[Insulin regimes and impact on glycemic control in patients with type 1 diabetes].
Objective: To describe the insulin regimens and their associations with glycemic control and to explore factors associated with intensive insulin therapy. Methods: Patients with type 1 diabetes (T1DM) were recruited from Guangdong Type 1 Diabetes Mellitus Translational Medicine Study which was conducted in 16 centers in Guangdong province. The demographic and clinical data were collected. Patients were grouped according to different insulin regimens: insulin pump (R1), basal insulin plus regular insulin or short-acting insulin (R2), insulin injection 1-3 times per day (R3). Distribution of insulin regimens and the relationships between insulin regimens and hemoglobin A1c (HbA1c) were described. Multivariate logistic regression was used to identify factors associated with intensive insulin therapy. Results: A total of 1 421 patients with the age of 27.8 (19.4, 38.3) years and a duration of T1DM of 3.3 (0.5, 7.1) years were recruited. There was 12.3% of patients in R1 (n=175), 35.5% in R2 (n=504), and 52.2% in R3 (n=742), respectively. HbA1c was 8.0 (6.8, 9.3)%, 8.9 (7.1, 11.8)%, and 9.2 (7.5, 11.4)% in R1, R2, R3, respectively, and it was associated with insulin regimens (P<0.001). HbA1c target rate was 32.3%, 21.1%, 17.8% in R1, R2, R3, respectively (P=0.002). Older age (OR=1.01, P=0.027), higher education level (college or above) (OR=1.56, P=0.003), and higher household income (>30 000 yuan per year per person)(OR=1.45, P=0.009) were associated with intensive insulin therapy in adult patients. Conclusions: The study suggested that insulin therapy need to be optimized in patients with T1DM. The optimization of insulin regimens and diabetes education may be helpful for improvement of glycemic control.


Effects of the foot strike pattern on muscle activity and neuromuscular fatigue in downhill trail running.
Minimizing musculo-skeletal damage and fatigue is considered paramount for performance in trail running. Our purposes were to investigate the effects of the foot strike pattern and its variability on (a) muscle activity during a downhill trail run and (b) immediate and delayed neuromuscular fatigue. Twenty-three runners performed a 6.5-km run (1264 m of negative elevation change). Electromyographic activity of lower-limb muscles was recorded continuously. Heel and metatarsal accelerations were recorded to identify the running technique. Peripheral and central fatigue was assessed in knee extensors (KE) and plantar flexors (PF) at Pre-, Post-, and 2 days post downhill run (Post2d). Anterior patterns were associated with (a) higher gastrocnemius lateralis activity and lower tibialis anterior and vastus lateralis activity during the run and (b) larger decreases in KE high-frequency stimulus-evoked torque Post and larger decrements in KE MVC Post2d. High patterns variability during the run was associated with (a) smaller decreases in KE Db100 Post and MVC Post2d and (b) smaller decreases in PF MVC Post and Post2d. Anterior patterns increase the severity of KE peripheral fatigue. However, high foot strike pattern variability during the run reduced acute and delayed neuromuscular fatigue in KE and PF.


Evolution under a model of functionally buffered deleterious mutations can lead to positive selection in protein-coding genes.
Selective pressures on DNA sequences often result in departures from neutral evolution that can be captured by the McDonald-Kreitman (MK) test. However, the nature of such selective forces often remains unknown to experimentalists. Amino acid fixations driven by natural selection in protein-coding genes are commonly associated with a genetic arms race or changing biological purposes, leading to proteins with new functionality. Here, we evaluate the expectations of population genetic patterns under a buffering mechanism driving selective amino acids to fixation, which is motivated by an observed phenotypic rescue of otherwise deleterious nonsynonymous substitutions at bag of marbles (bam) and Sex lethal (Sxl) in Drosophila melanogaster. These two genes were shown to experience strong episodic bursts of natural selection potentially due to infections of the endosymbiotic bacteria Wolbachia observed among multiple Drosophila species. Using simulations to implement and evaluate the evolutionary dynamics of a Wolbachia buffering model, we demonstrate that selectively fixed amino acid replacements will occur, but that the proportion of adaptive amino acid fixations and the statistical power of the MK test to detect the departure from an equilibrium neutral model are both significantly lower than seen for an arms race/change-in-function model that favors proteins with diversified amino acids. We find that the observed selection pattern at bam in a natural population of D. melanogaster is more consistent with an arms race model than with the buffering model.


Successful treatment of childhood onset symptomatic dystonia with levodopa.
Three patients with childhood onset symptomatic dystonia responded to levodopa. None fulfilled criteria for a diagnosis of "dopa responsive dystonia" (Segawa's disease). One may have had athetoid cerebral palsy for almost 25 years. All obtained dramatic and sustained benefit from levodopa therapy. A therapeutic trial of levodopa is advised in all patients in whom dystonia has developed in childhood or early adult life, regardless of suspected aetiology or duration of symptoms.


Clinicopathological features and survival of colorectal cancer patients younger than 50 years: a retrospective comparative study.
Colorectal cancer (CRC) is a disease of old age, but its incidence has been rising among younger population compared to older ones. Nevertheless, there is a controversy over survival of younger patients compared to the older ones. Therefore, in the current study, we investigated the clinicopathological features and survival of the younger (< 50 years) versus older (≥ 50 years) CRC patients. The younger and older groups consisted of 39.4% and 60.6% of patients, respectively. Both age groups were comparable regarding the symptom presentation and duration, and pre-operative carcinoembryonic antigen (CEA). The younger patients were diagnosed with a higher proportion of poorly differentiated (14.7% vs. 8.3%; p < 0.001) and more advanced tumors (53.2% vs. 45.9%; p = 0.266). The rectum tumor site was significantly more common among the younger patients (p = 0.021). The overall survival (OS) (p = 0.278), the cancer-specific survival (CSS) (p = 0.233), and the disease-free survival (DFS) (p = 0.497) did not differ significantly between the two groups. Based on Cox regression model, elevated pre-operative CEA level (HR = 1.41; 95%CI of 1.01-1.97), advanced tumor stage (6.06; 95%CI of 3.03-12.15), and poorly differentiated tumor (HR = 1.69; 95%CI of 1.05-2.71) were associated with decreased survival. The younger patients did not have poor prognosis compared to the older ones despite having an advanced tumor stage and a poor tumor differentiation.


Review paper: chitosan derivatives as promising materials for controlled drug delivery.
Chitosan, a natural based-polymer obtained by alkaline deacetylation of chitin, is nontoxic, biocompatible, and biodegradable. These properties make chitosan a good candidate for the development of conventional and novel drug delivery systems. Chitosan has been found to be used as a support material for gene delivery, cell culture, and tissue engineering. However, practical use of chitosan has been mainly confined to the unmodified forms. For a breakthrough in utilization, especially in the field of controlled drug delivery, graft copolymerization onto chitosan will be a key point, which will introduce desired properties and enlarge the field of the potential applications of chitosan by choosing various types of side chains. Chemical modification of chitosan is useful for the association of bioactive molecules to polymer and controlling the drug release profile. This paper reviews the various methods of preparation of chitosan derivatives intended for controlled drug delivery. From the studies reviewed it is concluded that chitosan derivatives are promising materials for controlled drug and nonviral gene delivery.


Pancreas-preserving duodenectomy in the management of duodenal familial adenomatous polyposis.
Most patients with familial adenomatous polyposis (FAP) develop disease in the duodenum. The duodenal lesions mostly occur in the periampullary region, but some patients develop diffuse polyposis involving all parts of the duodenum. These neoplastic polyps have malignant potential, and thus warrant surveillance and timely intervention. We reviewed our experience with management of FAP over a 10-year period, focusing on patients who had diffuse polyposis of the duodenum and their subsequent management. Three patients with FAP had diffuse duodenal involvement, documented by upper gastrointestinal endoscopy. Neoplasia was confirmed by endoscopic biopsy, but no patients had histologic evidence of carcinoma. The patients underwent resection of the entire duodenum from the pylorus to the ligament of Treitz with preservation of the pancreas. Our surgical technique is described. One patient had a postoperative wound infection and one patient had a biliary leak that resolved with closed suction drainage for 5 days. Long-term follow-up in these patients revealed excellent functional status. One patient had polyp recurrence in the jejunum at 5-year follow-up, but no patients have developed adenocarcinoma. We conclude that patients with duodenal polyps associated with FAP may be safely and effectively treated by pancreas-preserving duodenectomy.


Size-Dependent Immunochromatographic Assay with Quantum Dot Nanobeads for Sensitive and Quantitative Detection of Ochratoxin A in Corn.
Fluorescent microspheres are a novel luminescent nanomaterial proposed as an alternative probe to improve the detection sensitivity of competitive immunochromatographic assay (ICA). Quantum dot nanobeads (QBs) possess strong luminescence and resistance to matrix interference. Theoretically, large-sized QBs exhibit stronger luminescent intensity than small-sized QBs and are beneficial to ICA sensitivity. However, oversized QBs may reduce the sensitivity of competitive ICA. Thus, the relationship between the size and luminescent intensity of QBs and the competitive ICA sensitivity must be elucidated. In this study, QBs of different sizes (58, 124, 255, 365, and 598 nm) were synthesized. Ochratoxin A (OTA) was selected as the model analyte for competitive ICA. The effects of QB size on the detection performance of competitive ICA were then evaluated. The cutoff limit of QB-ICA for naked eye detection was used for qualitative analysis, and the half-maximal inhibitory concentration (IC50) and LOD were employed for quantitative analysis. Results indicated that 124 nm QBs used as labeling probes for competitive ICA showed the optimal detection performance and the lowest cutoff value of 5 ng/mL for qualitative detection and IC50 (0.39 ng/mL) for quantitative detection. Similar to commercial ELISA, QB124-ICA displayed good accuracy, specificity, reproducibility, and practicability. In summary, 124 nm QBs can be used as a new labeling probe for competitive ICA.


