Characterization of a novel porin protein from Moraxella catarrhalis and identification of an immunodominant surface loop.
Moraxella catarrhalis is a gram-negative bacterium that is mainly responsible for respiratory tract infections. In this study we report a novel outer membrane protein (OMP), designated M35, with a molecular mass of 36.1 kDa. This protein was structurally homologous to classic gram-negative porins, such as OMP C from Escherichia coli and OMP K36 from Klebsiella pneumoniae, with a predicted structure of 8 surface loops and 16 antiparallel beta-sheets. The DNA sequences of the genes from 18 diverse clinical isolates showed that the gene was highly conserved (99.6 to 100% of nucleotides), with only one isolate (ID78LN266) having base variations that resulted in amino acid substitutions. Electrophoresis and analysis of recognition of the protein using mouse anti-M35 sera showed that M35 was expressed on the bacterial surface and constitutively expressed across M. catarrhalis isolates, with only ID78LN266 showing poor antibody recognition. Our results showed that the single amino acid mutation in loop 3 significantly affected antibody recognition, indicating that loop 3 appeared to contain an immunodominant B-cell epitope. The antibody specificity to loop 3 may be a potential mechanism for evasion of host immune responses targeted to M35, since loop 3 should theoretically orientate into the porin channel. Thus, M35 is a highly conserved, surface-expressed protein that is of significance for its potential functional role as an M. catarrhalis porin and is of interest as a vaccine candidate.


[Applied evidence-based medicine].
The success of evidence-based medicine (EbM) will also depend whether its effectiveness is proven in empirical studies. The main question is how the information-seeking behaviour of physicians can be modified. A series of studies have shown that their information management is frequently not based on a rational model of knowledge acquisition. In particular, many studies concerning the implementation of guidelines as a practical application of EbM have demonstrated that, in addition to a general skepticism about guidelines, many practical obstacles are relevant. An optimal implementation strategy should consider these from the beginning.


[Correlation between plasma concentrations of homocysteine and diabetic polyneuropathy evaluated with the Semmes-Weinstein monofilament test in patients with type 2 diabetes mellitus].
Few modifiable risk factors are known to be associated with the presence and progression of diabetic polyneuropathy (DPN). We have analyzed in 405 type 2 diabetic (T2DM) subjects (169 women) the association of plasma homocysteine with the presence of DPN measured with the Semmes-Weinstein (SW) monofilament test. A score below 4 was considered an altered SW monofilament test. Plasma homocysteine, vitamin B12 and folic acid were measured using standard procedures (ELISA). Patients with T2DM with altered SW test have significantly higher age, evolution of disease, HbA1c and lower creatinine clearance values. In addition, plasma homocysteine values were independently and significantly higher in T2DM with DPN measured as altered SW test (13.64 ± 4.93 vs. 12.22 ± 4.48 μmol/l, P<.01) with similar vitamin B12 and folic acid values comparing the 2 groups. Plasma homocysteine and HbA1c values are the 2 modifiable biological factors associated with the presence of DPN evaluated as an altered SW monofilament test in T2DM subjects.


Immune thrombocytopenia due to Tranilast (Rizaben): detection of drug-dependent platelet-associated IgG.
Tranilast (Rizaben)-induced thrombocytopenia occurring in a 17-year-old man was reported. After withdrawal of the drug, he recovered within a week with oral prednisolone administration. Serological examination revealed no anti-platelet antibody, but platelet-associated IgG (PAIgG) was found. After incubation of peripheral blood of the patient with the drug in vitro, the level of PAIgG was significantly increased. These findings suggest the presence of a drug-dependent anti-platelet IgG in the patient's serum. This is the first report of immune thrombocytopenia caused by Tranilast. Our method for detecting drug-dependent platelet antibody in vitro is safe and useful for diagnosing drug-induced thrombocytopenia.


Word length and error types in Japanese left-sided neglect dyslexia.
Seven patients who showed left-sided neglect in reading single words were examined. Neglect errors typically involved omission of initial letters in our patients. Two patients with enough errors had a tendency that longer words were more susceptible to errors than short words. Most of the patients were less affected than the patients in the previous reports. Japanese people read strings of letters written not only from left to right but also from right to left. The seven patients continued to misread the letters on the left end when asked to read words from right to left. The two patients showed a significant deficit in reading words from left to right compared to reading from right to left.


Interleukin-2-deficient mice develop colitis in the absence of CD28 costimulation.
The intestinal lamina propria contains lymphocytes that are chronically activated by exposure to luminal antigens. Dysregulation of these cells is thought to be central to the pathogenesis of bowel inflammation in experimental models of inflammatory bowel disease. CD28 signals on peripheral T cells provide important costimulatory signals that enhance T-cell proliferation and activation responses to antigens. However, the role of CD28 signals in lamina propria T cells or models of inflammatory bowel disease have not been determined. Accordingly, we examined T lymphocyte activation and proliferation in CD28-deficient (CD28-/-) mice to examine the in vivo roles of CD28 signals in lamina propria T-cell homeostasis. We further generated CD28-/- interleukin (IL)-2-/- double mutant mice to assess the role of CD28 signals in supporting the spontaneously activated and pathogenic T cells that accumulate in IL-2-/- mice. CD28-/- lamina propria T cells displayed reduced activation markers, but were present in normal numbers and proliferated normally. IL-2-/- lymphocytes expressed high levels of bcl-xL, whereas CD28-/- IL-2-/- cells had substantially less bcl-xL. However, lymphadenopathy and ulcerative colitis-like disease occurred in both IL-2-/- and CD28-/- IL-2-/- mice. Thus, CD28 provides a functional costimulatory signal to lamina propria T cells but is not required for homeostasis of these cells. In addition, neither CD28 nor bcl-xL appears to be required for the spontaneous accumulation of T cells in IL-2-/- mice. This suggests that other costimulatory molecules or T-cell receptor ligation alone drive lymphocyte expansion in IL-2-deficient mice.


Both natural and induced murine anti-TNP antibodies possess anti-DNA activity.
Sera of BALB/c mice immunized with either trinitrophenyl (TNP) coupled to bovine serum albumin (TNP/BSA) and Freund's adjuvant or TNP/BSA and TNP coupled to mouse serum albumin (TNP/MSA) without adjuvant were tested for antibody activity against a panel of antigens: TNP/BSA, DNA, actin, myosin, tubulin and transferrin. Anti-DNA antibody activity in the serum increased significantly in immunized mice; this activity followed the increase in the anti-TNP titres. Sera from MRL/lpr/lpr autoimmune mice were also tested for antibody activity against a panel of antigens. Again, it was found that the level of the anti-TNP antibodies followed the level of anti-DNA antibodies. Purified antibodies isolated from both immunized BALB/c and MRL/lpr/lpr mice on a dinitrophenol(DNP)-lysine immunoadsorbent shared antibody activity against both TNP and DNA. The results obtained suggest that a single region in the antibody binding site is responsible for both anti-DNA and anti-TNP activities, that TNP-like groups may represent a "public epitope" carried by various antigens and that antibodies obtained after experimental immunization and antibodies appearing in autoimmunopathological situations apparently possess similar specificities.


Secondary structure prediction of anterior pituitary hormones. Lack of correlation between predicted values and circular dichroism data.
The secondary structures of human somatotropin, human choriomammotropin, ovine and porcine prolactin, human, ovine and porcine beta-lipotropin, human and ovine lutropin, human thyrotropin, human corticotropin, alpha-melanotropin and human beta-melanotropin have been predicted by the method of Chou & Fasman. Predicted contents of alpha-helix and beta-sheet do not correspond well with values estimated from circular dichroism spectra.


Comparison of transcription stimulating, phenol-soluble non-histone chromosomal proteins in normal rat liver and transplantable hepatocellular carcinomas.
The non-histone chromosomal proteins (NHCP) of a rapidly and slowly proliferating transplantable hepatocellular carcinoma (THC) were compared to those of normal and regenerating rat liver. The total quantity of NHCP is approximately threefold higher in the THCs than in either normal rat liver at 4 h and 44 h regenerating rat liver. Only those NHCP that can be extracted from chromatin by 0.35 M NaCl were further examined and it was observed that the proteins of this highly complex fraction could be further fractionated by their differential phenol-solubility. The phenol-soluble 0.35 NHCP contained protein(s) capable of stimulating the level of DNA-directed RNA synthesis in vitro. The total amount of this stimulatory activity was 5 times higher in the rapidly growing THC and 1.6 times higher in the slowly growing THC than in normal rat liver. In order to assess the contribution of cell-cycle dependent alterations on the increase in the amount of stimulatory activity in the THCs, 44 h regenerating rat livers were examined. This tissue represents a mix of cells in various stages of the cell cycle which is similar to that found in the THCs. It was found that the total quantity of NHCP in the 44 h regenerating rat liver was the same as in normal rat liver. The total amount of the stimulatory activity also was similar in both the normal and 44 h regenerating rat liver. The amount of the stimulatory activity was found to double in 4 h regenerating rat liver, however. These data suggest that the alterations observed in the NHCP of the THCs are not due solely to cell cycle dependent changes, but may represent malignancy dependent alterations.


