as in extreme situations, and in the following years. During the delayed periods development of an imbalance, immune in- sufficiency in T-lymphocytes and natural killer cells is revealed. By the end of the 3rd - the beginning of the 4th fifth anniversary after the accident the high frequency of clinical manifestations of immune dysfunction and chronic somatic diseases was defined. The immunological characteristic of an immunoproliferative syn- drome that allowed one to reveal predictors of early diagnostics of malignant new growths in immune status is for the first time established. Clinical-immunological signs of early aging of liquidators and features of changes in liquidators in the lipidic status depending on the age and risk factors of Chernobyl accident are revealed. Features of antiviral protection of an organism ofliquidators that is defined by changes in the cluster of genes of cytokines (IL28A, IL28B and IL29) localized on the 19th chromosome (19ql3) of the person are established. Establishment of genotypes can be associated with a positive effect of treatment, steady and long remission of GVI.


Age-dependent alterations in cAMP signaling contribute to synaptic plasticity deficits following traumatic brain injury.
The elderly have comparatively worse cognitive impairments from traumatic brain injury (TBI) relative to younger adults, but the molecular mechanisms that underlie this exacerbation of cognitive deficits are unknown. Experimental models of TBI have demonstrated that the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway is downregulated after brain trauma. Since the cAMP-PKA signaling pathway is a key mediator of long-term memory formation, we investigated whether the TBI-induced decrease in cAMP levels is exacerbated in aged animals. Aged (19 months) and young adult (3 months) male Fischer 344 rats received sham surgery or mild (1.4-1.6 atmospheres, atm) or moderate (1.7-2.1 atm) parasagittal fluid-percussion brain injury. At various time points after surgery, the ipsilateral parietal cortex, hippocampus, and thalamus were assayed for cAMP levels. Mild TBI lowered cAMP levels in the hippocampus of aged, but not young adult animals. Moderate TBI lowered cAMP levels in the hippocampus and parietal cortex of both age groups. In the thalamus, cAMP levels were significantly lowered after moderate, but not mild TBI. To determine if the TBI-induced decreases in cAMP had physiological consequences in aged animals, hippocampal long-term potentiation (LTP) in the Schaffer collateral pathway of the CA1 region was assessed. LTP was significantly decreased in both young adult and aged animals after mild and moderate TBI as compared to sham surgery animals. Rolipram rescued the LTP deficits after mild TBI for young adult animals and caused a partial recovery for aged animals. However, rolipram did not rescue LTP deficits after moderate TBI in either young adult or aged animals. These results indicate that the exacerbation of cognitive impairments in aged animals with TBI may be due to decreased cAMP levels and deficits in hippocampal LTP.


Density dependence of developmental instability in a dimorphic ungulate.
The use of fluctuating asymmetry (FA) for biomonitoring environmental stress is limited by the lack of work on how FA in particular traits responds to specific stresses. Here, by manipulating the number of individuals in an enclosed fallow deer (Dama dama) population, we describe, for the first time, clear density dependence in the FA of juvenile jaw morphology. The impact of high population density on FA was strong for both sexes, supporting the use of FA for indexing environmental stress. In addition, there was some indication that the change in FA was greater in males (43.6%) than females (28.5%). Finally, the ability to buffer density-dependent stress was independent of body condition. We suggest that, under highly limiting conditions, whole cohorts may be unable to buffer against developmental error, irrespective of individual quality.


Preparation of a size selective nanocomposite through temperature assisted co-assembly of gelatin and pluronic F127 for passive targeting of doxorubicin.
The preparation of a water dispersible and pH responsive gelatin-F127 nanocomposite using a thermal relaxation approach is reported. The results indicated that physical properties (size and surface charge) of the gelatin-F127 nanoparticle can be tuned by varying the F127 to gelatin weight ratio. The heating (60 °C) of a saline solution (pH 7.4) containing 0.5% (w/v) of gelatin and 20% (w/w of gelatin) of F127 followed by gradual cooling at room temperature yielded nanoparticles of desired size (160 ± 40 nm), viscosity (1.36 ± cP) and surface charge (-6.47 ± 0.7 mV). The drug delivery application of nanocarriers was investigated using doxorubicin hydrochloride (Dox) as a model drug. These nanocarriers showed high encapsulation efficiency of Dox (85%), a sustained release profile, and substantial cellular internalization. Additionally, Dox loaded nanocarriers (G-Dox) exhibited prolonged residence in blood as evidenced by their longer circulation time as compared to plain Dox. Moreover, G-Dox exhibited a higher availability of the drug in plasma as compared to nonspecific organs such as the heart, liver and kidneys, highlighting its significance in reducing drug associated side effects. Finally, the enhanced toxicity of G-Dox to a WEHI-164 (fibrosarcoma) tumor model as compared to that of plain Dox under an identical dosage of 6 mg per kg body weight (IP) confirmed its potential for chemotherapy application.


Case report of integrated supported employment for a person with severe mental illness.
We illustrate the implementation of an integrated supported employment (ISE) program that augments the individual placement and support model with social skills training in helping people with severe mental illness (SMI) achieve and maintain employment. A case illustration demonstrates how ISE helped a 41-year-old woman with SMI to get and keep a job with support from an employment specialist. An independent, blinded assessor conducted data collection of employment information, including self-efficacy and quality of life, at pretreatment and at 3-month, 7-month, 11-month, and 15-month follow-up assessments. The participant eventually stayed in a job for 8 months and reported improved self-efficacy and quality of life. The case report suggests that ISE could improve the employment outcomes of people with SMI. Moreover, changes in the participant's self-efficacy and quality of life were shown to be driven by the successful employment experience.