Unsuspected carcinoma found histologically after minor anorectal operations.
The unsatisfactory results of radical operations in advanced anal cancer could be bettered by earlier diagnosis of the malignant lesion. The possibility of cancer should always be kept in mind when treating any of the common chronic anal diseases. Preliminary biopsy studies should be done more frequently if suspicious lesions are present and all tissues removed during minor anorectal operations should always be examined by a pathologist. Each surgical specimen should be labeled to show the site from which it was removed. Follow-up care of the patient would be simplified if the exact site of cancer origin could be identified.A recent ten-year survey of minor anorectal surgical procedures at the University of California Medical Center showed clinically unsuspected anal cancer found in 2 per cent of cases on tissue examination by the pathologist. The cancers were generally early and of the keratinizing squamous cell and nonkeratinizing varieties.


[Adalimumab (Humira)--efficacy in rheumatoid arthritis treatment with particular reference to working ability].
Tumor-necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine demonstrated to play an important role in the pathogenesis of rheumatoid arthritis (RA). Adalimumab is a recombinant human monoclonal antibody to TNFalpha. In the PREMIER study, when administered in combination with methotrexate (MTX), adalimumab demonstrated that 49% patients with early RA achieved remission. Adalimumab was effective in improving radiographic outcomes, too. At week 28, 52 and 104 of follow-up there was significantly less radiographic progression in combination group (adalimumab/MTX) than in each monotherapy group (adalimumab or MTX), with adalimumab showing better result than MTX. In a large open-label study with active RA, during adalimumab treatment 25% of patients experienced clinical remission and nearly half achieved minimal disease activity. Combining results from different clinical trials adalimumab has demonstrated up to seven years of efficacy among long-standing RA patients when used in combination with MTX. The percentage ofpatients achieving clinical remission continued to increase after two or more years of continuous treatment with combination therapy. In Health economic outcome study performed in parallel with PREMIER study there was a big reduction of days lost in the combination group (adalimumab/MTX) in comparison with MTX at year 1 and a difference maintained to year 2. The combination therapy was much more successful in maintaining quality of work than MTX. PROWD study, which was the first one to actually look at job loss as the primary outcome, showed that the combination of adalimumab and methotrexate has the ability to reduce job loss and work time lost when compared to just MTX. Adalimumab is the newest developed anti-TNFalpha, which not only demonstrated significant and sustained reduction in signs and symptoms and inhibition of radiographic progression, but has also improved functional status, quality of life and work productivity in patients with RA, with acceptable safety profile.


Gas-phase peptide/protein cationizing agent switching via ion/ion reactions.
Polypeptide ions comprising different cationizing agents show distinct fragmentation behavior in the gas phase. Thus, it is desirable to be able to form ions with different cationizing agents such as protons and metal ions. Usually, metal-cationized peptide/protein ions are introduced to the mass spectrometer by electrospraying solutions containing a mixture of the peptide/protein of interest and a metal salt. A new technique for generating metal-containing polypeptide ions that involves gas-phase ion/ion reactions is described. In this strategy, solutions of metal-containing ions and solutions of proteins are each electrosprayed into separate ion sources. The approach allows for independent maximization of ion signal and selection of ions prior to gas-phase reactions. Selected ions are stored in a quadrupole ion trap where reactions of ions of opposite polarity form metal-cationized peptides and proteins in the gas phase by cation switching. This approach affords a high degree of flexibility in forming metal-containing peptide and protein ions via the ability to mass-select reactant ions. The ability to form a variety of peptide/protein ions with various cationizing reagents in the gas phase is attractive both for the study of intrinsic interactions of metal ions with polypeptides and for maximizing the structural information available from tandem mass spectrometry of peptides and proteins.


HIV-1 transcription is regulated by splicing factor SRSF1.
Efficient transcription of the HIV-1 genome is regulated by Tat, which recruits P-TEFb from the 7SK small nuclear ribonucleoprotein (snRNP) and other nucleoplasmic complexes to phosphorylate RNA polymerase II and other factors associated with the transcription complex. Although Tat activity is dependent on its binding to the viral TAR sequence, little is known about the cellular factors that might also assemble onto this region of the viral transcript. Here, we report that the splicing factor SRSF1 (SF2/ASF) and Tat recognize overlapping sequences within TAR and the 7SK RNA. SRSF1 expression can inhibit Tat transactivation by directly competing for its binding to TAR. Additionally, we provide evidence that SRSF1 can increase the basal level of viral transcription in the absence of Tat. We propose that SRSF1 activates transcription in the early stages of viral infection by recruiting P-TEFb to TAR from the 7SK snRNP. Whereas in the later stages, Tat substitutes for SRSF1 by promoting release of the stalled polymerase and more efficient transcriptional elongation.


[Retroperitoneoscopic approach for treatment of acute obstructive calculous pyelonephritis. Alternative or a method of choice?]
to compare the results of treatment of patients with acute obstructive calculous pyelonephritis, who underwent to retroperitoneoscopic procedure, with patients, who underwent to drainage of the collecting system by means of ureteral stent or nephrostomy tube as the first stage. A total of 121 patients were treated from 2011 to 2019. Of these, 78 patients were included in the main group. The stones were located in the ureteropelvic junction (n = 20) and the upper and middle ureter (n = 58). The average size of the stone was 12.9 +/- 4.8 mm. Preliminary upper urinary tract drainage was not carried out and the stone was removed completely. The group 2 consisted of 26 people. The stones were located in the upper (n = 18) and the middle ureter (n = 8); the average size was 9 +/- 2.8 mm. Renal drainage was done using ureteral stent and when pyelonephritis resolved, ureterolithotripsy was performed. The group 3 was represented by 17 patients. All stones were located in the ureteropelvic junction. The average size was 20.3 +/- 10.7 mm. Renal drainage was done using percutaneous nephrostomy; when there were no inflammatory changes, percutaneous nephrolithotripsy was performed. In the main group, normalization of body temperature and resolution of inflammatory changes in the blood and urine occurred earlier. The stone was removed completely and there were no residual fragments. Period of rehabilitation was are also significantly shorter than in groups 2 and 3. The retroperitoneoscopic method was more effective and safer for the treatment of patients with acute obstructive pyelonephritis caused by large stones located in the upper or middle ureter and ureteropelvic junction.


Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels.
Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).


PCNA/cyclin expression in transitional cell carcinomas of the human bladder: its correlation with Ki-67 and epidermal growth factor receptor immunostainings.
Cell kinetic data are an important adjunct to histologically based tumor classifications and provide reliable information about future tumor behaviour. The growth fraction of 62 transitional cell carcinomas was assessed using Ki-67 and PCNA (Proliferating cell nuclear antigen/cyclin) immunostainings. Ki-67 recognises an unknown nuclear antigen expressed in dividing cells and requires the use of frozen sections. PCNA, a non histone nuclear protein, identifies proliferating cells within fixed, embedded tissue sections. The percentage of labeled cells was expressed as the labeling index (LI). The median LI in normal urothelium and transitional cell carcinoma were 0.5% and 8%, respectively for Ki-67, and 1.5% and 12% for PCNA. A general agreement between indices of cell proliferation and histological grade and stage was demonstrated. Although some discrepancies were observed, there was a strong correlation between Ki-67 and PCNA Lis (r = 0.8308, P < 0.01). In addition, tumor EGFR positive had PCNA values greater than those found in cancer EGFR negative (P = 0.01). These findings suggest that immunohistochemical nuclear labeling with anti-PCNA on routinely processed tissue is a simple technique for the assessment of transitional cell carcinomas.


Estimating the size of the capillary-to-fiber interface in skeletal muscle: a comparison of methods.
Current evidence suggests that the size of the capillary-to-fiber (C/F) interface is a major determinant of O2 flux into muscle fibers, and methods have been developed for estimating the size of this region via the C/F perimeter ratio in perfusion-fixed material (Mathieu-Costello O, Ellis CG, Potter RF, MacDonald IC, and Groom AC. Am J Physiol Heart Circ Physiol 261: H1617-H1625, 1991) and the quotient of the individual, fiber-based C/F number ratio and fiber perimeter (C/F perimeter exchange index) in muscle biopsies (Hepple RT. Can J Appl Physiol 22: 11-22, 1997). The purpose of this study was to compare the two methods and examine how differences in muscle tissue preparation between perfusion fixation and frozen biopsy can influence the estimate of the size of the C/F interface. The left medial gastrocnemius muscle of nine purpose-bred dogs was perfusion fixed in situ, and a sample from the midportion of the midbelly was processed for microscopy. A corresponding sample from the right gastrocnemius muscle obtained by open biopsy in six of the nine animals was frozen for histochemistry. A significant correlation was found between the two estimates of the size of the C/F interface in the same sections of perfusion-fixed material (r = 0.75, P < 0.05). However, estimates of the size of the C/F interface were smaller in biopsies than perfusion-fixed material, and there was no significant relationship between the estimates in the two preparations. This was due to differences in fiber size (33% larger fiber cross-sectional area in biopsy material after normalization for sarcomere length; P < 0.05) and muscle sampling between the two tissue preparations.


Zuclopenthixol treatment of behavioral disturbances in mentally retarded children and adolescents: an open-label study.
The present open-label study assessed the efficacy of zuclopenthixol, an thioxanthene neuroleptic with combined dopamine receptors (D1/D2) antagonist activity, in the treatment of severe behavioral disturbances in mentally retarded children and adolescents. A sample of 15 (11 males, 4 females) mentally retarded children and adolescents, ages 5-18 years (12.2 +/- 2.3 [mean +/- SD] years), all exhibiting severe behavioral disturbances, was evaluated. The 12-week zuclopenthixol treatment (up to 26 mg/day) was initiated after a week's washout from previous antipsychotic agents. An assessment of the behavioral disturbances was performed using the 14-item Checklist for Behavior Problems Involving Limited or No Social Awareness (CBP-NSA). The Udvalg for kliniske undersøgelser (UKU) Side Effect Rating Scale was used to assess the pharmacologic side effects. Results show a significant reduction in total CBP-NSA scores and in individual items such as hyperactivity, aggressive behavior, and temper tantrums (p < 0.001 for each). It seems that zuclopenthixol monotherapy is effective and well tolerated in the treatment of severe behavioral disturbances in mentally retarded children and adolescents. Double-blind, placebo-controlled studies are needed before definitive conclusions can be drawn regarding the efficacy and safety of zuclopenthixol for this population.