Transesophageal evaluation of asymptomatic Wolff-Parkinson-White syndrome.
Risk stratification for Wolff-Parkinson-White (WPW) by intracardiac electrophysiology study (ICEPS) carries risks related to catheterization. We describe an alternative approach by using transesophageal electrophysiology study (TEEPS). The pediatric electrophysiology database was reviewed for patients with WPW and no documented clinical supraventricular tachycardia (SVT) who underwent risk stratification by TEEPS from October 2005 to November 2010. Of those who underwent subsequent ICEPS, only those with data available to compare accessory pathway (AP) conduction during ICEPS and TEEPS were included. Of 65 patients who underwent TEEPS, 42 were found to have an indication for ablation. The most common indication for ICEPS was inducible SVT, which was induced in 67% of patients. Of 42 patients who underwent subsequent ICEPS, 23 had sufficient data for comparison of AP conduction between ICEPS and TEEPS. There was no difference between the baseline minimum 1:1 antegrade conduction through the accessory pathway found at TEEPS versus ICEPS (312 ± 51 ms vs 316 ± 66 ms, P = 0.5). There was no significant difference between the baseline antegrade AP-effective refractory period found at TEEPS versus ICEPS (308 ± 34 ms vs 297 ± 37 ms, P = 0.07). There were no complications related to TEEPS or ICEPS. TEEPS is a safe and feasible alternative to ICEPS for risk stratification in patients with asymptomatic WPW and should be considered before ICEPS and ablation.


Stimulation of protein synthesis and phospholipase D activity by vasopressin and phorbol ester in L6 myoblasts.
The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and vasopressin on protein synthesis and phospholipase D (PLD) activity were investigated in L6 myoblasts. TPA stimulated a concentration-dependent increase in protein synthesis (EC50 approx. 10 nM) during a 90 min incubation, but had no effect after 6 h. The maximum increase was about 15% and was mediated through changes in translation, as TPA had no effect on RNA accretion and the response was not prevented by actinomycin D. TPA also stimulated PLD activity as measured by an 8-fold increase in the formation of phosphatidylbutanol (PtdBuOH) and the release of choline (EC50 5-10 nM). In contrast to TPA, vasopressin stimulated protein synthesis (maximum increase 30%, EC50 approx. 10 nM) and RNA accretion after 6 h, but had no effect after 90 min. Vasopressin also increased PtdBuOH production 4-5-fold (EC50 approx. 0.5 nM) and choline release (EC50 approx. 1 nM). The addition of a highly purified preparation of PLD (2-10 units/ml) from Streptomyces sp. to L6 cells stimulated a concentration-dependent increase in choline release and protein synthesis after both 90 min (maximum stimulation 13%) and 6 h (maximum stimulation 12%). PLD also stimulated RNA accretion after 6 h but not 90 min. The data support a role for PLD in the regulation of protein synthesis in L6 cells.


Complete structure, genomic organization, and expression of channel catfish (Ictalurus punctatus, Rafinesque 1818) matrix metalloproteinase-9 gene.
In this study, the channel catfish (CC) matrix metalloproteinase-9 (MMP-9) gene was cloned, sequenced, and characterized at both the cDNA and the genomic DNA levels. The complete sequence of the CC MMP-9 cDNA consisted of 2,551 nucleotides, including one open reading frame and 5'- and 3'-end untranslated regions. The open reading frame potentially encoded a 686-amino-acid peptide with a calculated molecular mass (without glycosylation) of approximately 77.4 kDa, which included a signal peptide and potentially heavy O-glycosylation sites. CC MMP-9 did not have the tripeptide Arg-Gly-Asp motif. The degree of conservation of the CC MMP-9 amino acid sequence to human and mouse counterparts was 55%, while to those of other fish species was 67-74%. The full-length CC MMP-9 genomic DNA comprised 5,663 nucleotides, much shorter than human or mouse counterparts. The exon-intron structure followed the splice acceptor/donor consensus rule, and the sequence contained 13 exons. The MMP-9 transcript was constitutively expressed in restrictive CC tissues. This result should provide fundamental information for further exploration of the role of MMP-9 in fish pathophysiology.


Development and internal validation of nomograms based on plasma metabolites to predict non-small cell lung cancer risk in smoking and nonsmoking populations.
Lung cancer has significantly higher incidence and mortality rates worldwide. In this study, we analyzed the metabolic profiles of non-small cell lung cancer (NSCLC) patients and constructed prediction models for smokers and nonsmokers with internal validation. Plasma was collected from all patients enrolled for metabolic profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The total population was divided into two groups according to smoking or not. Statistical analysis of metabolites was performed separately for each group and prediction models were constructed. A total of 1723 patients (1109 NSCLC patients and 614 healthy controls) were enrolled from the affiliated hospital during 2018 to 2021. After grouping by smoking history, each group was statistically analyzed and prediction models were constructed, which resulted in eight indicators (propionylcarnitine, arginine, citrulline, etc.) significantly associated with lung cancer risk for smokers and eight indicators (dodecanoylcarnitine, hydroxybutyrylcarnitine, asparagine, etc.) for nonsmokers (p < 0.05). The smoker model indicated an AUC of 0.860 in the training set and 0.850 in the validation set. The nonsmoker model showed an AUC of 0.783 in the training set and 0.762 in the validation set. Further calibration tests for both models indicated excellent goodness-of-fit results. In this study, we found a series of metabolites significantly associated with lung cancer incidence and constructed respectively prediction models for NSCLC risk in smokers and nonsmokers, with internal validation to confirm the efficiency to discriminate lung cancer risk in both smoking and nonsmoking states.


Effects of the prilocaine and of the association of prilocaine with different vasoconstrictors on the isolated hearts of rats.
This study aimed to observe the effects of prilocaine chloridate (P) and the associations of P with felypressin (P+F), and epinephrine (P+E) on the heart rate and force of contraction on the isolated hearts of rats. The hearts were perfused according to Langendorff's method. The experiments were performed with the following substances: prilocaine (P), felypressin (F), and epinephrine (E). P was used in doses of 1.25, 2.5, and 5.0 mg. The same doses of F and P (1.0, 1.5 and 3.0 microg) were used in association with the P, respectively. Right after the application of the three doses of P, a reduction in the force of contraction was observed, with higher intensity at a higher dose, which led to cardiac arrest. A similar result was obtained with the administration of the three associations of P+F. Also the application of the three associations P+E resulted in a reduction of the force of contraction, that was, however, less intense with the associations of 1.25 mg P + 1.0 microg E and 2.5 mg P+1.5 microg E, as compared to the same doses of P alone and P+F. The two higher doses of P and P+F on the heart rate elicited a significant reduction in relation to the control, but with the associations of P+E no alterations were observed, with any one of the doses used. The results obtained in the present study suggest that an association of P and E must be used in local anesthesia, since epinephrine may well protect the heart from the depressive effects of the anesthetic salts.


Designing sedative/hypnotic compounds from a novel substructural graph-theoretical approach.
A novel approach to computer-aided molecular design is illustrated. This approach is based on the calculation of the spectral moments of the bond adjacency matrix of graphs representing molecular structures. Spectral moments are then expressed as linear combinations of the different sub-structures present in molecules. Two series of compounds, one containing sedative/hypnotic and the other containing different classes of drugs were used to find a discriminant function with the present approach. Several compounds from the Merck Index were identified by the model as sedative/hypnotic, five of them were found in the recent literature as possessing this activity. The critical fragments, actives and inactive ones, were detected.


The effect of body size on animal abundance.
Although it is a commonplace that small animals are more abundant than large ones, few attempts have been made to quantify this and none for non-mammalian species. This study uses estimates of animal density and body mass culled from 12 journals published between 1961 and 1978 to test and extend Damuth's relationship between population density and body size of herbivorous mammals. In general, his analysis is supported, for density usually declines roughly as W -0.75 and poikilotherms maintain higher densities than homeotherms. However the residual variation is higher than Damuth's regressions might suggest and significant differences exist among animal groups. In particular, birds maintain much lower, and aquatic invertebrates much higher abundances than a general curve for all species would suggest. Carnivores are significantly rarer than herbivores. These relationships may be used to compare the average relative contributions of species of different size to community structure and function. Such relations also provide a necessary basis both for more complete empirical analyses of the determinants of animal abundance and for the construction of more realistic conceptual models in theoretical ecology.