The treatment of personality disorder in Jamaica with psychohistoriographic brief psychotherapy.
To assess the clinical outcome of patients with personality disorder, receiving treatment with psychohistoriographic brief psychotherapy (PBP). Patients seen in the author's private practice from 1974-2010 with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) personality disorder diagnosis were treated with PBP. Demographic, clinical responses and one-year clinical outcome measures were disaggregated and analysed, using SPSS, version 17. One hundred patients completed treatment with PBP, male:female 34:64; mean age of 35.86 ± 10.28 (range 16 - 66) years. Forty-five per cent were married, 73% were of predominantly African racial origin, with 59% from socio-economic class (SEC) I and 39% from SEC II and III. The presenting complaints were interpersonal conflict (35%), anxiety (21%) and depressed mood (20%). Major depression (30%), substance abuse disorder (18%) and generalized anxiety disorder (13%) were the most common Axis I diagnoses. Histrionic personality disorder (39%) and avoidant personality disorder (35%) were the main Axis II diagnoses. Psychohistoriography was completed with all patients, and charted by 96%. Transference variants were experienced by all patients and worked through with 87%. The quadranting process was completed by 42% with goal setting instituted by 96% and actualization scoring fully completed by 34%. A continuous exercise programme was instituted by all patients, and was maintained by 56% at one-year follow-up. Ninety-four per cent reported fair (10%), good (68%) to very good/excellent (16%) improvement on completion of PBP, with 72% assessed as maintaining fair to good clinical improvement by the therapist at one-year follow-up. Patients with personality disorders showed clinical improvement one year after being treated with psychohistoriographic brief psychotherapy.


Atomic-scale structure of misfit dislocations in CeO2/MgO heterostructures and thermodynamic stability of dopant-defect complexes at the heterointerface.
Complex oxide heterostructures and thin films have found applications across the board in some of the most advanced technologies, wherein the interfaces between the two mismatched oxides influence novel functionalities. It is imperative to comprehend the atomic-scale structure of misfit dislocations, which are ubiquitous in semi-coherent oxide heterostructures, and obtain a fundamental understanding of their interaction with point defects and dopants to predict and control their interface-governed properties. Here, we report atomistic simulations elucidating the atomic-scale structure of misfit dislocations in CeO2/MgO heterostructures. Our results demonstrate that the 45° rotation of CeO2 thin film is one of the potential fundamental mechanisms responsible for eliminating the surface dipole, leading to the experimentally observed mixed epitaxial relationship. We further report the thermodynamic stability of diverse dopant-defect complexes near misfit dislocations, wherein various scenarios for nearest neighbor bonding environments within the complexes are explored. Complex misfit dislocation structure, asymmetry, strain, and the availability of diverse nearest neighbor bonding environments between dopants and oxygen defects at the interface are accountable for a wide dispersion in energies within a given dopant-defect arrangement. As opposed to the bulk, the thermodynamic stability of oxygen vacancies is found to be sensitive to the dopant arrangement at the heterointerface. Extended stabilities of dopant-defect complexes at misfit dislocations reveal that they would influence ionic transport at heterointerfaces of fluorite-structured thin film electrolytes. Notably, the results herein offer a fundamental atomic-scale perspective of the intricate interplay between dopants, defects, and misfit dislocations at the heterointerfaces in mismatched oxide heterostructures.


Sugar-dependent alterations in cotyledon and leaf development in transgenic plants expressing the HDZhdip gene ATHB13.
ATHB13 is a new member of the homeodomain leucine zipper (HDZip) transcription factor family of Arabidopsis thaliana. Constitutive high-level expression of the ATHB13 cDNA in transgenic plants results in altered development of cotyledons and leaves, specifically in plants grown on media containing metabolizable sugars. Cotyledons and leaves of sugar-grown transgenic plants are more narrow and the junction between the petiole and the leaf blade less distinct, as compared to the wild type. High-level expression of ATHB13 affects cotyledon shape by inhibiting lateral expansion of epidermal cells in sugar-treated seedlings. Experiments with non-metabolizable sugars indicate that the alteration in leaf shape in the ATHB13 transgenics is mediated by sucrose sensing. ATHB13 further affects a subset of the gene expression responses of the wild-type plant to sugars. The expression of genes encoding beta-amylase and vegetative storage protein is induced to higher levels in response to sucrose in the transgenic plants as compared to the wild type. The expression of other sugar-regulated genes examined is unaffected by ATHB13. These data suggest that ATHB13 may be a component of the sucrose-signalling pathway, active close to the targets of the signal transduction.


ER stress and subsequent activated calpain play a pivotal role in skeletal muscle wasting after severe burn injury.
Severe burns are typically followed by hypermetabolism characterized by significant muscle wasting, which causes considerable morbidity and mortality. The aim of the present study was to explore the underlying mechanisms of skeletal muscle damage/wasting post-burn. Rats were randomized to the sham, sham+4-phenylbutyrate (4-PBA, a pharmacological chaperone promoting endoplasmic reticulum (ER) folding/trafficking, commonly considered as an inhibitor of ER), burn (30% total body surface area), and burn+4-PBA groups; and sacrificed at 1, 4, 7, 14 days after the burn injury. Tibial anterior muscle was harvested for transmission electron microscopy, calcium imaging, gene expression and protein analysis of ER stress / ubiquitin-proteasome system / autophagy, and calpain activity measurement. The results showed that ER stress markers were increased in the burn group compared with the sham group, especially at post-burn days 4 and 7, which might consequently elevate cytoplasmic calcium concentration, promote calpain production as well as activation, and cause skeletal muscle damage/wasting of TA muscle after severe burn injury. Interestingly, treatment with 4-PBA prevented burn-induced ER swelling and altered protein expression of ER stress markers and calcium release, attenuating calpain activation and skeletal muscle damage/wasting after severe burn injury. Atrogin-1 and LC3-II/LC3-I ratio were also increased in the burn group compared with the sham group, while MuRF-1 remained unchanged; 4-PBA decreased atrogin-1 in the burn group. Taken together, these findings suggested that severe burn injury induces ER stress, which in turns causes calpain activation. ER stress and subsequent activated calpain play a critical role in skeletal muscle damage/wasting in burned rats.