Bridging the Nanogap with Light: Continuous Tuning of Plasmon Coupling between Gold Nanoparticles.
The control of nanogaps lies at the heart of plasmonics for nanoassemblies. The plasmon coupling sensitively depends on the size and the shape of the nanogaps between nanoparticles, permitting fine-tuning of the resonance wavelength and near-field enhancement at the gap. Previously reported methods of molecular or lithographic control of the gap distance are limited to producing discrete values and encounter difficulty in achieving subnanometer gap distances. For these reasons, the study of the plasmon coupling for varying degrees of interaction remains a challenge. Here, we report that by using light, the interparticle distance for gold nanoparticle (AuNP) dimers can be continuously tuned from a few nanometers to negative values (i.e., merged particles). Accordingly, the plasmon coupling between the AuNPs transitions from the classical electromagnetic regime to the contact regime via the nonlocal and quantum regimes in the subnanometer gap region. We find that photooxidative desorption of alkanedithiol linkers induced by UV irradiation causes the two AuNPs in a dimer to approach each other and eventually merge. Light-driven control of the interparticle distance offers a novel means of exploring the fundamental nature of plasmon coupling as well as the possibility of fabricating nanoassemblies with any desired gap distance in a spatially controlled manner.


Populene D analogues: design, concise synthesis and antiproliferative activity.
An efficient and concise synthesis of nine populene D analogues was performed using an iodine-catalyzed Prins cyclization as the key transformation. The antiproliferative activity of these new pyrans against several cancer cell lines was then investigated. Among them, an isochromene with moderate activity (mean logGI(50) = 0.91) was found. Additionally, compounds with selectivity toward the tumor cell lines NCI-ADR/RES, OVCAR-3, and HT29 were discovered.


Direct interaction, instrumental for signaling processes, between LacCer and Lyn in the lipid rafts of neutrophil-like cells.
Lactosylceramide [LacCer; β-Gal-(1-4)-β-Glc-(1-1)-Cer] has been shown to contain very long fatty acids that specifically modulate neutrophil properties. The interactions between LacCer and proteins and their role in cell signaling processes were assessed by synthesizing two molecular species of azide-photoactivable tritium-labeled LacCer having acyl chains of different lengths. The lengths of the two acyl chains corresponded to those of a short/medium and very long fatty acid, comparable to the lengths of stearic and lignoceric acids, respectively. These derivatives, designated C18-[(3)H]LacCer-(N3) and C24-[(3)H]LacCer-(N3), were incorporated into the lipid rafts of plasma membranes of neutrophilic differentiated HL-60 (D-HL-60) cells. C24-[(3)H]LacCer-(N3), but not C18-[(3)H]LacCer-(N3), induced the phosphorylation of Lyn and promoted phagocytosis. Incorporation of C24-[(3)H]LacCer-(N3) into plasma membranes, followed by illumination, resulted in the formation of several tritium-labeled LacCer-protein complexes, including the LacCer-Lyn complex, into plasma membrane lipid rafts. Administration of C18-[(3)H]LacCer-(N3) to cells, however, did not result in the formation of the LacCer-Lyn complex. These results suggest that LacCer derivatives mimic the biological properties of natural LacCer species and can be utilized as tools to study LacCer-protein interactions, and confirm a specific direct interaction between LacCer species containing very long fatty acids, and Lyn protein, associated with the cytoplasmic layer via myristic/palmitic chains.


Contribution of the Rgg transcription regulator to metabolism and virulence of Streptococcus suis serotype 2.
The Rgg-like regulators, a family of transcription factors commonly found in many Gram-positive bacteria, play multiple roles, especially in the control of pathogen virulence. Here, we report an rgg homologue from a Chinese isolate, 05ZYH33, of Streptococcus suis serotype 2 (SS2). Deletion of the rgg gene in SS2 increased its adhesion to Hep-2 cells and hemolytic activity in vitro. Significantly, inactivation of the rgg gene attenuated SS2 virulence in an experimental piglet infection model. Using DNA microarrays and quantitative reverse transcription-PCR, we found that the Rgg regulator affects the transcriptional profile of 15.87% (n = 345) of all of the annotated chromosomal genes, including those involved in nonglucose carbohydrate metabolism, DNA recombination, protein biosynthesis, bacterial defense mechanisms, and others. It was experimentally verified that the deletion of rgg in SS2 reduced the utilization of nonglucose carbohydrates, such as lactose and maltose. In addition, the rgg gene was found to be associated with changes in the bacterial microscopic phenotype and growth curve. These data suggested that Rgg in SS2 is a global transcriptional regulator that plays an important role in promoting SS2 bacterial survival during pathogen-host interaction.


Normal variations in spirometry in health following placebo inhalation.
Normal i.e., chance variations in spirometry were evaluated in 80 healthy Indian adults by the measurement of base-line spirometric indices (FVC, FEV1 and FEF25-75%) and the per cent changes following placebo administration of aerosolized saline. There was a mean per cent change of 0.7, 0.4 and 0.3 per cent over the base-line values in FVC, FEV1 and FEF25-75% respectively following placebo inhalation. The cut off responses for 95 per cent confidence limits were 11.2 per cent for FVC and 12.7 per cent for FEV1 following placebo inhalation. Since the test sample represents a healthy Indian population, a per cent change greater than 12.7 per cent in FEV1 is more than that observed in 95 per cent of healthy Indians. It is suggested that for both delta FEV1 per cent and delta FVC per cent, the lower limit should be fixed at more than 15 per cent to define 'abnormality' in clinical practice.


Effects of 60 and 80% oxygen on cell division in lung alveoli of squirrel monkeys.
The purpose of this study was to determine the effects on cell division of 60 and 80% oxygen in the lung alveoli of squirrel monkeys. To accomplish this, squirrel monkeys were exposed to 60 and 80% oxygen for up to 8 d. Prior to sacrifice, cells preparing to divide were labeled with tritiated thymidine (3H-TdR). Labeled cells were visualized with autoradiographic techinques, counted with the light microscope, and expressed in terms of a labeling index. In the present study, it was shown that DNA synthesis was not changed by exposure to 60%; however, with exposure to 80% oxygen, cell labeling was well above control levels by 5 d. Analysis of the cell types involved showed an increase in labeling. due to an increase in dividing Type 2 cells. Other cells in the alveolar wall also showed an increase in labeling


Peritoneal biomarkers in the early detection of ovarian cancer.
Ovarian cancer remains to date the fifth most common cause of cancer-related mortality in women, with 75% of cases being detected at an advance stage. Despite the knowledge that early diagnosis of ovarian cancer is associated with better prognosis and outcome, at present, there are still no recommendations for screening of asymptomatic women and the general population. Although there have been many advances in technology, mortality rates for ovarian cancer have remained more or less unchanged throughout the years because the screening tools being used do not achieve the desired sensitivities and specificities. This review analyzes the currently available detection techniques and biomarkers in an attempt to deduce the most adequate screening tools. There is new emerging evidence on the potential use of peritoneal fluid and its biomarkers as a representation of the tumor microenvironment in order to aid in the early detection of ovarian cancer.


Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma?
With the recent approval by the FDA of an immunotherapy for prostate cancer and another positive immunotherapy trial in melanoma, immunotherapy may finally be coming of age. So what will it take for it to become part of the standard treatment for glioblastoma? To put this question into perspective, we summarize critical background information in neuro-immunology, address immunotherapy clinical trial design, and discuss a number of extrinsic factors that will impact the development of immunotherapy in neuro-oncology.


How the occupational physician works with the unions.
A few attitudinal and behavioural principles will bring about a productive liaison between the occupational physician and trade unions. An effective working relationship with these organizations and employee associations can be developed, provided the occupational health care professionals are impartial in their practice, the loyalty to medicine replacing any bias toward the favouring of a managerial view. Respect must be given union officials, for in their organization they have status and can advance or defeat various health programs. Union representation on an occupational health committee will gain union support and minimize the filing of health-based grievances. The presentation of occupational health information at union meetings will communicate the goals of in-plant programs and familiarize workers, through their accustomed channels, with the objectives of health care policies and procedures.


Methacholine-induced bronchoconstriction in dogs: effects of lung volume and O3 exposure.
The maximal effect induced by methacholine (MCh) aerosols on pulmonary resistance (RL), and the effects of altering lung volume and O3 exposure on these induced changes in RL, was studied in five anesthetized and paralyzed dogs. RL was measured at functional residual capacity (FRC), and lung volumes above and below FRC, after exposure to MCh aerosols generated from solutions of 0.1-300 mg MCh/ml. The relative site of response was examined by magnifying parenchymal [RL with large tidal volume (VT) at fast frequency (RLLS)] or airway effects [RL with small VT at fast frequency (RLSF)]. Measurements were performed on dogs before and after 2 h of exposure to 3 ppm O3. MCh concentration-response curves for both RLLS and RLSF were sigmoid shaped. Alterations in mean lung volume did not alter RLLS; however, RLSF was larger below FRC than at higher lung volumes. Although O3 exposure resulted in small leftward shifts of the concentration-response curve for RLLS, the airway dominated index of RL (RLSF) was not altered by O3 exposure, nor was the maximal response using either index of RL. These data suggest O3 exposure does not affect MCh responses in conducting airways; rather, it affects responses of peripheral contractile elements to MCh, without changing their maximal response.