Draft Genome Sequence of Bacteroidales Strain TBC1, a Novel Isolate from a Methanogenic Wastewater Treatment System.
We report here the draft genome sequence of Bacteroidales strain TBC1, isolated from a methanogenic wastewater treatment system. The draft genome has a size of 4,514,407 bp and a G+C content of 46.7%. The predicted genomic content provides the basis for characterizing the metabolism and ecological strategies of strain TBC1.


Analysis of tendon tension and hysteresis by tendon twisting and development of anti-twist tendon mechanism of robotic surgical instruments.
Control of the joints of robotic surgical instruments is difficult owing to hysteresis, and tendon twisting due to axial rotation of surgical tools also causes hysteresis. Therefore, a new mechanism is needed to prevent tendon twisting. Tendon tension and hysteresis change were analysed by observing the movement of the joint depending on whether the tendons twisted for the same input signal. An anti-twist tendon mechanism to prevent twisting was developed. A 3-mm needle driver applied with the proposed mechanism was manufactured. The anti-twist mechanism makes no tension change because of twisting or friction between the tendon and the system, that is, the operating performance was the same regardless of rotation. The proposed mechanism has been verified and can be applied to small surgical instruments 3 mm in size. These findings can be applied in the development of instruments for precise surgeries such as microsurgery.


Characterization of an Enterococcus faecium small-colony variant isolated from blood culture.
Small-colony variants (SCVs) of bacteria are slow-growing subpopulations which can cause latent or recurrent infections due to better intracellular survival compared to their wild-type counterparts. Atypical colony morphology and altered biochemical profile may lead to failure in identification of SCV strains. We here report for the first time the isolation of an Enterococcus faecium SCV phenotype. The case of a 65-year-old woman with acute myeloid leukaemia who developed symptoms of sepsis during induction chemotherapy is presented. E. faecium with normal and SCV phenotype was isolated from blood cultures. At the same time urine culture was positive with E. faecium suggesting that bacteraemia originated from the urinary tract. The SCV phenotype was characterized by atypical growth behaviour. Electron microscopic analyses revealed perturbation of the separation of daughter cells and the accumulation of cell wall material. Accordingly, the SCV variant showed a dysfunction or lack of spontaneous autolysis whereas the normal phenotype did not. In contrast to conventional identification systems based on biochemical characteristics, the E. faecium SCV was precisely identified by MALDI-TOF MS analysis implemented in our laboratory. Hence, the increasing use of MALDI-TOF MS analysis for the identification of bacteria might be an appropriate tool for the detection of SCV variants, the diagnosis of which is of importance for the clinical outcome and the antibiotic treatment.


A single step technique for preparation of porous solid phase microextraction fibers by electrochemically co-deposited silica based sol-gel/Cu nanocomposite.
In this study, electrochemically co-deposited 3-trimethoxysilyl propyl methacrylate (3TMSPMA)/Cu nanocomposite is introduced as a novel and single-step technique for preparation of efficient and unbreakable solid phase microextraction (SPME) fibers; having strong interaction between the substrate and the coating. The applicability of prepared nanocomposite films was evaluated through extraction of some aromatic pollutants as model compounds from the headspace of aqueous samples in combination with gas chromatography-mass spectrometry (GC-MS). Different parameters affecting the structure and composition of the deposited films including applied potential, electrodeposition time, and precursor concentration; and the parameters affecting extraction efficiency such as extraction temperature, extraction time, and salt content were investigated. The results showed that morphology and grain size of the films are strongly affected by the ratio between the sol-gel precursor and Cu(2+) ions. Furthermore, potential of deposition influences the composition of films as it controls the kinetics of sol-gel/Cu co-deposition. Finally, characterization of the deposited films was accomplished by scanning electron microscopy (SEM) and thermogravimetric analysis (TGA).


Swelling-induced K(+) fluxes in vascular smooth muscle cells are mediated by charybdotoxin-sensitive K(+) channels.
This study examines the relative contributions of K-Cl cotransport and K(+) channels to swelling-induced K(+) fluxes in vascular smooth muscle cells (VSMC). DIOA known as a potent inhibitor of erythrocyte K-Cl cotransport exerts diverse side-effects on VSMC and can not be used to analyze the role of this carrier in swelling-induced K(+) fluxes. Other inhibitors of K-Cl cotransport (furosemide, okadaic acid and calyculin A) did not affect K(+) fluxes in VSMC triggered by swelling. Swelling-induced K(+) fluxes in VSMC were also not affected by K(+) channel blockers such as TEA, glibenclamide and apamin, but were blocked by Ba(2+) and charybdotoxin (ChTX), a potent inhibitor of Ca(2+)- and voltage-gated K(+) channels. Swelling-induced K(+) influx in VSMC was diminished in Ca(2+)-free medium and in cells loaded with Ca(2+) chelator BAPTA, but was not accompanied by detectable elevation of [Ca(2+)](i). In contrast to Ca(2+)-induced hyperpolarization of erythrocytes triggered by activation of intermediate conductance Ca(2+)-gated K(+) channels (IK(Ca)), neither clotrimazole nor calmodulin antagonists (R24571, trifluoroperazine, fluphenazine) affected swelling-induced K(+) influx in VSMC. In conclusion, K(+) fluxes triggered in swollen VSMC are mediated by Ba(2+)- and ChTX-sensitive K(+) channels. These channels are distinct from IK(Ca) expressed in erythrocytes. Their molecular origin and systems involved in the swelling-induced Ca(2+)(i)-independent signal transduction pathway need further investigation.


Identifying hidden Zika hotspots in Pernambuco, Brazil: a spatial analysis.
Northeast Brazil has the world's highest rate of Zika-related microcephaly. However, Zika case counts cannot accurately describe burden because mandatory reporting was only established when the epidemic was declining in the region. To advance the study of the Zika epidemic, we identified hotspots of Zika in Pernambuco state, Northeast Brazil, using Aedes-borne diseases (dengue, chikungunya and Zika) and microcephaly data. We used Kulldorff's Poisson purely spatial scan statistic to detect low- and high-risk clusters for Aedes-borne diseases (2014-2017) and for microcephaly (2015-2017), separately. Municipalities were classified according to a proposed gradient of Zika burden during the epidemic, based on the combination of cluster status in each analysis and considering the strength of the evidence. We identified 26 Aedes-borne diseases clusters (11 high-risk) and 5 microcephaly clusters (3 high-risk) in Pernambuco. According to the proposed Zika burden gradient, our results indicate that the northeast of Pernambuco and the Sertão region were hit hardest by the Zika epidemic. The first is the most populous area of Pernambuco, while the second has one of the highest rates of social and economic inequality in Brazil. We successfully identified possible hidden Zika hotspots using a simple methodology combining Aedes-borne diseases and microcephaly information.


Broad scleral buckle in the management of retinal detachments with giant tears.
One of us (T.R.S.) operated on 24 patients with 26 retinal detachments caused by giant tears between 1969 and 1975 with the use of a broad silicone implant and diathermy. Minimum follow-up was six months. The technique included a scleral dissection extending at least three circumferential rows of diathermy posterior to the folded edge of the retinal flap, up onto the ora serrata, and two hours of the clock beyond each end of the tear. The retina was intentionally incarcerated on the buckle when subretinal fluid was drained. Sixty-nine percent of the cases were successfully reattached. If those patients with radial tears extending from the circumferential tears to the disk were excluded, the success rate rose to 75%. Seventeen percent of the successful reattachments required a second scleral buckle operation. Giant tears with radial tears extending to the disk, tears greater than 180 degrees, and immobile posteriorly everted flaps were poor prognostic signs. Thirty-five percent of the eyes with giant tears and a detachment had other holes or tears in the retina of that eye.


Presence and absence of virus particles in hybridomas secreting monoclonal antibodies against gliomas.
Hybridoma clones were produced by fusion of splenocytes from glioma-immunized hosts and the X63-Ag8.653 mouse myeloma line and Y3-Ag.1.2.3. rat myeloma line. Oncornavirus particles were found in all clones descending from the mouse myeloma line. No virus particles could be found in either the spleens of immunized Balb/c mice and Fischer rats or in the rat myeloma line and the hybridomas derived from it.