Beta adrenergic influence on oesophageal peristalsis in man.
The effects of the beta-1 adrenergic agonist prenalterol and the beta-2 adrenergic agonist terbutaline on oesophageal peristalsis were studied in nine healthy volunteers with pressures recorded in the proximal, middle, and distal oesophagus. Two doses of the agonists were given after pretreatment with placebo, propranolol, or metoprolol in a double blind randomised fashion. Terbutaline 0.25 +/- 0.25 mg iv decreased peristaltic pressure in middle oesophagus from 8.1 +/- 1.1 to 5.1 +/- 0.8 kPa (p less than 0.01) and in the distal oesophagus from 9.5 +/- 1.0 to 4.7 +/- 0.6 kPa (p less than 0.001). Peristaltic velocity was decreased in the distal oesophagus after terbutaline from 3.3 +/- 0.2 cm/sec to 2.9 +/- 0.2 cm/sec (p less than 0.05). Prenalterol 1 mg iv was followed by a decrease of peristaltic pressure in the middle oesophagus from 10.2 +/- 1.3 to 7.7 +/- 1.1 kPa (p less than 0.01) and a decrease of peristaltic velocity in upper oesophagus from 3.6 +/- 0.2 to 3.3 +/- 0.1 cm/sec (p less than 0.05) while no significant changes were seen in the distal oesophagus. Pretreatment with the beta-1 blocker metoprolol 15 mg iv blocked the effects of prenalterol 1 mg iv but not the effects of terbutaline. Propranolol 10 mg iv blocked the effects of terbutaline on peristaltic pressure. After metoprolol infusion mean distal peristaltic amplitude was 11.9 +/- 0.8 kPa compared with 8.5 +/- 1.2 kPa after placebo (p less than 0.01). It is concluded that both beta-1 and beta-2 adrenoceptor stimulation significantly decrease oesophageal peristaltic pressure in man. The body of the oesophagus seems to be under beta adrenergic inhibitory influence under physiological conditions.


Targeted delivery of an antibody-mutant human endostatin fusion protein results in enhanced antitumor efficacy.
The antiangiogenic protein endostatin showed considerable preclinical antitumor activity, but limited efficacy in phase I/II trials. Prior studies using an anti-HER2 antibody-murine endostatin fusion showed enhanced antitumor activity compared to anti-HER2 antibody or endostatin given alone, or in combination. We have generated two anti-HER2 human endostatin fusion proteins by fusing either wild-type or a mutant human endostatin (huEndo-P125A) to the 3' end of a humanized anti-HER2 IgG3 antibody. Antitumor efficacy was examined in murine and human breast tumor models. HuEndo-P125A antibody fusion protein (αHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and tube formation in vitro, more efficiently than endostatin alone, wild-type endostatin fusion protein (αHER2-huEndo), or parental anti-HER2 antibody (αHER2 IgG3). Wild-type and mutant human endostatin was rapidly cleared from serum in mice (T½(2) = 2.0-2.1 hours), whereas αHER2-huEndo fusion proteins had a significantly prolonged half-life (T½(2) = 40.7-57.5 hours). Treatment of SK-BR-3 breast cancer xenografts with anti-HER2 IgG3-huEndo-P125A fusion resulted in greater inhibition of tumor growth and improved survival, compared to treatment with either αHER2 IgG3 (P = 0.025), human endostatin (P = 0.034), or anti-HER2 IgG3-huEndo (P = 0.016). αHER2-huEndo-P125A specifically inhibited tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor EMT6 cells and with EMT6 engineered to express HER2 antigen (EMT6-HER2). Targeting of endostatin using antibody fusion proteins could improve antitumor activity of either anti-HER2 antibody and/or endostatin and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities.


Genkwanin suppresses mitochondrial dysfunction to alleviate IL-1β-elicited inflammation, apoptosis, and degradation of extracellular matrix in chondrocytes through upregulating DUSP1.
Osteoarthritis (OA) is a form of chronic degenerative disease contributing to elevated disability rate among the elderly. Genkwanin is an active component extracted from Daphne genkwa possessing pharmacologic effects. Here, this study is designed to expound the specific role of genkwanin in OA and elaborate the probable downstream mechanism. First, the viability of chondrocytes in the presence or absence of interleukin-1 beta (IL-1β) treatment was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to assess cell apoptosis. Inflammatory response was estimated through enzyme-linked immunosorbent assay and Western blot. In addition, immunofluorescence staining and Western blot were utilized to measure the expression of extracellular matrix (ECM)-associated proteins. Dual-specificity protein phosphatase-1 (DUSP1) expression was tested by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Following DUSP1 elevation in genkwanin-treated chondrocytes exposed to IL-1β, inflammatory response and ECM-associated factors were evaluated as forementioned. In addition, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide staining was to assess the mitochondrial membrane potential. Adenosine triphosphate (ATP) level was examined with ATP assay kit, and RT-qPCR was used to test mitochondrial DNA expression. Results indicated that genkwanin administration enhanced the viability while ameliorated the apoptosis, inflammatory response, and ECM degradation in IL-1β-induced chondrocytes. Besides, genkwanin treatment fortified DUSP1 expression in IL-1β-exposed chondrocytes. DUSP1 interference further offsets the impacts of genkwanin on the inflammation, ECM degradation, and mitochondrial dysfunction in IL-1β-challenged chondrocytes. In short, genkwanin enhanced DUSP1 expression to mitigate mitochondrial dysfunction, thus ameliorating IL-1β-elicited inflammation, apoptosis, and degradation of ECM in chondrocytes.


Characterization of DNA binding sites of the ComE response regulator from Streptococcus mutans.
In Streptococcus mutans, both competence and bacteriocin production are controlled by ComC and the ComED two-component signal transduction system. Recent studies of S. mutans suggested that purified ComE binds to two 11-bp direct repeats in the nlmC-comC promoter region, where ComE activates nlmC and represses comC. In this work, quantitative binding studies and DNase I footprinting analysis were performed to calculate the equilibrium dissociation constant and further characterize the binding site of ComE. We found that ComE protects sequences inclusive of both direct repeats, has an equilibrium dissociation constant in the nanomolar range, and binds to these two direct repeats cooperatively. Furthermore, similar direct repeats were found upstream of cslAB, comED, comX, ftf, vicRKX, gtfD, gtfB, gtfC, and gbpB. Quantitative binding studies were performed on each of these sequences and showed that only cslAB has a similar specificity and high affinity for ComE as that seen with the upstream region of comC. A mutational analysis of the binding sequences showed that ComE does not require both repeats to bind DNA with high affinity, suggesting that single site sequences in the genome may be targets for ComE-mediated regulation. Based on the mutational analysis and DNase I footprinting analysis, we propose a consensus ComE binding site, TCBTAAAYSGT.