Up-regulation of sortase-dependent pili in Bifidobacterium longum BBMN68 in response to bile stress enhances its adhesion to HT-29 cells.
Adhesion to gastrointestinal tract is crucial for bifidobacteria to exert their probiotic effects. Our previous work found that bile salts significantly enhance the adhesion ability of Bifidobacterium longum BBMN68 to HT-29 cells. In this study, trypsin-shaving and LC-MS/MS-based surface proteomics were employed to identify surface proteins involved in bile stress response. Among the 829 differentially expressed proteins, 56 up-regulated proteins with a fold change >1.5 were subjected to further analysis. Notably, the minor pilin subunit FimB was 4.98-fold up-regulated in response to bile stress. In silico analysis and RT-PCR confirmed that gene fimB, fimA and srtC were co-transcribed and contributed to the biosynthesis of sortase-dependent pili Pil1. Moreover, scanning electron microscopy and immunogold electron microscopy assays showed increased abundance and length of Pil1 on BBMN68 under bile stress. As the major pilin subunit FimA serves as adhesion component of Pil1, an inhibition assay using anti-FimA antibodies further confirmed the critical role of Pil1 in mediating the adhesion of BBMN68 to HT-29 cells under bile stress. Our findings suggest that the up-regulation of Pil1 in response to bile stress enhances the adhesion of BBMN68 to intestinal epithelial cells, highlighting a novel mechanism of gut persistence in B. longum strains.


An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans.
[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/μmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 μSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) μSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.


[The advent of surgical gloves].
The advent of surgical gloves had a double evolution. Evolution of the material: cecum of a sheep, cotton, silk, leather, rubber. Originally introduced to protect theatre staff's hands from corrosive solutions, subsequent use was to protect the patient from contamination by theatre staff. Many surgeons contributed to the evolution of the surgical gloves. The use of gloves was truly part of an evolutionary process than a discovery. The turning of surgical gloves is now incontestable, and their use more and more important. Surgical gloves must secure a crossing protections between surgeon and patient.


Antigenic competition between heterologous erythrocytes in mice: interference with competition-inducing effect of sheep erythrocytes by inclusion of non-competing antigen.
Antigenic competition was studied on reciprocal combinations of non-cross-reacting erythrocyte (RBC) antigens, i.e., sheep erythrocytes (SRBC), horse erythrocytes (HRBC), and chicken erythrocytes (CRBC), as competing antigen or as test antigen. Unlike SRBC and HRBC, CRBC did not induce antigenic competition, and mice previously injected with CRBC showed normal direct and indirect hemolysin plaque-forming cell (PFC) responses to the other RBC subsequently injected. Formaldehyde-treated (F) SRBC that retained the capacity to prime mouse for secondary anti-SRBC antibody response but lost the capacity to elicit primary antibody response also could not induce antigenic competition. CRBC or F-SRBC, i.e., non-competing antigen, included with SRBC interfered with the competition-inducing effect of the latter RBC. When mice that had been injected with SRBC together with either one of the non-competing antigens were subsequently immunized with HRBC their anti-HRBC PFC responses were significantly restored, whereas mice pre-injected with SRBC alone showed markedly suppressed PFC responses to HRBC. Although the non-competing antigen was found not to affect both the direct and indirect PFC responses to the simultaneously injected SRBC, the response of the immune system to the non-competing antigen should alter the concurrent response to SRBC, and probably should prevent the generation of the suppressor thymus-derived (T) lymphocytes, allowing the generation of the helper T lymphocytes for IgM and IgG anti-SRBC antibody formation.


Repeated Sevoflurane Exposure in Neonatal Rats Enhances the Sensitivity to Pain and Traumatic Stress Later in Juvenile Life.
Sevoflurane exposure in the neonatal period of rodent animals was reported to be associated with neuroendocrine dysregulations later in life. We tested the hypothesis that repeated sevoflurane exposure in neonatal rats enhances the sensitivity to pain and acute traumatic stress response later in juvenile life and investigated whether the neonatal brain depolarizing γ-aminobutyric acid type A receptor (GABAAR) activity is involved in mediating these abnormalities. The postnatal 6 days (P6) Sprague-Dawley male rat pups pretreated with vehicle or the NKCC1 inhibitor, bumetanide, received sequential exposures to 2.1% sevoflurane exposure for 2 hours daily in 3 consecutive days. The results showed that repeated exposures to sevoflurane in neonatal rats significantly reduced the paw withdrawal thermal latency (PWTL) at P9, P45. Repeated exposures to sevoflurane in neonatal rats did not significantly affect the basal secretion of serum corticosterone at juvenile period P45, whereas the level of corticosterone for neonatal sevoflurane-exposed rats at P45 was significantly higher than the CON group after subject to conditioned fear traumatic stress (CFTS). The resulting NKCC1/KCC2 mRNA ratio was significantly increased immediately after the neonatal rats received the last sevoflurane exposure, which was alleviated by pretreated with the NKCC1 inhibitor bumetanide. Repeated exposures to sevoflurane in neonatal rats enhanced the sensitivity to pain and acute traumatic stress response in juvenile life. The neonatal brain depolarizing GABAAR activity is involved in mediating these abnormalities.


Interferon-Free Regimen for Hepatitis C: Insight and Management.
The rapid development of direct-acting antiviral agents (DAA) for hepatitis C virus (HCV) therapy dramatically altered the treatment landscape of this disease. The DAA regimen is associated with various advantages including high sustained virological response (SVR) with minimum side effects and low pill load and specific inhibition of viral replication, which lowers dependence on the host cell. This regimen has substantially replaced conventional (interferon) therapy with high cure rates (> 90%) in most HCV populations. This review provides insight into clinical studies of NS3/4A protease inhibitors, NS5B viral polymerase inhibitor (nucleotide and non-nucleotide), and NS5A inhibitors, alone and in combination.


Magnetic Targeting and Ultrasound Activation of Liposome-Microbubble Conjugate for Enhanced Delivery of Anticancer Therapies.
Effective delivery of chemotherapeutics with minimal toxicity and maximal outcome is clinically important but technically challenging. Here, we synthesize a complex of doxorubicin (DOX)-loaded magneto-liposome (DOX-ML) microbubbles (DOX-ML-MBs) for magnetically responsive and ultrasonically sensitive delivery of anticancer therapies with enhanced efficiency. Citrate-stabilized iron oxide nanoparticles (MNs) of 6.8 ± 1.36 nm were synthesized, loaded with DOX in the core of oligolamellar vesicles of 172 ± 9.2 nm, and covalently conjugated with perfluorocarbon (PFC)-gas-loaded microbubbles to form DOX-ML-MBs of ∼4 μm. DOX-ML-MBs exhibited significant magnetism and were able to release chemotherapeutics and DOX-MLs instantly upon exposure to ultrasound (US) pulses. In vitro studies showed that DOX-ML-MBs in the presence of US pulses promoted apoptosis and were highly effective in killing both BxPc-3 and Panc02 pancreatic cancer cells even at a low dose. Significant reduction in the tumor volume was observed after intravenous administration of DOX-ML-MBs in comparison to the control group in a pancreatic cancer xenograft model of nude mice. Deeply penetrated iron oxide nanoparticles throughout the magnetically targeted tumor tissues in the presence of US stimulation were clearly observed. Our study demonstrated the potential of using DOX-ML-MBs for site-specific targeting and controlled drug release. It opens a new avenue for the treatment of pancreatic cancer and other tissue malignancies where precise delivery of therapeutics is necessary.


A Risk Assessment Model for Bacterial Leaf Spot of Pepper (Capsicum annuum), Caused by Xanthomonas euvesicatoria, Based on Concentrations of Macronutrients, Micronutrients, and Micronutrient Ratios.
The phytopathogenic bacterium Xanthomonas euvesicatoria causes bacterial leaf spot (BLS) of pepper and has a worldwide distribution. BLS is difficult to control and an integrated management strategy that incorporates crop rotation, use of clean seed and clean plants, weed control, resistant varieties, applications of bactericides, biocontrol agents, and systemic acquired resistance (SAR) inducers is generally recommended. However, even with that arsenal of weapons, BLS can still be responsible for severe losses under favorable environmental conditions. Thus, additional tools need to be added to an overall integrated management strategy to combat BLS. In this article, we developed several models from 2012 to 2014 that were based on how macronutrients, micronutrients, and micronutrient ratios affect BLS severity. Factors used to select a model for validation included highly significant P values, high adjusted R2 values, low variance inflation factor values (<5), root mean square error, Mallow's Cp, and high Akaike's information criterion correction values. In addition, salicylic acid (SA) concentrations and relative expression of nonexpresser pathogenesis-related gene1 (NPR1) and pathogenesis-related protein 1 (PR1) in pepper tissues were also considered in model selection. A model (ECGA1) consisting of concentrations of copper, manganese, potassium, and the iron/zinc ratio as independent variables was used for validation in three different commercial pepper fields in Georgia: Colquitt County and Worth County in 2015 and Tift County in 2016. When area under the disease progress curve (AUDPC) values for two field sites (Colquitt and Worth Counties) in 2015 were pulled together and plotted against ECGA1-predicted values for both sites, the resulting relationship was highly significant (P = 0.0001) with an R2 value of 0.92. A significant relationship between observed AUDPC versus predicted values was also observed in Tift County in 2016 (P < 0.001; adjusted R2 = 0.98). Relative gene expression of both NPR1 and PR1 genes was significantly (P < 0.01) higher in pepper grown in predicted low-risk sites compared with pepper from high-risk sites in Colquitt, Worth, and Tift Counties. Although BLS severity will fluctuate depending on environmental conditions, the data indicate that the level of risk at a particular location may be influenced by how macronutrient and micronutrient concentrations affect plant disease resistance genes in the SAR pathway.


Ascertainment of causes of neonatal death using verbal autopsy in Rishikesh, Uttarakhand: A cross-sectional study.
India shares a huge burden of the total number of global neonatal deaths. The neonatal mortality rate in Uttarakhand is higher in comparison to the national rate. Understanding the causes and contextual factors that contribute to neonatal deaths is critical for developing a health programme and policy. Therefore, this study was aimed to ascertain causes of neonatal deaths using verbal autopsy in Rishikesh, Uttarakhand. A community-based cross-sectional study was conducted in Rishikesh, Uttarakhand from July 2018 to June 2019. The study participants were mothers or primary caregivers of deceased neonates. The verbal autopsy tool of the National Health Mission, Government of India was used to collect data. All neonatal deaths from July 2018 to June 2019 were included in this study. The cause of neonatal death was ascertained by two independent doctors. A total of 23 neonatal deaths could be traced during July 2018 through June 2019 in Rishikesh. One death was excluded from the study. Sixty-eight percent (15/22) of neonatal deaths occurred in the first week of life. Major causes of neonatal deaths were perinatal asphyxia (7/22), congenital malformation (6/22), and prematurity (4/22). Most (9/22) of the delays were in making a decision to seek medical care for neonates. The major causes of neonatal deaths were perinatal asphyxia, congenital malformation, and prematurity. Most of the deaths occurred during the early neonatal period.