A Weight of Evidence approach to classify nanomaterials according to the EU Classification, Labelling and Packaging Regulation criteria.
In the context of the European Union (EU) Horizon 2020 GRACIOUS project (Grouping, Read-Across, Characterisation and classification framework for regulatory risk assessment of manufactured nanomaterials and Safer design of nano-enabled products), we proposed a quantitative Weight of Evidence (WoE) approach for hazard classification of nanomaterials (NMs). This approach is based on the requirements of the European Regulation on Classification, Labelling and Packaging of Substances and Mixtures (the CLP regulation), which implements the United Nations' Globally Harmonized System of Classification and Labelling of Chemicals (UN GHS) in the European Union. The goal of this WoE methodology is to facilitate classification of NMs according to CLP criteria, following the decision trees defined in ECHA's CLP regulatory guidance. In the WoE, results from heterogeneous studies are weighted according to data quality and completeness criteria, integrated, and then evaluated by expert judgment to obtain a hazard classification, resulting in a coherent and justifiable methodology. Moreover, the probabilistic nature of the proposed approach enables highlighting the uncertainty in the analysis. The proposed methodology involves the following stages: (1) collection of data for different NMs related to the endpoint of interest: each study related to each NM is referred as a Line of Evidence (LoE); (2) computation of weighted scores for each LoE: each LoE is weighted by a score calculated based on data quality and completeness criteria defined in the GRACIOUS project; (3) comparison and integration of the weighed LoEs for each NM: A Monte Carlo resampling approach is adopted to quantitatively and probabilistically integrate the weighted evidence; and (4) assignment of each NM to a hazard class: according to the results, each NM is assigned to one of the classes defined by the CLP regulation. Furthermore, to facilitate the integration and the classification of the weighted LoEs, an online R tool was developed. Finally, the approach was tested against an endpoint relevant to CLP (Aquatic Toxicity) using data retrieved from the eNanoMapper database, results obtained were consistent to results in REACH registration dossiers and in recent literature.


Synthesis and hybridization properties of oligonucleotides containing (2S,3R)-9-(2,3,4-trihydroxybutyl)adenine.
The synthesis and properties of oligonucleotides (ONs) containing 9-(2,3,4-trihydroxybutyl)adenine, A(C2) and A(C3), are described. The ON containing A(C2) involves the 3'-->4' and 3-->5' phosphodiester linkages in the strand, whereas that containing A(C3) possesses the 3'-->4' and 2'-->5' phosphodiester linkages. It was found that incorporation of the analogs, A(C2) or A(C3), into ONs significantly reduces the thermal and thermodynamic stabilities of the ON/DNA duplexes, but does not largely decrease the thermal and thermodynamic stabilities of the ON/RNA duplexes as compared with the case of the ON/DNA duplexes. It was revealed that the base recognition ability of A(C2) is greater than that of A(C3) in the ON/RNA duplexes.


Does emissions trading affect labor demand? Evidence from the mining and manufacturing industries in China.
We use "China's sulfur dioxide (SO2) emissions trading program" as a quasi-natural experiment to identify the causal effect of this market-based environmental regulation on firm's labor demand. Based on the difference-in-differences (DID) method and a series of robustness tests, we observe robust evidence that the emissions trading program significantly increases the labor demand of regulated firms, and that this positive employment effect is driven by the expansion of firm's production scale. The observable evidence leads us to cautiously conclude that the market-based environmental regulations in even developing countries could achieve the double dividend of coexistence of environmental protection and employment growth.


Alterations of hepatocyte Ca2+ homeostasis by triethylated lead (Et3Pb+): are they correlated with cytotoxicity?
Isolated rat hepatocytes were used to investigate the biochemical mechanisms of toxicity of triethyllead (Et3Pb+), a highly neurotoxic degradation product of the antiknocking petrol additive tetraethyllead. As early as 5 min from the addition of 50 microM Et3Pb+ to hepatocyte suspensions a decrease of mitochondrial membrane potential and of the capacity of mitochondria and microsomes to retain Ca2+ occurred. A dose-dependent release of mitochondrial Ca2+ as well as an inhibition of microsomal Ca(2+)-ATPase activity were also evident when Et3Pb+ (from 2.5 microM up to 50 microM) was added to, respectively, isolated liver mitochondria and microsomes. Further experiments using hepatocytes loaded with the Ca2+ indicator Fura-2AM demonstrate that 1 min from addition of Et3Pb+ the cytosolic free Ca2+ levels increased by about 3-fold. High affinity plasma membrane Ca(2+)-ATPase activity was also significantly inhibited in hepatocytes treated with Et3Pb+, suggesting that an impairement of the mechanisms controlling the efflux of extracellular Ca2+ was concomitantly involved in the rise in cytosolic Ca2+ concentration. The increase in the cytosolic Ca2+ levels caused by Et3Pb+ was followed by a rapid decline of cell viability. However, the addition of EGTA or of the intracellular Ca2+ chelator BAPTA/AM did not affect either the time-course or the extent of cytotoxicity. Conversely, fructose, a glycolytic substrate that was able to support ATP production, prevented hepatocyte death. Thus, the depletion of cellular energy stores rather than the increase in cytosolic Ca2+ appears to be the mechanism by which Et3Pb+ causes irreversible injury in isolated hepatocytes.


Ghent developmental balance test: a new tool to evaluate balance performance in toddlers and preschool children.
Balance is a fundamental component of movement. Early identification of balance problems is important to plan early intervention. The Ghent Developmental Balance Test (GDBT) is a new assessment tool designed to monitor balance from the initiation of independent walking to 5 years of age. The purpose of this study was to establish the psychometric characteristics of the GDBT. To evaluate test-retest reliability, 144 children were tested twice on the GDBT by the same examiner, and to evaluate interrater reliability, videotaped GDBT sessions of 22 children were rated by 3 different raters. To evaluate the known-group validity of GDBT scores, z scores on the GDBT were compared between a clinical group (n = 20) and a matched control group (n = 20). Concurrent validity of GDBT scores with the subscale standardized scores of the Movement Assessment Battery for Children-Second Edition (M-ABC-2), the Peabody Developmental Motor Scales-Second Edition (PDMS-2), and the balance subscale of the Bruininks-Oseretsky Test-Second Edition (BOT-2) was evaluated in a combined group of the 20 children from the clinical group and 74 children who were developing typically. Test-retest and interrater reliability were excellent for the GDBT total scores, with intraclass correlation coefficients of .99 and .98, standard error of measurement values of 0.21 and 0.78, and small minimal detectable differences of 0.58 and 2.08, respectively. The GDBT was able to distinguish between the clinical group and the control group (t(38) = 5.456, P<.001). Pearson correlations between the z scores on GDBT and the standardized scores of specific balance subscales of the M-ABC-2, PDMS-2, and BOT-2 were moderate to high, whereas correlations with subscales measuring constructs other than balance were low. The GDBT is a reliable and valid clinical assessment tool for the evaluation of balance in toddlers and preschool-aged children.


Comparison of the corticotropic action of two synthetic, substituted analogues of ACTH: ACTH1--17 and ACTH1--18.
The effect of a recently synthesized analogue of ACTH, Ala1, lys17-ACTH(1-17-4-amino-n-butylamide; (ACTH1-17) upon serum cortisol levels in 9 healthy males was compared with that of ACTH1-18, D-ser1-lys17, 18-ACTH(1-18). Both compounds induced an identical rise in serum cortisol which lasted for at least 8 hours. It is concluded that the amino acid in position 18 is not essential for the corticotropic properties of the synthetic heptadecapeptide. The prolonged effect of these compounds indicates a potential therapeutic significance for ACTH analogues of low molecular weight.


[Staining properties and applicability of spectrally pure thionine and its isomeres (author's transl)].
Paraffin-embedded human and animal tissues were stained with spectrally pure thionine, 1,3-diaminophenthiazoniumchlorate and 1,7-diaminophenthiazoniumperchlorate. They were examined by light microscopy to determine their applicability in histologic diagnosis. Furthermore the effect of salts and of the type of dye solvent on the staining properties of histological preparations was being investigated. Essentially the following results were obtained: 1. All 3 dyes can be applied rapidly and unproblematically on all types of tissues. Under standardized conditions, i.e. dye concentration, length of staining time and kind of staining procedure, the results are reproducable. 2. Thionine and its isomeres, being basic dyes, demonstrate a special affinity for nuclei, but also do stain cytoplasm sufficiently well to make counter-staining methods unnecessary. 3. Thionine -- in contrary to its isomeres -- reacts metachromatically with certain cellular structural elements, i.e. RNA, acid mucopolysaccharides, mucin. This property aids in morphological diagnosis and additionally enlightens certain activity states. 4. Addition of salts interferes with the staining procedure. 5. Water has special significance as solvent. Furthermore the appearance and function of metachromasia, the influence of ethanol on the metachromatic reaction, the mode of action of anorganic salts are being discussed as well as the reciprocal action of biologic substrates with the dyes having been incorporated by them.