Subfascial Primary Breast Augmentation with Fat Grafting: A Review of 156 Cases.
Composite breast augmentation with fat grafting and an implant has become very popular in the past 5 years. This achieves the core volume projection of an implant complemented by the natural appearance and feel of fat. However, no study has looked at the complications and reoperation rates of this technique. A retrospective chart review examined all patients who underwent the combined use of an implant and fat grafting for primary breast augmentation. The study identified 156 patients between 2007 and 2013. The mean patient age was 31.7 years and the average body mass index was 18.85 kg/m. The average implant size was 252 cc. Patients received a mean of 126 cc of fat (range, 30 to 250 cc) in subcutaneous soft tissue. Follow-up averaged 22.25 months (range, 1 to 86 months). The total complication rate was 7.7 percent and the reoperation rate was 9.94 percent. Baker grade II/III contracture was the most common complication [Baker grade II, n = 4 (2.56 percent); Baker grade III, n = 2 (2 percent)], followed by infections [n = 2 (1.28 percent)], hematoma [n = 2 (1.28 percent)], and malrotation [n = 1 (0.64 percent)]. Delayed reoperation was performed in nine patients (9.94 percent) after a mean interval of 31.7 months. Two patients who developed Baker grade III contractures needed surgery to correct the problem. Three cases (1.92 percent) required additional fat grafting for insufficient soft-tissue coverage. The mean volume of fat reinjection was 170 cc. Composite breast augmentation is a valuable, stable, reliable technique in breast aesthetic surgery with good, natural-appearing results. It provides long-term aesthetic benefits and avoids the submuscular plane. Therapeutic, IV.


Abnormal dysbindin expression in cerebellar mossy fiber synapses in the mdx mouse model of Duchenne muscular dystrophy.
The dystrophin-associated protein complex (DPC), comprising sarcoglycans, dystroglycans, dystrobrevins, and syntrophins, is a component of synapses both in muscle and brain. Dysbindin is a novel component of the DPC, which binds to beta-dystrobrevin and may serve as an adaptor protein that links the DPC to an intracellular signaling cascade. Disruption of the DPC results in muscular dystrophy, and mutations in the human ortholog of dysbindin have been implicated in the pathogenesis of schizophrenia. In both cases, patients also present with neurological symptoms reminiscent of cerebellar problems. In the mouse cerebellum, dysbindin immunoreactivity is expressed at high levels in a subset of mossy fiber synaptic glomeruli in the granular layer. Lower levels of dysbindin immunoreactivity are also detected in Purkinje cell dendrites. In the cerebellar vermis, dysbindin-immunoreactive glomeruli are restricted to an array of parasagittal stripes that bears a consistent relationship to Purkinje cell parasagittal band boundaries as defined by the expression of the respiratory isoenzyme zebrin II/aldolase c. In a mouse model of Duchenne muscular dystrophy, the mdx mutant, in which dystrophin is not expressed, there is a dramatic increase in the number of dysbindin-immunoreactive glomeruli in the posterior cerebellar vermis. Moreover, the topography of the terminal fields is disrupted, replacing the stripes by a homogeneous distribution. Abnormal synaptic organization in the cerebellum may contribute to the neurological problems associated with muscular dystrophy and schizophrenia.


Clonal polymorphisms of outer membrane protein OspB of Borrelia burgdorferi.
The outer membrane protein OspB of Borrelia burgdorferi, the Lyme borreliosis agent, differs in relative molecular weight (Mr) among strains. To determine whether antigenic variation occurs in B. burgdorferi, a cell population of the human isolate HB19 was cloned first by being diluted in broth and then by being plated on agar medium. Several clones were obtained and characterized by polyacrylamide gel electrophoresis, in situ protease treatment, and Western (immunoblot), Southern, and Northern (RNA) blot analyses. Variants featuring OspB proteins that differed in Mrs and in reactivities with monoclonal antibodies were found. One variant made increased amounts of a 21,000-molecular-weight protein (21K protein) in addition to normal amounts of a 33K OspB protein. Another variant did not produce an OspB protein at all but did express an 18.5K protein. Both the 18.5K and 21K proteins were susceptible in situ to trypsin and were bound by a monoclonal antibody directed against the OspB of strain HB19. There were no differences in the Southern and Northern blot analyses of the different variants. The results led to the following conclusions. (i) Clonal polymorphisms in the surface protein OspB occurred in B. burgdorferi. (ii) Hitherto uncharacterized 18.5K and 21K proteins were protease susceptible, antigenically related to OspB, and apparently produced in greater amounts when an OspB either was not produced or was altered in structure. (iii) The OspB variations, including its absence from cells, were not accounted for by major DNA rearrangements or failure of transcription of the ospB gene.


Newborn Pulse Oximetry for Infants Born Out-of-Hospital.
Conventional timing of newborn pulse oximetry screening is not ideal for infants born out-of-hospital. We implemented a newborn pulse oximetry screen to align with typical midwifery care and measure its efficacy at detecting critical congenital heart disease. Cohort study of expectant mothers and infants mainly from the Amish and Mennonite (Plain) communities with limited prenatal ultrasound use. Newborns were screened at 1 to 4 hours of life ("early screen") and 24 to 48 hours of life ("late screen"). Newborns were followed up to 6 weeks after delivery to report outcomes. Early screen, late screen, and combined results were analyzed on the basis of strict algorithm interpretation ("algorithm") and the midwife's interpretation in the field ("field") because these did not correspond in all cases. Pulse oximetry screening in 3019 newborns (85% Plain; 50% male; 43% with a prenatal ultrasound) detected critical congenital heart disease in 3 infants. Sensitivity of combined early and late screen was 66.7% (95% confidence interval [CI] 9.4% to 99.2%) for algorithm interpretation and 100% (95% CI 29.2% to 100%) for field interpretation. Positive predictive value was similar for the field interpretation (8.8%; 95% CI 1.9% to 23.7%) and algorithm interpretation (5.4%; 95% CI 0.7% to 18.2%). False-positive rates were ≤1.2% for both algorithm and field interpretations. Other pathologies (noncritical congenital heart disease, pulmonary issues, or infection) were reported in 12 of the false-positive cases. Newborn pulse oximetry can be adapted to the out-of-hospital setting without compromising sensitivity or prohibitively increasing false-positive rates.