Oral anticoagulant treatment: friend or foe in cardiovascular disease?
Calcification is a common complication in cardiovascular disease and may affect both arteries and heart valves. Matrix gamma-carboxyglutamic acid (Gla) protein (MGP) is a potent inhibitor of vascular calcification, the activity of which is regulated by vitamin K. In animal models, vitamin K antagonists (oral anticoagulants [OACs]) were shown to induce arterial calcification. To investigate whether long-term OAC treatment may induce calcification in humans also, we have measured the grade of aortic valve calcification in patients with and without preoperative OAC treatment. OAC-treated subjects were matched with nontreated ones for age, sex, and disease. Calcifications in patients receiving preoperative OAC treatment were significantly (2-fold) larger than in nontreated patients. These observations suggest that OACs, which are widely used for antithrombotic therapy, may induce cardiovascular calcifications as an adverse side effect.


Electrophysiological effects of antidepressants on mammalian hearts and crayfish giant axon.
Cardiotoxicity is known to occur in patients with or without preexisting cardiac diseases during treatments with the tricyclic antidepressants, amitriptyline and imipramine. The antiarrhythmic action of tricyclics was also demonstrated in clinical studies and in animal experiments. Bupropion, a novel antidepressant, is being studied in man and to date has been found to be effective and devoid of cardiovascular toxicity. This study was intended to show the direct effect of tricyclic antidepressants on excitable membrane and to compare their potential toxicity with bupropion in isolated tissues. In crayfish giant axon, all antidepressants exhibited local anesthetic-like action by reducing the action potential amplitude and maximal rate of upstroke (dv/dt). The tricyclics slowed spontaneous sinus discharges in rat atrium and prolonged the duration of evoked action potential in guinea pig atrium with a concomitant decrease in dv/dt. A quinidine-like action of the tricyclic agents is displayed in the termination of spontaneous depolarization and the suppression of dv/dt of evoked action potential in canine Purkinje fibers. The membrane depressant action of antidepressants resulted in the reduction of dv/dt and increased membrane refractoriness in both atrial and ventricular tissues; excitation is blocked even when resting membrane potential remained fully polarized. The present results confirmed the direct quinidine-like action on cardic tissues, which is probably related to the antiarrhythmic and/or cardiotoxic manifestation in man and animals. On on excitable tissues studied, tricyclic antidepressants are the most potent in blocking membrane excitation, while bupropion is the least toxic on the molar basis.


Survival analysis and nomogram for pulmonary sarcomatoid carcinoma: an SEER analysis and external validation.
Uncommon and particularly deadly, pulmonary sarcomatoid carcinoma (PSC) is an aggressive type of lung cancer. This research aimed to create a risk categorisation and nomogram to forecast the overall survival (OS) of patients with PSC. To develop the model, 899 patients with PSC were taken from the Surveillance, Epidemiology, and End Results database from the USA. We also used an exterior verification sample of 34 individuals with PSC from Fujian Provincial Hospital in China. The Cox regression hazards model and stepwise regression analysis were done to screen factors in developing a nomogram. The nomogram's ability to discriminate was measured employing the area under a time-dependent receiver operating characteristic curve (AUC), the concordance index (C-index) and the calibration curve. Decision curve analysis (DCA) and integrated discrimination improvement (IDI) were used to evaluate the nomogram to the tumour-node-metastasis categorisation developed by the American Joint Committee on Cancer (AJCC-TNM), eighth edition, and an additional sample confirmed the nomogram's accuracy. We further developed a risk assessment system based on nomogram scores. Six independent variables, age, sex, primary tumour site, pathological group, tumour-node-metastasis (TNM) clinical stage and therapeutic technique, were chosen to form the nomogram's basis. The nomogram indicated good discriminative ability with the C-index (0.763 in the training cohort and 0.746 in the external validation cohort) and time-dependent AUC. Calibration plots demonstrated high congruence between the prediction model and real-world evidence in both the validation and training cohorts. Nomogram outperformed the AJCC-TNM eighth edition classification in both DCA and IDI. Patients were classified into subgroups according to their risk ratings, and significant differences in OS were observed between them (p<0.001). We conducted a survival analysis and nomogram for PSC. This developed nomogram holds potential to serve as an efficient tool for clinicians in prognostic modelling.


Action of celecoxib on hepatic metabolic changes induced by the Walker-256 tumour in rats.
The purpose of the present work was to investigate the influence of celecoxib on some hepatic metabolic parameters affected by the Walker-256 tumour in rats. Celecoxib was administered daily (5-50 mg/kg body weight) beginning at the day in which the tumour cells were inocculated. At day 14, the liver was isolated and perfused in order to measure alanine transformation, glycolysis and arginine transformation. Maximal reduction of tumour growth (75%), accompanied by an almost normal weight gain, was attained with a celecoxib dose of 12.5 mg/kg. Diminution of glucose utilization (glycolysis) and inhibition of gluconeogenesis and ureogenesis from alanine caused by the tumor were totally reversed by celecoxib. Oxygen uptake by the liver was also normalized by the drug. Hepatic arginine transformation, which is normally enhanced in rats bearing the Walker-256 tumour, remained elevated in celecoxib-treated animals. It was concluded that preservation of gluconeogenesis and normalization of hepatic glucose utilization can explain, partly at least, the clinical improvement of cancer patients treated with the drug. The lack of action of celecoxib on arginine hydrolysis might indicate that reduction in polyamine synthesis is not a factor contributing to the diminished tumour growth.


Identification and functional evaluation of two STAT3 variants in grass carp: Implication for the existence of specific alternative splicing of STAT3 gene in teleost.
A STAT family member, STAT3, becomes activated as a DNA binding protein in response to cytokines and growth factors. In teleost, STAT3 cDNA has been cloned and identified in a few species, but only a single STAT3 transcript is revealed in these studies. In the present study, two variants of STAT3 gene generated by alternative splicing were isolated from grass carp and nominated as STAT3α1 and STAT3α2 based on the homology with their mammalian orthologs. In particular, the homologs of STAT3α1/2 were also found in various fish species, including zebrafish, takifugu, tilapia, medaka and goldfish. Intriguingly, sequence alignment and genomic structure analysis revealed that fish STAT3α1/2 are generated through similar alternative splicing events, implying the potential physiological significance of generating STAT3 variants in fish. Grass carp STAT3α1/2 (gcSTAT3α1/2) were ubiquitously expressed although the transcript levels of STAT3α2 were markedly higher than STAT3α1 in all examined tissues. In vivo and in vitro studies showed that the expression patterns of these two variants were similar under the stimulation of immune stimuli. To reveal the role of gcSTAT3α1/2 in fish immunity, their phosphorylation and involvement in IL-17A/F1 mRNA expression were demonstrated in grass carp peripheral blood lymphocytes upon LPS or PHA challenge, providing evidence for the functional conservation of STAT3 signaling in fish. These findings also raise a question of whether both gcSTAT3α1/2 participate in transcriptional regulation in fish. Actually, our results showed that both of them had the ability to translocate into the nucleus upon activation, and to amplify IL-10 signaling, indicating the existence of STAT3 isoforms with functional redundancy in teleost.


Laparoscopic Cholecystectomy in a Child Using Slender Forceps.
Laparoscopic procedures in children are technically demanding because of reduced working space with careful monitoring of pneumoperitoneum pressure. We report a case of laparoscopic cholecystectomy performed in a 9-year-old boy using slender forceps which addressed all the above mentioned concerns. This shows a possibility of needlescopic surgery in children.


[Effect of 5-aminolevulinic acid-mediated photodynamic therapy on human gastric cancer xenografts in nude mice in vivo].
To investigate the effect of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on human gastric cancer xenografts in vivo and to explore its potential tumoricidal mechanism. Cultured MGC-803 human gastric cancer cells were injected below the skins of the nude mice to develop the tumor model. The tumor-bearing nude mice were examined under the Leica LT-9 MACIMSYSPULS to detect the fluorescence. The tumor volume of day 1, 3, 7, 14, 21 after treatment were measured, and its histological changes were also studied. The tissues of the tumors in nude mice of the control group, light group, 5-ALA group and PDT group were examined with the electron microscope and apoptosis was detected by TUNEL assay. The tumor model was successfully developed. The tumor in the nude mice emitted the red fluorescence under the Leica LT-9 MACIMSYSPULS. The tumor volumes were (0.189+/-0.010) cm(3), (0.183+/-0.011) cm(3), (0.185+/-0.019)cm(3), (0.182+/-0.015)cm(3) for the control group, light group, 5-ALA group, PDT group, respectively at day 1 after treatment, while at day 3, (0.294+/-0.010) cm(3), (0.280+/-0.013) cm(3), (0.278+/-0.016) cm(3), (0.183+/-0.014) cm(3); at day 7, (0.409+/-0.016) cm(3), (0.411+/-0.009) cm(3), (0.407+/-0.015) cm(3), (0.221+/-0.008) cm(3); at day 14, (0.970+/-0.055) cm(3), (0.976+/-0.054) cm(3), (0.981+/-0.032)cm(3), (0.318+/-0.005) cm(3); at day 21, (1.495+/-0.059) cm(3), (1.513+/-0.057) cm(3), (1.524+/-0.063) cm(3), (0.446+/-0.042) cm(3) (F=1003.086, P=0.000). The histology demonstrated that most tumor blood vessels were congested and necrosis developed after PDT while not in the control group, light group and 5-ALA group. Necrosis and apoptosis were observed in the cells of the tumors of the PDT group examined by TUNEL and electron microscope while not in the cells of the tumors of the other groups. 5-aminolevulinic acid-mediated photodynamic therapy (PDT) can induce injury to human gastric cancer xenografts and inhibit the tumor growth while light only and 5-ALA only can not. 5-aminolevulinic acid-mediated photodynamic therapy (ALA- PDT) appears to be a promising therapy for human gastric cancer, whose mechanism involves in the destruction of the tumors partly by apoptosis other than necrosis.


Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: A meta-analysis of immunohistochemical studies.
Emerging preclinical evidence suggests the involvement of sex hormones and their receptor signals in the development and progression of bladder cancer. Meanwhile, previous studies have demonstrated conflicting results on the relationship between the status of sex hormone receptors in urothelial tumors and histopathological characteristics of the tumors or patient outcomes. We therefore conducted this meta-analysis to assess the clinicopathological impact of the expression of androgen receptor (AR) and estrogen receptors (ERs) in bladder cancer. A comprehensive literature search in databases (i.e. PubMed, Web of Science, Cochrane) was performed for all immunohistochemical studies stained for AR, ERα, and/or ERβ in surgically resected bladder cancer specimens and analyzed for patient outcomes. We selected eligible studies in accordance with the PRISMA guidelines and analyzed data using R software. A total of 2,049 patients from 13 retrospective studies were included in this meta-analysis. The difference in ERα expression between non-tumors and tumors was significant [odds ratio (OR) = 0.412; P<0.001], while those of AR (OR = 3.256; P = 0.336) or ERβ (OR = 0.580; P = 0.674) were not statistically significant. AR positivity in tumors was strongly correlated with gender (male vs. female: OR = 0.658; P = 0.027) or tumor grade (low-grade vs. high-grade: OR = 0.575; P<0.001). ERβ positive rates were significantly higher in high-grade (OR = 2.169; P<0.001) and muscle-invasive (OR = 3.104; P<0.001) tumors than in low-grade and non-muscle-invasive tumors, respectively. Survival analysis in patients with non-muscle-invasive bladder cancer revealed associations between AR expression and better recurrence-free survival [hazard ration (HR) = 0.593; P = 0.006) as well as between ERβ expression and worse recurrence-free (HR = 1.573; P = 0.013) or progression-free (HR = 4.148; P = 0.089) survivals. These data suggest down-regulation of ERα expression in bladder tumors, compared with non-neoplastic urothelial tissues. AR or ERβ expression was down- or up-regulated, respectively, in high-grade and/or muscle-invasive bladder cancers. Moreover, immunohistochemistry of AR/ERβ in surgical specimens may serve as prognosticators in patients with non-muscle-invasive bladder tumor.


Synthesis of furanophane derivatives through [8+2]-cycloaddition of dienylisobenzofurans and alkynes.
The coupling of various dienylisobenzofurans with dimethyl acetylenedicarboxylate (DMAD) has been examined. In most cases, this reaction proceeds via [8+2]-cycloaddition to afford furan-bridged decatetraene ring systems. The major competing reaction pathway is [4+2]-cycloaddition between DMAD and the isobenzofuran nucleus. Isobenzofuran intermediates were generated using either a chromium carbene-based method or an acid-catalyzed method.


Emulsification and fatty-acid chain length affect the utilization of medium-chain triglycerides by neonatal pigs.
Three experiments were conducted using 52 pigs between 22 and 35 h of birth to determine the effects of emulsification and fatty-acid chain length on utilization of medium-chain triglycerides (MCT). After a 4-h period during which feed was withheld, pigs were force-fed 6 mL of nonemulsified (NE) MCT or 20 mL of a 30% (vol/vol) Tween 80-(polyoxy-ethylene [20] sorbitan monooleate) MCT emulsion, marking time 0, and serial blood samples were drawn throughout 8 h for analysis of medium-chain fatty acid (MCFA) concentrations by HPLC. In Exp. 1, pigs received either NE or emulsified Tri-C4, -C5, -C6, or -C7. The emulsified treatments were discontinued due to deaths caused by coma resulting from high concentrations (up to 12 mM) of plasma MCFA. Concentrations in pigs fed emulsified MCT were 2.5-fold higher than those in pigs fed NE MCT. In pigs fed NE MCT, concentrations of even-chain-length MCFA were higher than those of odd-chain-length MCFA (P < .001), with a tendency for C6 to be higher than C4 (P < .1). In Exp. 2 and 3, pigs received an equimolar mixture of MCT in either emulsified or NE form. In Exp. 2, the mixture contained Tri-C4 through Tri-C7; whereas, in Exp. 3 the mixture contained Tri-C4, -C6, -C8, and -C10. A three-way interaction (emulsion x fatty acid x sample time; P < .05) was observed in both experiments.(ABSTRACT TRUNCATED AT 250 WORDS)


Update in the epidemiology of Parkinson's disease.
In the past 18 months, several important studies on the epidemiology of Parkinson's disease have been published. In particular, large cohorts have identified sufficient incident patients with Parkinson's disease to study risk or protective factors of Parkinson's disease; one of the important recent events in the field is the publication of some of their findings. We will first review findings of descriptive studies on the frequency of the disease and its geographic or temporal distribution. We will then summarize the findings of analytical studies dealing with risk or protective factors in the fields of dietary and lifestyle factors (cigarette smoking, coffee and tea drinking, uric acid, dairy products), environmental exposures (pesticides, lead, manganese, welding), hormonal factors (oophorectomy), vascular risk factors (diabetes, hypertension, cholesterol level), pharmacoepidemiology (NSAIDs, statins), and familial aggregation. Epidemiologic studies have consistently found that some exposures are inversely (e.g., cigarette smoking) or positively associated with Parkinson's disease (e.g., pesticides), while their findings are, at the present time, less consistent for other exposures (e.g., NSAIDs, vascular risk factors). Finally, recent studies have investigated new research fields (e.g., hormonal factors, uric acid, pharmacoepidemiology) and additional data need to be collected.


Coxiella burnetii abortion in a dairy farm selling artisanal cheese directly to consumers and review of Q fever as a bovine abortifacient in South America and a human milk-borne disease.
Coxiella burnetii is a highly transmissible intracellular bacterium with a low infective dose that causes Q fever (coxiellosis), a notifiable zoonotic disease distributed worldwide. Livestock are the main source of C. burnetii transmission to humans, which occurs mostly through the aerogenous route. Although C. burnetii is a major abortifacient in small ruminants, it is less frequently diagnosed in aborting cattle. We report a case of C. burnetii abortion in a lactating Holstein cow from a dairy farm producing and selling artisanal cheese directly to consumers in Uruguay, and review the literature on coxiellosis as a bovine abortifacient in South America and as a milk-borne disease. The aborted cow had severe necrotizing placentitis with abundant intratrophoblastic and intralesional C. burnetii confirmed by immunohistochemistry and PCR. After primo-infection in cattle, C. burnetii remains latent in the lymph nodes and mammary glands, with milk being a significant and persistent excretion route. Viable C. burnetii has been found in unpasteurized milk and cheeses after several months of maturing. The risk of coxiellosis after the consumption of unpasteurized dairy products, including cheese, is not negligible. This report raises awareness on bovine coxiellosis as a potential food safety problem in on-farm raw cheese manufacturing and sales. The scant publications on abortive coxiellosis in cattle in South America suggest that the condition has probably gone underreported in all countries of this subcontinent except for Uruguay. Therefore, we also discuss the diagnostic criteria for laboratory-based confirmation of C. burnetii abortion in ruminants as a guideline for veterinary diagnosticians.


Investigating the interaction of pleasantness and arousal and the role of aesthetic emotions on episodic memory using a musical what-where-when paradigm.
Recent evidence suggests that the presence of music experienced as pleasant positively influences episodic memory (EM) encoding. However, it is unclear whether this impact of pleasant music holds regardless of how arousing the music is, and what influence, if any, music-induced aesthetic emotions have. Furthermore, most music EM studies have used verbal or facial memory tasks limiting the generalisability of these findings to everyday EMs with spatiotemporal richness. The current study used an online what-where-when paradigm to assess music's influence on EM encoding in a rich spatiotemporal environment. 105 participants carried out the what-where-when task in the presence of either silence or one of four musical stimuli falling into the four corners of the 2-D circumplex emotion model. We observed an interaction effect between the pleasantness and arousingness of music stimuli, whereby for pleasant stimuli, the low arousing excerpt was associated with better recall performance compared to the high arousing excerpt. We also observed that, across all excerpts, experience of negative aesthetic emotions was associated with compromised recall performance. Together, our results confirm the deleterious influence arousing stimuli can have on memory and support the notion that aesthetic-emotional experience of music can influence how memories are encoded in everyday life.


Revisiting Mandell's 'least adult' role and engaging with children's voices in research.
This paper is intended to re-examine Mandell's classic work on the 'least adult' role and to show that the principles that underpin Mandell's work are useful if combined with a reflexive approach to working with children. Researching with children (Christensen and James 2008) using participatory methods has become an accepted research methodology. However, research reports that claim to represent the views of children rarely detail how the research relationships between children and adults are managed. Mandell's work on the least-adult role in studying children and other contemporary texts on researching with children. Re-examination of the principles of Mandell's approach to conducting participatory research with children using other contemporary texts on researching with children and participatory research with children. The work of other researchers with children would appear to endorse the principles that Mandell suggests as useful when engaging children in research: to minimise the social difference between adult and child, to value the child's social world, and to join with children in activities such as play or arts-based participatory methods. The issue of trust seems to extend beyond the relationship between researcher and participant to include building trust with other adults in whom the child has confidence. In applying these principles and building trust, researchers need to be reflexive about their understanding of children and childhood. To evaluate research with children, research reports need to include discussions of how the researchers addressed Mandell's principles and built trust. Data given by children are influenced by how social differences are minimised, the perceived value the researcher places on children's social worlds and how children are engaged in the research process. IMPLICATION FOR PRACTICE/RESEARCH: Further research is required to understand how various approaches to minimising social difference, valuing children's social worlds, joining children in activities and building trust can influence children's participation and the data they give.