Identification of the Binding Site of Chroman-4-one-Based Sirtuin 2-Selective Inhibitors using Photoaffinity Labeling in Combination with Tandem Mass Spectrometry.
Photoaffinity labeling (PAL) was used to identify the binding site of chroman-4-one-based SIRT2-selective inhibitors. The photoactive diazirine 4, a potent SIRT2 inhibitor, was subjected to detailed photochemical characterization. In PAL experiments with SIRT2, a tryptic peptide originating from the covalent attachment of photoactivated 4 was identified. The peptide covers both the active site of SIRT2 and the proposed binding site of chroman-4-one-based inhibitors. A high-power LED was used as source for the monochromatic UV light enabling rapid photoactivation.


Mannan-binding lectin levels related to spontaneous abortion in Brazilian patients with celiac disease.
Low concentration of mannan-binding lectin (MBL) has been related to unexplained spontaneous abortion (SA), which has also been observed in an increased frequency in patients with celiac disease (CD). In this study, plasma levels of MBL were determined in patients with CD and irritable bowel syndrome (IBS) in order to investigate whether there is an association of MBL levels and the occurrence of SA in these patients. MBL concentration was determined in 46 patients with CD (28 without and 18 with report of SA) and 38 patients with IBS (25 without and 13 with report of SA). A higher frequency of SA was observed in women with CD when compared to IBS patients (23.2 vs. 13.9%; P = 0.046). No significant difference was observed in MBL concentrations between patients with CD, IBS, and healthy controls, nor between patients with or without occurrence of SA. These results suggest that the serum levels of MBL and the occurrence of SA in women with CD and IBS are not causally related.


Prostaglandin E2 induced changes in renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat.
Prostaglandin E2, when infused into the renal artery of the dog, is a vasodilator and increases both renal interstitial hydrostatic pressure and sodium excretion. Similar studies in the rat, however, have been inconclusive. The present study examined the effect of prostaglandin E2 infusion into the renal interstitium, by means of a chronically implanted matrix, on renal blood flow, renal interstitial hydrostatic pressure and sodium excretion in the rat. Prostaglandin E2 was continuously infused directly into the kidney interstitium to mimic endogenous prostaglandin E2 production by renal cells. The maximum change in each of these parameters occurred when 10(-5) M PGE2 was infused. Renal blood flow increased from 4.70 +/- 0.91 to 5.45 +/- 0.35 ml/min (p less than 0.05) while renal interstitial hydrostatic pressure decreased from 3.9 +/- 0.4 to 2.6 +/- 0.5 mmHg (p less than 0.05) and fractional excretion of sodium decreased from 1.02 +/- 0.20 to 0.61 +/- 0.12% (p less than 0.05). Thus, the present study demonstrates that renal interstitial infusion of prostaglandin E2 increases total renal blood flow but decreases both renal interstitial hydrostatic pressure and urinary sodium excretion in the rat.


Organellar lipidomics--background and perspectives.
The basic structural units of eukaryotic cells are membrane-bound organelles and many essential cellular processes take place in and on membranes. It is becoming increasingly clear that these processes are influenced by the biophysical properties of the organelle membranes, which in turn are affected by their lipid composition. Even subtle changes in lipid composition can have a tremendous impact on membrane properties and the processes occurring within them. Therefore, in order to understand the contribution of membrane lipid composition to the functionality of membrane-bound cellular processes, comprehensive structural and quantitative information on the organellar lipidome is essential. Here we argue that only mass spectrometry-based organellar lipidomics can provide this information today.


Human papillomavirus testing for primary cervical cancer screening.
With our understanding of human papillomavirus (HPV) and cervical cancer, the availability of HPV testing, and the known limitations of cervical cytology, it is time to reassess cervical cancer screening technologies. This article reviews recent randomized trials comparing primary HPV testing with cervical cytology in screening for cervical cancer, and also analyzes the impact of the HPV vaccine on screening cytology.


Neck pain driving index: appropriateness of the rating scale and unidimensionality of the strategic, tactical, and operational levels.
To establish an appropriate scoring system using Rasch scores for the strategic, tactical, and operational levels of the Neck Pain Driving Index (NPDI) and to refine the NPDI by testing the unidimensionality of each driving performance level using Rasch analysis. Cross-sectional. Tertiary institution. Individuals with chronic whiplash-associated disorders (WAD) (N=123). Not applicable. The NPDI, which was developed to evaluate self-reported driving difficulty in people with chronic WAD. On the basis of Rasch analyses, modifications were made to the response format, changing it from a 0 to 4 scale (0=no difficulty, 1=slight difficulty, 2=moderate difficulty, 3=great difficulty, 4=unable to drive because of the injury) to a 0 to 3 scale (0=no difficulty, 1=slight difficulty, 2=moderate difficulty, 3=great difficulty and unable to drive because of the injury). Unidimensionality of the strategic and operational levels was confirmed. Modification of the tactical level was necessary to ensure its unidimensionality. After removing the tasks "driving near (your) collision site," "driving in a bad weather condition," and "driving at night," unidimensionality of the 4-item tactical level was confirmed. A 9-item NPDI was established. A table converting raw total scores into Rasch scores was created for each level. This study established the 9-item NPDI, and its 3 subsections (strategic, tactical, and operational levels) are unidimensional. The magnitude of self-reported driving difficulty at each of the 3 subsections can be assessed with the use of a 0 to 3 scale and Rasch scores.


The unexpected origin of plasmaspheric hiss from discrete chorus emissions.
Plasmaspheric hiss is a type of electromagnetic wave found ubiquitously in the dense plasma region that encircles the Earth, known as the plasmasphere. This important wave is known to remove the high-energy electrons that are trapped along the Earth's magnetic field lines, and therefore helps to reduce the radiation hazards to satellites and humans in space. Numerous theories to explain the origin of hiss have been proposed over the past four decades, but none have been able to account fully for its observed properties. Here we show that a different wave type called chorus, previously thought to be unrelated to hiss, can propagate into the plasmasphere from tens of thousands of kilometres away, and evolve into hiss. Our new model naturally accounts for the observed frequency band of hiss, its incoherent nature, its day-night asymmetry in intensity, its association with solar activity and its spatial distribution. The connection between chorus and hiss is very interesting because chorus is instrumental in the formation of high-energy electrons outside the plasmasphere, whereas hiss depletes these electrons at lower equatorial altitudes.


Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells.
Non-small cell lung cancer (NSCLC) is a global health concern. NSCLC treatment outcomes are generally poor due to treatment resistance or toxicity. Ferroptosis is a novel cell death triggered by iron accumulation, reactive oxygen species (ROS), and lipid peroxidation. Ferroptosis may kill cancer cells, particularly those resistant to apoptosis. The Cell Counting Kit-8 assay assessed NSCLC cell viability after trabectedin treatment. Flow cytometry with Annexin V-FITC staining evaluated cell death. ROS, iron, lipid peroxidation, and GSH levels were measured using commercial kits. qRT-PCR and western blots evaluated messenger RNA and protein levels. Proteins were inhibited using short interfering RNA transfection and specific inhibitors. Trabectedin was cytotoxic to NSCLC cells regardless of p53 status. Trabectedin upregulated iron, ROS, and lipid peroxidation in NSCLC cells, causing ferroptosis. Trabectedin increases iron and ROS levels by upregulating transferrin receptor 1 and the HIF-1/IRP1 axis. In NSCLC cells, trabectedin suppresses glutathione peroxidase 4, followed by the Keap1/Nrf2 axis. Our findings imply that trabectedin may treat NSCLC effectively.