Demographics and treatment options for orbital roof fractures.
The purpose of this article was to review the frequency, germane anatomy, management modalities, and complications associated with the treatment of orbital roof fractures in the pediatric and the adult population. A review of the past 30 years of the English-language maxillofacial surgical literature was undertaken. Important concepts were coupled with the authors' experience to provide a synopsis of contemporary thought on this topic. More than 235 articles in the oral and maxillofacial, plastic and reconstructive, otolaryngology-head and neck, ophthalmologic, oculoplastic, neurologic, and pediatric surgical literature were reviewed and assessed. From this group, 50 articles were found to contain useful information. It has been estimated that 1% to 9% of all facial fractures involve the orbital roof. The typical adult with an orbital roof fracture is a man (89%-93%) who has been involved in a high-energy impact and who has sustained concomitant multisystem injuries (57%-77%). Orbital roof fractures most commonly coexist with other craniofacial injuries. In contrast, in pediatric patients with an orbital roof injury, we see nearly equal sex distribution; the typical patient in this case has a frontobasal fracture that is minimally displaced or nondisplaced (53%-93%) and has sustained concomitant multisystem injuries. The pediatric patient is usually managed by means of observation alone (53%-86%). For the adult patient, a subcranial approach to the orbital roof by means of a bitemporal flap or superior blepharoplasty incision offers wide access with minimal morbidity. Currently available titanium microscrew and miniscrew and mesh systems offer a near-ideal modality for orbital roof reconstruction. The coexisting neurocranial, frontal sinus, and supraorbital rim fractures take priority over the management of orbital roof fractures. Complications associated with orbital roof injuries can be categorized as those attributed to the following: concomitant injury, surgical access, postreconstruction volume discrepancy, muscle entrapment, hemorrhage, and/or infection.


Baroreceptor control of heart rate in chickens (Gallus domesticus).
The baroreceptor control of heart rate was examined in nonanesthetized, nonrestrained, White Leghorn chickens (n = 10) by measuring the heart period response to modest increases in systolic blood pressure induced by IV boluses of phenylephrine (0.04 micrograms/g). In each animal, a sciatic artery and a femoral vein were chronically instrumented for the measurement of blood pressure and heart rate, together with venous access. Sustained and consistent cardiac slowing was seen in all chickens in response to small increases in systolic pressure. The mean slope of the regression equation between heart period and systolic pressure was 13.9 +/- 0.8 s X 10(-4)/mm of Hg. This sensitivity was reduced to 2.1 +/- 1.5 s X 10(-4)/mm of Hg by anesthetizing the chickens with isoflurane (inspired concentrations of 1%).


Group A human rotavirus genomics: evidence that gene constellations are influenced by viral protein interactions.
Group A human rotaviruses (HRVs) are the major cause of severe viral gastroenteritis in infants and young children. To gain insight into the level of genetic variation among HRVs, we determined the genome sequences for 10 strains belonging to different VP7 serotypes (G types). The HRVs chosen for this study, D, DS-1, P, ST3, IAL28, Se584, 69M, WI61, A64, and L26, were isolated from infected persons and adapted to cell culture to use as serotype references. Our sequencing results revealed that most of the individual proteins from each HRV belong to one of three genotypes (1, 2, or 3) based on their similarities to proteins of genogroup strains (Wa, DS-1, or AU-1, respectively). Strains D, P, ST3, IAL28, and WI61 encode genotype 1 (Wa-like) proteins, whereas strains DS-1 and 69M encode genotype 2 (DS-1-like) proteins. Of the 10 HRVs sequenced, 3 of them (Se584, A64, and L26) encode proteins belonging to more than one genotype, indicating that they are intergenogroup reassortants. We used amino acid sequence alignments to identify residues that distinguish proteins belonging to HRV genotype 1, 2, or 3. These genotype-specific changes cluster in definitive regions within each viral protein, many of which are sites of known protein-protein interactions. For the intermediate viral capsid protein (VP6), the changes map onto the atomic structure at the VP2-VP6, VP4-VP6, and VP7-VP6 interfaces. The results of this study provide evidence that group A HRV gene constellations exist and may be influenced by interactions among viral proteins during replication.


Development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel SARS-CoV-2.
The previous outbreaks of SARS-CoV and MERS-CoV have led researchers to study the role of diagnostics in impediment of further spread and transmission. With the recent emergence of the novel SARS-CoV-2, the availability of rapid, sensitive, and reliable diagnostic methods is essential for disease control. Hence, we have developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the specific detection of SARS-CoV-2. The primer sets for RT-LAMP assay were designed to target the nucleocapsid gene of the viral RNA, and displayed a detection limit of 102 RNA copies close to that of qRT-PCR. Notably, the assay has exhibited a rapid detection span of 30 min combined with the colorimetric visualization. This test can detect specifically viral RNAs of the SARS-CoV-2 with no cross-reactivity to related coronaviruses, such as HCoV-229E, HCoV-NL63, HCoV-OC43, and MERS-CoV as well as human infectious influenza viruses (type B, H1N1pdm, H3N2, H5N1, H5N6, H5N8, and H7N9), and other respiratory disease-causing viruses (RSVA, RSVB, ADV, PIV, MPV, and HRV). Furthermore, the developed RT-LAMP assay has been evaluated using specimens collected from COVID-19 patients that exhibited high agreement to the qRT-PCR. Our RT-LAMP assay is simple to perform, less expensive, time-efficient, and can be used in clinical laboratories for preliminary detection of SARS-CoV-2 in suspected patients. In addition to the high sensitivity and specificity, this isothermal amplification conjugated with a single-tube colorimetric detection method may contribute to the public health responses and disease control, especially in the areas with limited laboratory capacities.