A novel RNA binding protein-associated prognostic model to predict overall survival in hepatocellular carcinoma patients.
Hepatocellular carcinoma (HCC) is 1 of the deadliest malignancies worldwide. Despite significant advances in diagnosis and treatment, the mortality rate from HCC persists at a substantial level. Construction of a prognostic model that can reliably predict HCC patients' overall survival is urgently needed.Two RNA-seq dataset (the Cancer Genome Atlas and International Cancer Genome Consortium) and 1 microarray dataset (GSE14520) were included in our study. RNA-binding proteins (RBPs) in HCC patients was examined by differentially expressed genes analysis, functional enrichment analysis and protein-protein interaction network analysis. Subsequently, the Cancer Genome Atlas dataset was randomly divided into training and testing cohort with a prognostic model developed in the training cohort. In order to evaluate the prognostic value of the model, a comprehensive survival assessment was conducted.Five RBPs (ribosomal protein L10-like, enhancer of zeste homolog 2 (EZH2), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), zinc finger protein 239, interferon-induced protein with tetratricopeptide repeats 1) were used to construct the model. The model accurately predicted the prognosis of liver cancer patients in both the training cohort and validation cohort. HCC patients could be assigned into a high-risk group and a low-risk group by this model, and the overall survival of these 2 groups was significantly different (P < .05). Furthermore, the risk scores obtained by this model were highly correlated with immune cell infiltration.The prognostic model helps to identify HCC patients at high risk of mortality, which optimizes decision-making for individualized treatment.


Role of the U.S. Food and Drug Administration in the regulatory management of human listeriosis in the United States.
From 1986 to 2006, the incidence of listeriosis in the United States dropped from approximately seven to three cases per million population, a reduction that most likely reflects the joint efforts of industry, government, consumers, and academia. Herein, we describe the U.S. Food and Drug Administration (FDA) strategy over the past three decades to combat listeriosis. Specifically, we discuss early actions taken to address outbreaks during the 1980s, policy decisions regarding the presence of Listeria monocytogenes in FDA-regulated foods, FDA compliance programs with L. monocytogenes components, enforcement actions to remove L. monocytogenes-contaminated products from the market (i.e., recalls) or to prevent entry of such products into the market (i.e., import detentions and refusals), research milestones, outreach and education efforts, and selected special projects. Evolving demographic trends in the United States may pose a challenge to further reduction of the incidence of listeriosis.


Control of concerted two bond versus single bond dissociation in CH(3)Co(CO)(4) via an intermediate state using pump-dump laser pulses.
Wavepacket propagations on ab initio multiconfigurational two-dimensional potential energy surfaces for CH(3)Co(CO)(4) indicate that after irradiation to the lowest first and second electronic excited states, concerted dissociation of CH(3) and the axial CO ligand takes place. We employ a pump-dump sequence of pulses with appropriate frequencies and time delays to achieve the selective breakage of a single bond by controlling the dissociation angle. The pump and dump pulse sequence exploits the unbound surface where dissociation occurs in a counterintuitive fashion; stretching of one bond in an intermediate state enhances the single dissociation of the other bond.


The response of liver macrophages to inflammatory stimulation.
The gut is the major source of inflammatory agents that affect the liver. Of these compounds, the endotoxins are the most frequent and best studied intruders. The resident macrophages of the liver, the Kupffer cells, are among the first to respond to this complex. Following contact with the cluster of differentiation (CD) 14 protein, the complex triggers a signal cascade involving the nuclear factor kappa B. This factor enhances the expression of inflammation-related genes, e.g. those encoding cytokines. Tumor necrosis factor-alpha is responsible for nearly all of the effects ascribed to endotoxins (lipopolysaccharides). Interleukin (IL)-6, also a product of lipopolysaccharide-activated Kupffer cells, may be instrumental in eliciting the acute-phase response of hepatocytes, while transforming growth factor-beta promotes conversion of quiescent hepatic stellate cells into a collagen-producing myofibroblast-like form. A different signal pathway triggered by bound endotoxin involves a mitogen-activated protein kinase and leads to the activation of phospholipase A2 and the synthesis of the eicosanoids. Endotoxin also induces a nitric oxide synthase in Kupffer cells. This inorganic mediator may participate in the relaxation of the hepatic sinusoid, but may also, together with macrophage-derived superoxide, produce strong oxidants. Tumor necrosis factor-alpha and nitric oxide play a significant role during liver regeneration after partial hepatectomy. Of the various effects of eicosanoids, their regulatory role in cytokine production by Kupffer cells may be the most important. The regulation of Kupffer cell functions by cell volume change has very recently become apparent.


Automated GMP production and long-term experience in radiosynthesis of CB1 tracer [18 F]FMPEP-d2.
Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB1 receptor imaging tracer (3R,5R)-5-(3-([18 F]fluoromethoxy-d2 )phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([18 F]FMPEP-d2 ), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic 18 F-fluorination of an alkylating agent and its GC purification, the subsequent 18 F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the 18 F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the 18 F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013-2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.


Involvement of miR-Let7A in inflammatory response and cell survival/apoptosis regulated by resveratrol in THP-1 macrophage.
Resveratrol, a natural polyphenol, has multiple functions in cellular responses including apoptosis, survival, and differentiation. It also participates in the regulation of inflammatory response and oxidative stress. MicroRNA-Let-7A (miR-Let7A), known as a tumor suppressor miRNA, was recently reported to play a crucial role in both inflammation and apoptosis. Therefore, we examined involvement of miR-Let7A in the modulation of inflammation and cell survival/apoptosis regulated by resveratrol. mRNA expression of pro-/anti-inflammatory cytokines and sirtuin 1 (SIRT1), and protein expression of apoptosis signal-regulating kinase 1 (ASK1), p-ASK1, and caspase-3 and cleaved caspase-3 were measured, and cell viability and Hoechst/PI staining for apoptosis were observed in Lipopolysaccharide (LPS)-stimulated human THP-1 macrophages with the treatment of resveratrol and/or miR-Let7A overexpression. Pre-treatment with resveratrol (25-200 µM) resulted in significant recovery of the reduced cell viabilities under LPS-induced inflammatory condition and in markedly increased expression of miR-Let7A in non-stimulated or LPS-stimulated cells. Increased mRNA levels of tumor necrosis factor-α and interleukin (IL)-6 induced by LPS were significantly attenuated, and decreased levels of IL-10 and brain-derived neurotrophic factor were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. Decreased expression of IL-4 mRNA by LPS stimulation was also significantly increased by miR-Let7A overexpression co-treated with resveratrol. In addition, decreased SIRT1 mRNA levels, and increased p-ASK1 levels and PI-positive cells by LPS stimulation were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. miR-Let7A may be involved in the inflammatory response and cell survival/apoptosis modulated by resveratrol in human THP-1 macrophages.


Structural and Functional Characterization of Covalently Modified Proteins Formed By a Glycating Agent, Glyoxal.
Glycation, the main consequence of hyperglycemia, is one of the major perpetrators of diabetes and several other conditions, including coronary and neurodegenerative complications. Such a hyperglycemic condition is represented by a large increase in levels of various glycation end products including glyoxal, methylglyoxal, and carboxymethyl-lysine among others. These glycation end products are known to play a crucial role in diabetic complications due to their ability to covalently modify important proteins and enzymes, specifically at lysine residues (a process termed as glycation), making them non-functional. Previous studies have largely paid attention on characterization and identification of these reactive glycating agents. Structural and functional consequences of proteins affected by glycation have not yet been critically investigated. We have made a systematic investigation on the early conformational changes and functional alterations brought about by a glycating agent, glyoxal, on different proteins. We found that the early event in glycation includes an increase in hydrodynamic diameter, followed by minor structural alterations sufficient to impair enzyme activity. The study indicates the importance of glyoxal-induced early structural alteration of proteins toward the pathophysiology of hyperglycemia/diabetes and associated conditions.


Case of acute mixed liver injury due to hypothyroidism.
The effects of hypothyroidism on the liver are not well understood. A 77-year-old woman with Hashimoto's thyroiditis had stopped taking levothyroxine on her own for 6 months. Her thyroid stimulating hormone (TSH) level was consistent with severe hypothyroidism. She resumed thyroid replacement therapy. The following month, her liver function tests were significantly elevated. Seven weeks after resumption of therapy, her TSH and liver tests had returned to normal. We attribute the mixed hepatocellular injury to hypothyroidism that resolved on correction of the hypothyroid state. This case reminds us that thyroid disease should be considered when evaluating acute liver injury.


Abnormalities of regional spontaneous brain activity in poststroke aphasia: a meta-analysis.
Poststroke aphasia is an acquired language disorder and has been proven to have adverse effects on patients' social skills and quality of life. However, there are some inconsistencies in the neuroimaging studies investigating poststroke aphasia from the perspective of regional alterations. A meta-analysis has been employed to examine the common pattern of abnormal regional spontaneous brain activity in poststroke aphasia in the current study. Specifically, the Anisotropic effect-size version of seed-based d mapping was utilized, and 237 poststroke aphasia patients and 242 healthy controls (HCs) from 12 resting-state functional magnetic resonance imaging studies using amplitude of low-frequency fluctuations (ALFF), fractional ALFF, or regional homogeneity were included. The results showed that compared with HCs, patients with poststroke aphasia demonstrated increased regional spontaneous brain activity in the right insula, right postcentral gyrus, left cerebellar lobule IX, left angular gyrus, right caudate nucleus, left parahippocampal gyrus, and right supplementary motor area, and decreased regional spontaneous brain activity in the left cerebellar lobule VI, left median cingulate and paracingulate gyri, right cerebellar crus I, and left supplementary motor area. The study could provide further evidence for pathophysiological mechanism of poststroke aphasia and help find targets for treatment.