Bioaugmentation with methanogenic culture to improve methane production from chicken manure in batch anaerobic digestion.
This study sought to investigate the effect of bioaugmentation on batch anaerobic digestion of chicken manure. The digestion performance with and without bioaugmentation and bioaugmented efficiency under different dosages were compared. The results demonstrated that bioaugmentation increased the methane yield and shortened the methane production time in batch reactors. Compared to the un-bioaugmented control, the methane yield of bioaugmented digesters was increased by 1.2-, 1.7-, 2.2-, 3.4-, and 3.6-fold at addition ratios of 0.07, 0.14, 0.21, 0.27, and 0.34 g VS bioaugmentation seed (BS)/g VSCM, respectively. However, higher bioaugmentation doses (0.34 g VSBS/g VSCM) did not exhibit significantly improved bioaugmentation efficiency, thus, the recommended dose is 0.27 g VSBS/g VSCM for biomethane conversion of CM. Moreover, whole genome pyrosequencing revealed that Methanoculleus and Methanobrevibacter predominated the non-bioaugmentation digesters, whereas Methanothrix, Methanobacterium, and Methanomassiliicoccus were the dominant methanogens in bioaugmentation digesters. The increased methane may be explained by an increase in the Methanothrix population, which accelerated acetic acid degradation. With bioaugmentation the mainly methanogenic pathways have become more diverse. From gene function perspective, bioaugmentation enhanced metabolic activities in digestor which function better in metabolism.


Patterns of Cortical Oscillations Organize Neural Activity into Whole-Brain Functional Networks Evident in the fMRI BOLD Signal.
Recent findings from electrophysiology and multimodal neuroimaging have elucidated the relationship between patterns of cortical oscillations evident in EEG/MEG and the functional brain networks evident in the BOLD signal. Much of the existing literature emphasized how high-frequency cortical oscillations are thought to coordinate neural activity locally, while low-frequency oscillations play a role in coordinating activity between more distant brain regions. However, the assignment of different frequencies to different spatial scales is an oversimplification. A more informative approach is to explore the arrangements by which these low- and high-frequency oscillations work in concert, coordinating neural activity into whole-brain functional networks. When relating such networks to the BOLD signal, we must consider how the patterns of cortical oscillations change at the same speed as cognitive states, which often last less than a second. Consequently, the slower BOLD signal may often reflect the summed neural activity of several transient network configurations. This temporal mismatch can be circumvented if we use spatial maps to assess correspondence between oscillatory networks and BOLD networks.


Prematurely aging female mice improve their behavioural response, immunity, redox state, and lifespan after a short social interaction with non-prematurely aging mice.
Adult prematurely aging mice (PAM), characterized by inadequate stress response, show premature immunosenescence and shorter lifespan compared to adult exceptional non-PAM (E-NPAM). Aging can be influenced by lifestyle factors, such as social environment. The continuous cohabitation of female PAM with E-NPAM improved behavioral responses, immunity, redox state, and longevity of PAM, but caused deterioration in E-NPAM. The objective of this study was to investigate whether the social interaction of only 15 min/day for 2 months of PAM with E-NPAM, can produce that improvement in PAM without causing deterioration in E-NPAM. After that short social interaction PAM and E-NPAM were submitted to behavioral tests and peritoneal leukocytes were collected to assess immune functions, oxidative and inflammatory state parameters as well as catecholamine concentrations. The lifespan of each animal was recorded. Plasmatic concentration of oxytocin was also studied. Results showed that PAM presented better behavioral responses, immunity and oxi-inflammatory state after interacting with E-NPAM, and consequently a longer lifespan. E-NPAM, in general, did not show any changes after interaction with PAM, not affecting their longevity either. In conclusion, a short social interaction between PAM and E-NPAM could be an excellent strategy for improving the health state and longevity of PAM without causing deleterious effect on E-NPAM.


Not just quantity: gluteus maximus muscle characteristics in able-bodied and SCI individuals--implications for tissue viability.
Some individuals with spinal cord injury (SCI) remain pressure ulcer (PU) free whilst others experience a recurring cycle of tissue breakdown. Detailed analysis of gluteal muscle characteristics may provide insights to local tissue viability variability. The study hypothesis was that SCI individuals have altered muscle composition compared to able-bodied (AB). Ten AB and ten SCI received a supine pelvic CT scan, with contrast. Cross-sectional area (CSA) and overall muscle volume were derived using image analysis. Gluteal muscle tissue type was classified at the S2/S3 sacral vertebrae midpoint, the superior greater trochanters margin (GT) and the inferior ischial tuberosities margin (IT) using the linear transformation Hounsfield Unit scale. SCI gluteal CSA was less than for AB throughout the muscle, with the greatest relative atrophy at the IT (48%). Average AB gluteal volume was nearly double SCI. Eight SCI had over 20% infiltrative adipose tissue, three with over 50%. SCI gluteal CSA and intramuscular fat infiltration were significantly negatively correlated (p < 0.05). SCI IT axial slices showed less lean muscle and higher intramuscular fat infiltration than more proximally (p < 0.05). SCI gluteal muscle characteristics were indicative of impaired tissue viability. SCI disuse muscle atrophy was anticipated; the analytic approach further indicated that intramuscular atrophy was not uniform. SCI muscle composition showed increased proportions of both low density muscle and adipose tissue. CT scan with contrast is effective for gluteal muscle characterization. This assessment technique may contribute to determination of personalized risk for PU development and other secondary complications.


A community split among dolphins: the effect of social relationships on the membership of new communities.
Little is known about community splitting among dolphins because such events are rare in dolphin populations. A case of a community split was confirmed in a population of Indo-Pacific bottlenose dolphins (Tursiops aduncus) in Japan, where a group of approximately 30 dolphins moved to a new habitat some 60 km from the original habitat. We examined the associations among the dolphins before the community split to determine whether the new community members were already socially different before the split, using 7-year identification data. Before the split, the males in the same community after the split more often associated with each other than they did with those in different community. In contrast, the association patterns among females and between sexes showed no relationships with their post-split community membership. These results indicate that the males of new community were socially different from the other males for a long time before the split, but the females might not have been different. Our findings suggest that at time of the community split, the factors determining the memberships of the subsequent communities are sex-linked. The long-term social relationships among males could be maintained in the subsequent communities.


Giant keystone type III perforator flaps for dermatofibrosarcoma protuberans defect reconstruction.
Dermatofibrosarcoma protuberans (DFSP) is a relatively rare malignant tumor, with important local aggressiveness. We present a case of a 59-years-old man with a history of Psoriasis and viral hepatitis C presented in our department with a giant lesion on the posterior trunk, of 24/36 cm, with pus and local bleeding, causing important anemia. The tumor was excised, creating an elliptical defect of around 34 × 42 cm down to fascial level, which was covered by two lateral flaps - modified Keystone type III. The flaps were completely viable and integrated with small dehiscence, which were assisted to heal secondarily. Our paper presents a reliable alternative to skin grafting for a very large defect on the posterior trunk, the modified type III keystone flap, to our knowledge, for the first time presented for such a wide defect and on adult.


Anconeus epitrochlearis muscle (epitrochlearisanconeus muscle; Musculus epitrochleoanconeus) with cubital tunnel syndrome - a rare but relevant clinical entity.
Compression of the ulnar nerve at the elbow within the cubital tunnel is related to the anatomical structures and is generally believed to be caused by Osborne's ligament (also known as the cubital retinaculum). However, in rare cases an anatomical variation of the developmental peculiarity of a remaining anconeus epitrochlearis muscle may be responsible for the disease. We present a series of five cases in which an anconeus epitrochlearis muscle was found as the cause of illness. All patients presented with typical symptoms of numbness and tingling in the hand and ulnar fingers, and recurring pain as well as weakness of the ulnar innervated muscles. With neurophysiologically confirmed diminished nerve conduction velocity and unsuccessful conservative treatment, surgical decompression revealed an anconeus epitrochlearis muscle as the reason of compression. Full symptom relief was achieved immediately after the procedure in all cases. This article strives to call attention to this entity when diagnosing ulnar nerve compression. Myectomy and medial epicondylectomy is the preferred treatment option in such cases.


Effects of prenatal acetaminophen exposure at different stages, doses and courses on articular cartilage of offspring mice.
Previous studies showed that chondrodysplasia has intrauterine origin. Although prenatal acetaminophen exposure (PAcE) can cause nervous and reproductive abnormalities in offspring, its effect on cartilage is uninvestigated. Herein, mice were treated with different doses and courses of acetaminophen at various gestational stages (100 or 400 mg/kg∙d on gestational days 10-12 (GD10-12), 400 mg/kg∙d on GD12 or GD15-17) based on clinical administration and conversion between humans and mice. Fetal knee joints were harvested on GD18 to analyze cartilage morphology, chondrocyte proliferation and apoptosis, and matrix content, synthesis and degradation. Results showed that 400 mg/kg∙d acetaminophen exposure during GD10-12 decreased chondrocyte numbers, safranin O staining, proliferation and matrix synthesis, without elevating matrix degradation and apoptosis. Low-dose, single-course, or late-pregnancy exposure had no effect on above indexes. Moreover, Tgfβ pathway was inhibited, showing a positive correlation with the expression of Col2a1, Acan, Ki67, and Pcna. Overall, clinical doses of PAcE can inhibit chondrocyte proliferation and matrix synthesis, causing fetal mice chondrodysplasia, especially after multi-course exposure of 400 mg/kg∙d acetaminophen during GD10-12, the mechanism of which might involve Tgfβ pathway inhibition. This study provides an experimental basis for assessing fetal developmental toxicity and standardizing the clinical use of acetaminophen during pregnancy.