Oropharyngeal pH Testing Does Not Predict Response to Proton Pump Inhibitor Therapy in Patients with Laryngeal Symptoms.
Predicting response to proton pump inhibitor (PPI) therapy in patients with laryngeal symptoms is challenging. The Restech Dx-pH probe is a transnasal catheter that measures oropharyngeal pH. In this study, we aimed to investigate the prognostic potential of oropharyngeal pH monitoring to predict responsiveness to PPI therapy in patients with laryngeal symptoms. We conducted a physician-blinded prospective cohort study at a single academic institution between January 2013 and October 2014. Adult patients with Reflux Symptom Index scores (RSI) ≥13 off PPI therapy were recruited. Patients underwent video laryngoscopy and 24-h oropharyngeal pH monitoring, followed by an 8- to 12-week trial of omeprazole 40 mg daily. Prior to and following PPI therapy, patients completed various symptom questionnaires. The primary outcome was the association between PPI response and oropharyngeal pH metrics. PPI response was separated into three subgroups based on the post-treatment RSI score and % RSI response: non-response=RSI ≥13; partial response=post-treatment RSI <13 and change in RSI <50%; and complete response=post-treatment RSI <13 and change in RSI ≥50%. The primary analysis utilized a multinomial logistic regression controlling for the pre-treatment RSI score. A secondary analysis assessed the relationship between the change in RSI (post-pre) and oropharyngeal pH metrics via ordinary least square regression. Thirty-four patients completed the study and were included in final analysis. Symptom response to PPI therapy was as follows: 50% no response, 15% partial response, and 35% complete response. Non-responders had a higher pre-treatment RSI (P<0.01). There were no significant differences in oropharyngeal acid exposure (below pH of 4.0, 5.0, 5.5, 6.0, and RYAN scores) between responder types. The secondary analysis noted a trend between lower PPI response and a greater total percent time below pH of 5.0 (P=0.03), upright percent time below pH of 5.0 (P=0.07), and RYAN supine (corrected; P=0.03), as well as an association between PPI response and greater decreases in the Anxiety Sensitivity Inventory (P<0.01), Brief Symptom Inventory-18 (P<0.01), and Negative Affect Scale (P<0.01). Oropharyngeal pH testing did not predict laryngeal symptom response to PPI therapy. Contrary to hypothesis, our study signaled that the degree of oropharyngeal acid exposure is inversely related to PPI response. In addition, reduction in negative affect and psychological distress parallels PPI response.


On the translation of some stimulus features to response force.
Romaiguère et al. (1993) reported an stimulus-response (S-R) experiment in which the participants had to respond to bright or dim stimuli by pressing a key strongly or weakly. Reaction time (RT) for a compatible S-R assignment (bright-strong; dim-weak) was substantially shorter than for an incompatible S-R assignment (dim-strong; bright-weak). This effect was explained as a direct translation of stimulus intensity to response force (RF). In the present study, we looked for other stimulus features that could be directly transferred to RF. We investigated stimulus size (large/small), vertical location (above/below), and brightness (bright/dim). Delays of RT for incompatible trials were found in case of brightness and size, but not location. In a second experiment, we tested whether such a direct translation might even cause changes of spontaneous RF. Without being instructed about RF, participants made simple reactions to stimuli which differed either in location, size or brightness. Indeed, stimulus size affected RF: larger stimuli were associated with stronger responses. In contrast, brightness had no effect. Thus, we replicated and extended Romaiguère et al.'s (1993) finding. However, the direct-translation account for RF variations received only partial support from our data.


A Drug Eluting Scaffold for the Treatment of Arthrofibrosis.
The inflammatory cascade and production of prostaglandins may play a role in the pathogenesis of arthrofibrosis, a debilitating condition after joint replacement and other orthopedic procedures. Cyclooxygenase 2 (COX-2) inhibitors may mitigate the inflammatory response and formation of arthrofibrosis, but oral delivery is associated with risk of systemic side effects in many patients. The nonsteroidal anti-inflammatory drug, celecoxib, may have therapeutic benefits for arthrofibrosis, but current methods for its local delivery (e.g., biologically derived microspheres) are not translatable to immediate clinical use. Therefore, we investigated the use of a drug scaffold for sustainable intra-articular delivery of therapeutic doses of celecoxib. Celecoxib was eluted from clinically approved biodegradable collagen membranes over 7 days as measured by UV spectroscopy and high-performance liquid chromatography/mass spectroscopy. Eluted concentrations of celecoxib were examined for toxicity (live/dead staining) and profibrotic gene expression (real-time-quantitative polymerase chain reaction) in rabbit knee capsular fibroblasts in vitro. Sustained concentrations of celecoxib eluted from the membrane over 7 days from both a wet and dry scaffold, with a burst release (30-45%) of celecoxib in the first 2 h. Rabbit cells treated with eluted concentrations experienced a toxic response to the burst release doses, and inhibitory effects on profibrotic genes were seen in response to the sustained doses eluted from the scaffold. This study characterized the novel use of collagen scaffolds for intra-articular drug delivery to treat arthrofibrosis. Scaffolds exhibit celecoxib release through an initial burst release followed by sustained release of antifibrotic doses over 7 days. Thus, collagen scaffolds are promising for clinician-directed treatment of arthrofibrosis.