A longitudinal investigation of the affective environment in families with young children: from infancy to early school age.
We examined the affective environment in 102 families studied longitudinally when children were 7, 15, 25, 38, 52, and 67 months of age. At each assessment, every mother-child and father-child dyad was observed in typical daily contexts. Each person's emotions of affection, joy, and anger were coded. Both parents rated marital satisfaction when children were 15, 52, and 67 months. Growth curve analyses, using Actor-Partner Interdependence Modeling, examined (a) developmental changes in emotions, (b) within-relationship influences of the partner's emotions, (c) across-relationship influences of emotions in other parent's interactions with the child, and (d) associations between marital quality and emotions over time. Parents' emotional expressiveness was highest early in the child's development, and declined thereafter. Children's anger was highest at 15 months of age, and declined thereafter, and their positive emotions, particularly with mothers, increased over time. Generally, one's positive emotions and better marital quality were associated with greater positive emotion within- and across-relationships, whereas one's anger was associated with greater anger within- and across-relationships. However, any emotion expression elicited greater affection in the interaction partner. Parents' neuroticism did not account for the convergence of emotions across relationships.


Regulation of RANKL-induced osteoclastogenesis by RING finger protein RNF114.
Normal bone remodeling is a continuous process orchestrated by bone-resorbing osteoclasts and bone-forming osteoblasts, which an imbalance in bone remodeling results in metabolic bone diseases. RANKL, a member of the TNF cytokine family, functions as a key stimulator for osteoclast differentiation and maturation. Here, we report that RNF114, previously identified as a psoriasis susceptibility gene, plays a regulatory role in the RANKL/RANK/TRAF6 signaling pathway that mediates osteoclastogenesis. Our results demonstrated that RNF114 expression was significantly down-regulated in mouse osteoclast precursor cells undergoing RANKL-induced osteoclast differentiation. RNF114 knockout did not affect development or viability of the subpopulation of bone marrow macrophages capable of differentiating into osteoclasts in culture. However, in the presence of RANKL, RNF114 knockout bone marrow macrophages exhibited enhanced cell proliferation and augmented osteoclast differentiation, as shown by an increased expression of mature osteoclast markers, increased osteoclastic TRAP activity and bone resorption. Conversely, ectopic expression of RNF114 inhibited CTSK expression, TRAP activity, and bone resorption in RANKL-treated pre-osteoclasts. RNF114 also suppressed RANKL-activated NFATc1 expression and NFAT-regulated promoter activity. RNF114 suppressed TRAF6-, but not TAK1/TAB2-mediated NF-κB activation downstream of RANKL/RANK. In particular, TRAF6 protein levels were down-regulated by RNF114, possibly via K48-mediated proteasome-dependent degradation. These data suggested that RNF114's inhibitory effect on RANKL-stimulated osteoclastogenesis was mediated by blocking RANK/TRAF6/NF-κB signal transduction. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:159-166, 2018.


Community violence exposure, social cognition, and aggression among urban elementary school children.
The effects of witnessing community violence on aggressive cognitions and behavior were investigated in an ethnically diverse sample of 4,458 children living in urban neighborhoods. Prior violence exposure had a significant effect in increasing aggression, normative beliefs about aggression, and aggressive fantasy. Although exposure to violence predicted aggressive behavior both in Grades 1 through 3 (ages 5-8) and Grades 4 through 6 (ages 9-12), the effects on social cognition were only evident in the later grades. Furthermore, the effect of violence exposure on aggression in the later grades was partially mediated by its effect on social cognition. These findings suggest that witnessing community violence has an effect on children's aggressive behavior through both imitation of violence and the development of associated cognitions as children get older.


[Garlicin and formocresol in the treatment of chronic periapical periodontitis].
To evaluate the short period clinical responses after sealed garlicin and formocresol small cotton ball in the root canal entrance to treat chronic periapical periodontitis. Treatment records of 185 teeth with chronic periapical periodontitis were compared. Of them, 94 teeth were treated by sealed small garlicin cotton ball in the root canal entrance, 78 were treated by sealed small formocresol cotton ball in the root canal entrance, and the other 13 were treated by sealed small normal saline cotton ball. The curative effects were evaluated through clinical observation. The ratios of acute reaction in 3 days following sealed garlicin, formocresol and normal saline small cotton ball were 5.1%, 10.7%, and 50% in the anterior teeth, and 5.5%, 8.0%, and 60%, in the posterior teeth, respectively. The clinical curative effects were similar between garlicin and formocresol in the short period. Formocresol can be substituted by garlicin.


Cytotoxic T cell interactions with antigen. Potential relevance for drug-related lupus.
Understanding of cytotoxic T cell recognition may be relevant to the study of drug-related lupus because either cell-mediated cytotoxicity (CMC) contributes to triggering the disease or CMC provides an informative model to study T cell recognition of foreign antigen. As a model, CMC demonstrates the following: 1) Antigen presentation can occur by membrane insertion of the antigen, covalent modification of the cell surface, or cell surface adsorption of the antigen; these may be modes of presentation by which drug-related antigens induce adverse responses. 2) HLA antigens regulate a wide variety of immune responses; this may be crucial in drug-related lupus since HLA antigens may regulate autoimmune responses, may affect an individual's susceptibility to lupus, and may increase the risk for other specific adverse drug reactions.


Hospital Admission following Acute Kidney Injury in Kidney Transplant Recipients Is Associated with a Negative Impact on Graft Function after 1-Year.
The incidence and outcomes of acute kidney injury (AKI) in kidney transplantation are poorly known. Retrospective cohort analysis was performed on the data of all patients (≥3 months after transplantation and ≥16 years of age) admitted to the hospital due to medical or surgical complications from 2007 to 2010. We analyzed 458 kidney transplant recipients, 55.2% men, median age 49 (IQR, 36-58) years, median of 12.5 (IQR, 3-35) months after kidney transplantation; admitted to the hospital due to medical or surgical complications. Most of the patients received a kidney from a deceased donor (62.2%), the primary cause for hospital admission was infection (60.7%) and 57 (12.4%) individuals were diagnosed with acute rejection (AR). The incidence of AKI was 82.3%: 31.9% stage 1, 29.3% stage 2 and 21.2% stage 3. Intensive care unit (ICU) admission (OR 8.90, 95% CI: 1.77-44.56 p = 0.008), infection (OR 5.73, 95% CI: 2.61-12.56, p<0.001) and the use of contrast media (OR 9.34, 95% CI: 2.04-42.70, p = 0.004) were the independent risk factors for AKI development. The mortality rate was 2.1% and all patients who died were diagnosed with AKI. Even after the exclusion of AR cases, at the end of 12 months, the individuals with AKI exhibited higher percent changes in creatinine values when compared with individuals without AKI (9.1% vs. -4.3%; p<0.001). According to KDIGO system, we found a high incidence of AKI among the complications of renal transplantation. As in other scenarios, AKI was associated with renal function loss at 1-year after the hospital discharge.


Engineering Single Pan-Specific Ubiquibodies for Targeted Degradation of All Forms of Endogenous ERK Protein Kinase.
Ubiquibodies (uAbs) are a customizable proteome editing technology that utilizes E3 ubiquitin ligases genetically fused to synthetic binding proteins to steer otherwise stable proteins of interest (POIs) to the 26S proteasome for degradation. The ability of engineered uAbs to accelerate the turnover of exogenous or endogenous POIs in a post-translational manner offers a simple yet robust tool for dissecting diverse functional properties of cellular proteins as well as for expanding the druggable proteome to include tumorigenic protein families that have yet-to-be successfully drugged by conventional inhibitors. Here, we describe the engineering of uAbs composed of human carboxyl-terminus of Hsc70-interacting protein (CHIP), a highly modular human E3 ubiquitin ligase, tethered to differently designed ankyrin repeat proteins (DARPins) that bind to nonphosphorylated (inactive) and/or doubly phosphorylated (active) forms of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Two of the resulting uAbs were found to be global ERK degraders, pan-specifically capturing all endogenous ERK1/2 protein forms and redirecting them to the proteasome for degradation in different cell lines, including MCF7 breast cancer cells. Taken together, these results demonstrate how the substrate specificity of an E3 ubiquitin ligase can be reprogrammed to generate designer uAbs against difficult-to-drug targets, enabling a modular platform for remodeling the mammalian proteome.


New York Community Health Centers' Population Health Activities: Findings from a Statewide Assessment.
The U.S. spends just 5% of its health care budget to prevent morbidity and mortality. This study surveyed N.Y. State community health centers' (CHCs) population health activities aligned with the N.Y. Prevention Agenda (response rate of 72%). More than half of CHCs considered population health a high priority. Chronic disease and reducing preventable infections were the leading activity areas. One third of activities were dedicated to patient treatment follow-up. Community health centers reported that more than two-thirds of all activities received no funding. Despite a commitment to population health among CHCs, widespread improvements in population health may remain limited without an increase in dedicated funding to support community-based prevention strategies.


Plantar flexion influences radiographic measurements of the ankle mortise.
The treatment of ankle fractures often depends on the integrity of the deltoid ligament. Diagnosis of a deltoid ligament tear depends on the measurement of the medial clear space. We sought to evaluate the impact of ankle plantar flexion on the medial clear space. Mortise radiographs were made for twenty-five healthy volunteers, with the ankle in four positions of plantar flexion (0 degrees, 15 degrees, 30 degrees, and 45 degrees). Four observers measured the medial clear space and the superior clear space on each radiograph. The mean medial clear space at 0 degrees was defined as the control, and the deviation of the medial clear space from the control value was calculated at 15 degrees, 30 degrees, and 45 degrees of plantar flexion. The ratio of the medial clear space to the superior clear space was determined on all radiographs, and ratios that were false-positive for a deltoid ligament injury were identified. Fourteen male and eleven female volunteers were evaluated. The average increase in the medial clear space when ankle plantar flexion was increased from 0 degrees to 45 degrees was 0.38 mm (95% confidence interval, 0.18 to 0.58 mm). This increase was significant (p = 0.005). The average increase in the medial clear space was 0.04 mm when ankle plantar flexion was increased from 0 degrees to 15 degrees and 0.22 mm when it was increased from 0 degrees to 30 degrees. Neither of these changes was significant (p = 0.99 and 0.20). The prevalence of false-positive findings of deltoid injury based on the ratio of the medial clear space to the superior clear space increased as ankle plantar flexion increased, but this increase did not reach significance in our study group (p = 0.18). Plantar flexion of the ankle produces changes in radiographic measurements of the medial clear space. The potential for false-positive findings of deltoid disruption increases with increasing ankle plantar flexion.