AHR gene-dioxin interactions and birthweight in the Seveso Second Generation Health Study.
2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is proposed to interfere with fetal growth via altered activity of the aryl hydrocarbon receptor (protein: AHR; gene: AHR) pathway which regulates diverse biological and developmental processes including xenobiotic metabolism. Genetic variation in AHR is an important driver of susceptibility to low birthweight in children exposed to prenatal smoking, but less is known about these genetic interactions with TCDD, AHR's most potent xenobiotic ligand. The Seveso Women's Health Study (SWHS), initiated in 1996, is a cohort of 981 Italian women exposed to TCDD from an industrial explosion in July 1976. We measured TCDD concentrations in maternal serum collected close to the time of the accident. In 2008 and 2014, we followed up the SWHS cohort and collected data on birth outcomes of SWHS women with post-accident pregnancies. We genotyped 19 single nucleotide polymorphisms (SNPs) in AHR among the 574 SWHS mothers. Among 901 singleton births, neither SNPs nor TCDD exposure alone were significantly associated with birthweight. However, we found six individual SNPs in AHR which adversely modified the association between maternal TCDD and birthweight, implicating gene-environment interaction. We saw an even stronger susceptibility to TCDD due to interaction when we examined the joint contribution of these SNPs in a risk allele score. These SNPs were all located in noncoding regions of AHR, particularly in proximity to the promoter. This is the first study to demonstrate that genetic variation across the maternal AHR gene may shape fetal susceptibilities to TCDD exposure.


A bibliometric analysis of the 103 top-cited articles in endodontics.
Objective: The purpose of this study was to identify the 100 top-cited articles in endodontics and analyse their bibliometric characteristics. Material and methods: The Web of Science database was reviewed to identify the relevant articles. Results: One hundred and three articles were included because the last four articles had the same number of citations. The top-cited article received 2115 citations. The articles were published in 28 different journals, with the most popular publication being the Journal of Endodontics (n = 36). The most prolific country was the United States (n = 41), followed by Sweden (n = 17) and Switzerland (n = 8). The most prolific author and institution were M. Torabinejad (n = 12) and Umeå University (n = 9), respectively. The majority of articles were of a basic science nature (n = 55), while endodontic microbiology (n = 24) was the most frequent subspecialty. The most common study design used in clinical articles was non-randomized experimental study (n = 5). Half of the clinical articles (n = 11) had a level III evidence score. Conclusions: The present citation analysis provides insights into the historical progress and current trends in endodontics.


Quantitative assessment of the velocity-dependent increase in resistance to passive stretch in spastic plantarflexors.
Although numerous studies revealed that isokinetic dynamometers were valuable tools for assessing spastic hypertonia, no standard methodology using such devices is currently widespread in clinical setting. The aim of this study was to standardize a protocol to assess spastic hypertonia in the triceps surae. The passive resistance during dorsiflexions imposed from 10 to 300 degrees /s with an isokinetic dynamometer was measured at the neutral position in 15 patients with spastic hypertonia and 12 healthy subjects. The normalized passive resistance was obtained by expressing raw passive resistance as a percent of the values measured at the lowest velocity (10 degrees /s). EMG signals from plantar and dorsiflexors were also recorded. While no significant difference between spastic patients and control subjects was observed in raw passive resistance values, the difference was significant for each tested velocity when considering the normalized values. Furthermore, the Ashworth score was significantly correlated with the normalized passive resistance for each velocity whereas no correlation was observed with the raw passive resistance. For the patients, except at the highest velocity, the normalized passive resistance was not affected by the fact that reflex responses in the triceps surae were elicited or not. The normalized passive resistance, expressed with respect to the initial one, i.e., measured at very low velocity, seems a very effective parameter to quantify the velocity-dependent increase in resistance to passive stretch in spastic plantarflexors. However, while the simplicity of the isokinetic tests and the reduced time of data treatment seems to support the clinical use of this methodology, further investigations are required to definitely standardize the protocol.


The mediating role of fear of COVID-19 in the association between COVID-19-related work stressors and subjective well-being: path analysis by cross-sectional evidence in the child care sector across three samples.
COVID-19 has changed work conditions and instilled fear. Yet, research overlooked the contributing factors to fear of COVID-19 and its impact on well-being. We addressed this research gap and focused on the essential workforce of child care. Three samples of early childhood professionals (ECPs) (NT1 = 423, NT2 = 142, NT3 = 584) were gathered in Germany between June 2020 and May 2021. We tested via path analysis whether (1) fear of COVID-19 relates to well-being, (2) COVID-19-related work stressors relate to fear of COVID-19, (3) fear of COVID-19 mediates the relationship of work stressors and well-being. Findings of NT1 and NT3 lent support, while results of NT2 differed. This study underlines the importance of adapting the work conditions during pandemics to reduce the fear of infection, thus preserve ECPs' well-being.


Characterization of delta opioid receptors in lung cancer using a novel nonpeptidic ligand.
Cancer cells are often characterized by the presence of membrane receptors not normally associated with nontransformed cells from the same tissue type. Recent studies have demonstrated increased expression of high-affinity binding sites for opioid receptor-selective ligands in lung cancer cell lines relative to normal lung tissue. We investigated the binding of a nonpeptidic delta opioid receptor ligand in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells with the aim of developing the ligand as a novel lung cancer imaging agent. The ligand, [3H] (+)-4-[alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethylbenzamide ([3H](+)BW373U86), bound with high-affinity [Kd (dissociation constant) = 0.066 +/- 0.012 nM] to membranes prepared from six different SCLC cell lines but not to those from seven NSCLC cell lines, including one mesothelioma. The number of biding sites varied from 10 to 300 fmol/mg membrane protein. Competition binding studies demonstrated displacement of [3H](+)BW373U86 binding by the delta-selective antagonists naltriben and 7-benzylidenenaltrexone but not with the mu- and kappa- selective antagonists D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 and trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]ben zeneacetamide methanesulfonate. Mean apparent Kis for naltriben and 7-benzylidenenaltrexone in membranes from two SCLC cell lines were 0.17 and 3.9 nM, respectively, but were >10 microM for the mu and kappa ligands. The nonselective antagonist naloxone displaced [3H](+)BW373U86 binding with an apparent Ki of approximately 29 nM. On the basis of these data, we believe the lung cancer receptor to be similar, if not identical, to the human brain delta opioid receptor. The lack of high-affinity [3H](+)BW373U86 binding in normal mouse lung membranes suggests a potential role for this ligand as a novel therapeutic or imaging agent.


Relationship between hair cortisol and perceived chronic stress in a diverse sample.
Hair cortisol (CORT) is a biomarker of chronic stress via long-term alterations in hypothalamus-pituitary-adrenal axis activity. Relationships to perceived stress measures, however, have rarely been specifically investigated. A diverse sample of 135 adults participated in a study assessing relationships between chronic stress indicator CORT to perceived stress and health indicators. CORT was not correlated to single perceived domain indices but with a global stress composite. Differences in objective and subjective measures were found for sociodemographics: racial/ethnic identity, sex and socioeconomic status (SES). Race by SES interactions predicted both CORT and perceived stress, but produced a complex and partially unanticipated pattern of results. For minorities, low and high SES showed the highest CORT, with mid-SES showing the lowest CORT; there was little change in perceived stress at all levels of SES. For non-minorities, mid-SES showed the highest CORT, with decreases in both CORT and perceived stress in high SES. The unanticipated findings of deleterious outcomes for high SES minorities highlight the importance of investigating potential stressors and moderators, including perceived discrimination and social identity. Moreover, these results suggest that CORT may not always correlate with single stress indices but may provide a global assessment of chronic stress, with implications for the allostatic load literature.


Strain analysis from M-edge resonant inelastic X-ray scattering of nickel oxide films.
Electronic structure modifications due to strain are an effective method for tailoring nano-scale functional materials. Demonstrated on nickel oxide (NiO) thin films, Resonant Inelastic X-ray Scattering (RIXS) at the transition-metal M2,3-edge is shown to be a powerful tool for measuring the electronic structure modification due to strain in the near-surface region. Analyses from the M2,3-edge RIXS in comparison with dedicated crystal field multiplet calculations show distortions in 40 nm NiO grown on a magnesium oxide (MgO) substrate (NiO/MgO) similar to those caused by surface relaxation of bulk NiO. The films of 20 and 10 nm NiO/MgO show slightly larger differences from bulk NiO. Quantitatively, the NiO/MgO samples all are distorted from perfect octahedral (Oh) symmetry with a tetragonal parameter Ds of about -0.1 eV, very close to the Ds distortion from octahedral (Oh) symmetry parameter of -0.11 eV obtained for the surface-near region from a bulk NiO crystal. Comparing the spectra of a 20 nm film of NiO grown on a 20 nm magnetite (Fe3O4) film on a MgO substrate (NiO/Fe3O4/MgO) with the calculated multiplet analyses, the distortion parameter Ds appears to be closer to zero, showing that the surface-near region of this templated film is less distorted from Oh symmetry than the surface-near region in bulk NiO. Finally, the potential of M2,3-edge RIXS for other investigations of strain on electronic structure is discussed.


Base-specific binding of copper(II) to Z-DNA. The 1.3-A single crystal structure of d(m5CGUAm5CG) in the presence of CuCl2.
The single crystal structure of d(m5CGUAm5CG) soaked with copper(II) chloride was solved to atomic (1.3 A) resolution to study the base specificity of copper binding to double-stranded DNA. In the present copper(II) chloride-soaked structure, four crystallographically unique copper(II) complexes were observed bound to five of the six purine bases in the hexamer duplex. Covalent copper(II) binding occurred at N-7 of all four guanine bases and at one of the two adenine bases in the DNA duplex. Copper binding was not observed at the position (Ade4) located in an open solvent channel, whereas the second adenine site (Ade10) shared a complex with a guanine residue (Gua12) of a neighboring symmetry-related hexamer. The coordination geometries and distribution of these copper(II) complexes at the guanine bases in the crystal were comparable to the analogous sites in the isomorphous copper(II) chloride-soaked d(CGCGCG) crystal (Kagawa, T., Geierstanger, B. H., Wang, A. H.-J., and Ho, P.S. (1991) J. Biol. Chem. 266, 20175-20184). Thus, the decreased copper(II) binding affinity for Ade4 was not an artifact of crystal packing, but is intrinsic to the chemical properties of this purine base in duplex DNA. This suggests that the adenine bases in dilute solutions of Z-DNA and more generally other duplex DNA conformations are not susceptible to copper(II) modification. Thus, preferential copper(II) binding at guanine bases over adenine bases in double-stranded DNA may explain the observed specificity of copper(II)-induced oxidative DNA damage near guanine residues (Yamamoto, K., and Kawanishi, S. (1989) J. Biol. Chem. 264, 15435-15440; Sagripanti, J.-L., and Kraemer, K. H. (1989) J. Biol. Chem. 264, 1729-1734). The sharing of a single copper(II) complex by Ade10 and Gua12 of an adjacent hexamer suggests that additional and perhaps specific DNA-DNA interactions, as may be found in the densely packed environment of the nuclear matrix in the cell, may render N-7 of adenine bases prone to copper(II) modification.


The influence of landscape on gene flow in the eastern massasauga rattlesnake (Sistrurus c. catenatus): insight from computer simulations.
Understanding how gene flow shapes contemporary population structure requires the explicit consideration of landscape composition and configuration. New landscape genetic approaches allow us to link such heterogeneity to gene flow within and among populations. However, the attribution of cause is difficult when landscape features are spatially correlated, or when genetic patterns reflect past events. We use spatial Bayesian clustering and landscape resistance analysis to identify the landscape features that influence gene flow across two regional populations of the eastern massasauga rattlesnake, Sistrurus c. catenatus. Based on spatially explicit simulations, we inferred how habitat distribution modulates gene flow and attempted to disentangle the effects of spatially confounded landscape features. We found genetic clustering across one regional landscape but not the other, and also local differences in the effect of landscape on gene flow. Beyond the effects of isolation-by-distance, water bodies appear to underlie genetic differentiation among individuals in one regional population. Significant effects of roads were additionally detected locally, but these effects are possibly confounded with the signal of water bodies. In contrast, we found no signal of isolation-by-distance or landscape effects on genetic structure in the other regional population. Our simulations imply that these local differences have arisen as a result of differences in population density or tendencies for juvenile rather than adult dispersal. Importantly, our simulations also demonstrate that the ability to detect the consequences of contemporary anthropogenic landscape features (e.g. roads) on gene flow may be compromised when long-standing natural features (e.g. water bodies) co-exist on the landscape.