Metastatic uterine fibroid in postmenopausal woman suspected of leiomyosarcoma: A case report and literature review.
Benign metastatic leiomyoma is a unique event presenting most commonly in premenopausal women especially those with a previous history of gynecological surgery as management of uterine fibroids. In this case report, we investigate a rare case of benign metastatic leiomyoma in a 54-year-old postmenopausal female presented with a huge pelvic mass that was rapidly growing along with pulmonary nodules. The patient is suspected to have leiomyosarcoma which is eventually confirmed pathologically as benign metastatic leiomyoma. Although rare, describing the challenging diagnostic and management approach of such entity is essential and to consider it one of the differential diagnoses of patients who present with similar history.


Plasma glucose regulation and insulin secretion in hypertriglyceridemic mice.
In this study, we examined glucose homeostasis and insulin secretion in transgenic mice overexpressing the human apolipoprotein CIII gene (apo CIII tg). These mice have elevated plasma levels of triglycerides, FFA and cholesterol compared to control mice. The body weight, plasma glucose, and insulin levels, glucose disappearance rates, areas under the ipGTT curve for adult (4 - 8 mo. old) and aged (20 - 24 mo. old) apo CIII tg mice and the determination of insulin during the ipGTT were not different from those of control mice. However, an additional elevation of plasma FFA by treatment with heparin for 2 - 4 h impaired the ipGTT responses in apo CIII tg mice compared to saline-treated mice. The glucose disappearance rate in heparin-treated transgenic mice was slightly lower than in heparin-treated controls. Glucose (22.2 mmol/l) stimulated insulin secretion in isolated islets to the same extent in saline-treated control and apo CIII tg mice. In islets from heparin-treated apo CIII tg mice, the insulin secretion at 2.8 and 22.2 mmol glucose/l was lower than in heparin-treated control mice. In conclusion, hypertriglyceridemia per se or a mild elevation in FFA did not affect insulin secretion or insulin resistance in adult or aged apo CIII tg mice. Nonetheless, an additional elevation of FFA induced by heparin in hypertriglyceridemic mice impaired the ipGTT by reducing insulin secretion.


Comparison of DNA binding between the carcinogen 2,6-dinitrotoluene and its noncarcinogenic analog 2,6-diaminotoluene.
We used 32P-postlabelling to compare DNA binding between the potent hepatocarcinogen 2,6-dinitrotoluene and its noncarcinogenic analog 2,6-diaminotoluene. The two compounds were compared to determine whether differences in DNA binding could partly explain the differences in their carcinogenicity. Fischer-344 rats were administered 1.2 mmol/kg of a compound by single i.p. injection and examined for DNA adduct formation in the liver. Four adducts were detected following administration of 2,6-dinitrotoluene, with a total adduct yield of 13.5 adducted nucleotides per 10(7) nucleotides. Qualitatively identical adducts were also detected after treatment with the derivative 2-amino-6-nitrotoluene. Adduct yields from 2,6-dinitrotoluene were 30 times greater than from 2-amino-6-nitrotoluene. No adducts were observed following treatment with 2,6-diaminotoluene. 2,6-Dinitrotoluene and 2,6-diaminotoluene were also compared for qualitative differences in hepatotoxicity. 2,6-Dinitrotoluene produced extensive hemorrhagic necrosis in the liver, whereas no evidence of hepatocellular necrosis was detected following administration of the latter. The differences between the two compounds in both DNA binding and cytotoxicity were consistent with the differences in their carcinogenicity.


S4(13)-PV cell-penetrating peptide induces physical and morphological changes in membrane-mimetic lipid systems and cell membranes: implications for cell internalization.
The present work aims to gain insights into the role of peptide-lipid interactions in the mechanisms of cellular internalization and endosomal escape of the S4(13)-PV cell-penetrating peptide, which has been successfully used in our laboratory as a nucleic acid delivery system. A S4(13)-PV analogue, S4(13)-PVscr, displaying a scrambled amino acid sequence, deficient cell internalization and drug delivery inability, was used in this study for comparative purposes. Differential scanning calorimetry, fluorescence polarization and X-ray diffraction at small and wide angles techniques showed that both peptides interacted with anionic membranes composed of phosphatidylglycerol or a mixture of this lipid with phosphatidylethanolamine, increasing the lipid order, shifting the phase transition to higher temperatures and raising the correlation length between the bilayers. However, S4(13)-PVscr, in contrast to the wild-type peptide, did not promote lipid domain segregation and induced the formation of an inverted hexagonal lipid phase instead of a cubic phase in the lipid systems assayed. Electron microscopy showed that, as opposed to S4(13)-PVscr, the wild-type peptide induced the formation of a non-lamellar organization in membranes of HeLa cells. We concluded that lateral phase separation and destabilization of membrane lamellar structure without compromising membrane integrity are on the basis of the lipid-driven and receptor-independent mechanism of cell entry of S4(13)-PV peptide. Overall, our results can contribute to a better understanding of the role of peptide-lipid interactions in the mechanisms of cell-penetrating peptide membrane translocation, helping in the future design of more efficient cell-penetrating peptide-based drug delivery systems.


A stochastic hierarchical model for low grade glioma evolution.
A stochastic hierarchical model for the evolution of low grade gliomas is proposed. Starting with the description of cell motion using a piecewise diffusion Markov process (PDifMP) at the cellular level, we derive an equation for the density of the transition probability of this Markov process based on the generalised Fokker-Planck equation. Then, a macroscopic model is derived via parabolic limit and Hilbert expansions in the moment equations. After setting up the model, we perform several numerical tests to study the role of the local characteristics and the extended generator of the PDifMP in the process of tumour progression. The main aim focuses on understanding how the variations of the jump rate function of this process at the microscopic scale and the diffusion coefficient at the macroscopic scale are related to the diffusive behaviour of the glioma cells and to the onset of malignancy, i.e., the transition from low-grade to high-grade gliomas.


Into the dark.
A European space telescope sets off to discover the nature of dark energy-the biggest ingredient in the universe.


Deplasticizing or etching of epoxy sections with different concentrations of sodium ethoxide to enhance the immunogold labeling.
The study's purpose was to obtain improved "deplasticizing" of epoxy sections for immunoelectron microscopy. Epoxy-embedded renal swine tissue with immune complex deposits was used. Ultrathin sections were mounted on uncoated grids or on carbon-stabilized formvar grids. The sections were exposed to different concentrations of sodium ethoxide, and they were subjected to immunogold labeling with anti-IgG. Etching with > or =8% of saturated solution gave completely deplasticized sections. Sections etched with 2-4% solution were only partly deplasticized, but these sections were detached if mounted on uncoated grids, and the yields of immunolabeling were significantly decreased compared with the deplasticized ones. Sections exposed to < or =1% solution were not detached from the uncoated grids. Double-sided labeling of uncoated sections etched with 1% solution yielded approximately the same immunolabeling as for the completely deplasticized formvar-supported sections, and they gave better ultrastructural preservation of the tissue. We have established that etching epoxy sections on non-supported grids with a diluted solution of sodium ethoxide may be preferable for immunoelectron microscopy.


Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells.
Coptisine is isoquinoline alkaloid derived from Coptidis Rhizoma and is known to have potential anti-cancer activity toward various carcinomas. Targeting autophagy is one of the main approaches for cancer therapy, but whether the anti-cancer efficacy of coptisine involves autophagy is still unclear. Therefore, this study investigated the effect of coptisine on autophagy in hepatocellular carcinoma (HCC) Hep3B cells, and identified the underlying mechanism. Our results showed that coptisine increased cytotoxicity and autophagic vacuoles in a concentration-dependent manner. Furthermore, the expressions of light chain 3 (LC3)-I/II, Beclin-1 and autophagy genes were markedly increased by coptisine, while the expression of p62 decreased. In addition, we found that pretreatment with bafilomycin A1, an inhibitor of autophagosome-lysosome fusion, markedly reduced coptisine-mediated autophagic cell death, but 3-methyladenine, an inhibitor for autophagosome formation did not. Moreover, our results showed that although coptisine up-regulated AMP-activated protein kinase (AMPK) that partially induced LC3-I/II, coptisine-mediated AMPK signaling did not directly regulate autophagic cell death. Additionally, we found that coptisine suppressed the phosphorylation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), and this effect was notably enhanced by PI3K inhibitor LY294002. Meanwhile, coptisine significantly increased both the production of mitochondrial reactive oxygen species (ROS) and the recruitment of mitophagy-regulated proteins to mitochondria. Furthermore, N-acetylcysteine, a potential ROS scavenger, substantially suppressed the expression of mitophagy-regulated proteins and LC3 puncta by coptisine. Overall, our results demonstrate that coptisine-mediated autophagic cell death was regulated by PI3K/Akt/mTOR signaling and mitochondrial ROS production associated with mitochondrial dysfunction. Taken together, these findings suggest that coptisine exerts its anti-cancer effects through induction of autophagy in HCC Hep3B cells.


Complete remission of nephrotic syndrome of hepatitis B virus-associated membranous glomerulopathy after lamivudine monotherapy.
We present the case of a 22-year-old male with chronic hepatitis B virus (HBV) infection, who developed nephrotic syndrome and had complete remission after lamivudine monotherapy. Renal biopsy showed membranous glomerulopathy, and the serum titer of HBV DNA increased to 1,130,000 copies/mL. As symptomatic therapy with angiotensin converting enzyme inhibitors did not improve the nephrotic syndrome, lamivudine 100 mg per day was started. His alanine aminotransferase level normalized 2 months after treatment, then hepatitis B e antigen seroconversion developed and serum HBV DNA became undetectable. His proteinuria improved subsequently and his leg edema disappeared completely 6 months after treatment. Neither hepatitis nor nephrotic syndrome had relapsed by month 13 when he came for follow-up. This suggests that lamivudine monotherapy may induce and maintain complete remission of membranous glomerulopathy associated with hepatitis B.


Difficult and complicated oral ulceration: an expert consensus guideline for diagnosis.
The complexity of oral ulcerations poses considerable diagnostic and therapeutic challenges to oral specialists. The expert consensus was conducted to summarize the diagnostic work-up for difficult and complicated oral ulcers, based on factors such as detailed clinical medical history inquiry, histopathological examination, and ulceration-related systemic diseases screening. Not only it can provide a standardized procedure of oral ulceration, but also it can improve the diagnostic efficiency, in order to avoid misdiagnosis and missed diagnosis.


Anger and hostility predict the development of atrial fibrillation in men in the Framingham Offspring Study.
Conflicting findings in the literature with regard to the ability of type A behavior, expressions of anger, or hostility to predict incident coronary heart disease (CHD) have created controversy. In addition, there are no prospective studies relating these characteristics to the development of atrial fibrillation (AF). From 1984 to 1987, 3873 men and women, 18 to 77 years of age, participating in the Framingham Offspring Study, were examined and monitored for 10 years for the incidence of CHD, AF, and total mortality. Measures of type A behavior, anger, hostility, and risk factors for CHD and AF were collected at the baseline examination. After controlling for age, diabetes, hypertension, history of myocardial infarction, history of congestive heart failure, and valvular heart disease in Cox proportional hazards models, trait-anger (RR=1.1; 95% CI, 1.0 to 1.4; P=0.04), symptoms of anger (RR=1.2; 95% CI, 1.0 to 1.4; P=0.008), and hostility (RR=1.3; 95% CI, 1.1 to 1.5; P=0.003) were predictive of 10-year incidence of AF in men. After controlling for risk factors for CHD, none of the measures of anger, type A behavior, or hostility were related to incident CHD; however, trait-anger (RR=1.2; 95% CI, 1.1 to 1.4; P<0.01) was related to total mortality in men. None of the psychosocial variables were related to the 3 outcomes in women. This is the first study to examine and demonstrate a predictive relation between measures of anger and hostility to the development of AF in men. As opposed to type A behavior, measures of anger and hostility may be more productive avenues for research in studying the risk of arrhythmias and total mortality in men.


Can the use of the CROS system provide head shadow effect contribution to unilateral Cochlear Implant Users?
The aim of this study was to evaluate the contribution of the CROS system on the head shadow effect in unilateral implant users. Prospective cross-sectional study, approved by the ethics committee under protocol 2.128.869. Eleven adults with post-lingual deafness users of unilateral Advanced Bionics CI were selected. Speech recognition was evaluated with recorded words presented at 65dBA at 0o azimuth and at 90o on the side contralateral to the CI, with noise at 55dBA, using CI alone and CI + CROS system. The results were analyzed using paired t-test with a 0.05 alpha. The mean speech recognition scores were significantly better with CI + CROS in relation to the condition of CI alone (p <0.05, p <0.005 and p <0.005 respectively). In the presentation at 0o azimuth, no significant differences were found. Users of unilateral CI without useful residual hearing for the use of hearing aids or unable to undergo bilateral surgery can benefit from the CROS device for speech recognition, especially when the speech is presented on the side contralateral to the CI.


Persistent Plasmodium falciparum infections enhance transmission-reducing immunity development.
Subclinical infections that serve as reservoir populations to drive transmission remain a hurdle to malaria control. Data on infection dynamics in a geographical area is required to strategically design and implement malaria interventions. In a longitudinal cohort, we monitored Plasmodium falciparum infection prevalence and persistence, and anti-parasite immunity to gametocyte and asexual antigens for 10 weeks. Of the 100 participants, only 11 were never infected, whilst 16 had persistent infections detected by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and one participant had microscopic parasites at all visits. Over 70% of the participants were infected three or more times, and submicroscopic gametocyte prevalence was high, ≥ 48% of the parasite carriers. Naturally induced responses against recombinant Pfs48/45.6C, Pfs230proC, and EBA175RIII-V antigens were not associated with either infection status or gametocyte carriage, but the antigen-specific IgG titers inversely correlated with parasite and gametocyte densities consistent with partial immunity. Longitudinal analysis of gametocyte diversity indicated at least four distinct clones circulated throughout the study period. The high prevalence of children infected with distinct gametocyte clones coupled with marked variation in infection status at the individual level suggests ongoing transmission and should be targeted in malaria control programs.


Still searching for the engram.
For nearly a century, neurobiologists have searched for the engram-the neural representation of a memory. Early studies showed that the engram is widely distributed both within and across brain areas and is supported by interactions among large networks of neurons. Subsequent research has identified engrams that support memory within dedicated functional systems for habit learning and emotional memory, but the engram for declarative memories has been elusive. Nevertheless, recent years have brought progress from molecular biological approaches that identify neurons and networks that are necessary and sufficient to support memory, and from recording approaches and population analyses that characterize the information coded by large neural networks. These new directions offer the promise of revealing the engrams for episodic and semantic memories.


Resting, and rate-dependent depression of Vmax of guinea-pig ventricular action potentials by amiodarone and desethylamiodarone.
1 The cellular electrophysiological effects of amiodarone and its metabolite desethylamiodarone (DEA) were studied in guinea-pig ventricular myocardium by use of standard microelectrode techniques. 2 Both compounds produced significant increases in action potential duration (Class III antiarrhythmic effect) and decreases in maximum rate of depolarization (Class I effect), at clinically relevant concentrations. 3 The Class I effects were rate-dependent, with small (0-16%) falls in maximum depolarization rate in the absence of stimulation ('resting block') and progressively larger effects at decreasing interstimulus intervals (range 1200-300 ms). 4 The kinetics of onset and offset of the Class I effect in response to a step change in driving rate were quite fast for both drugs (comparable to those reported for Class Ib agents). 5 It is concluded that this unique combination of Class III action plus Class I effects with fast onset and offset kinetics may help explain the great efficacy of amiodarone in antiarrhythmic therapy.


Stable Zn Anodes with Triple Gradients.
Aqueous zinc-ion batteries are highly desirable for sustainable energy storage, but the undesired Zn dendrites growth severely shortens the cycle life. Herein, a triple-gradient electrode that simultaneously integrates gradient conductivity, zincophilicity, and porosity is facilely constructed for a dendrite-free Zn anode. The simple mechanical rolling-induced triple-gradient design effectively optimizes the electric field distribution, Zn2+ ion flux, and Zn deposition paths in the Zn anode, thus synergistically achieving a bottom-up deposition behavior for Zn metals and preventing the short circuit from top dendrite growth. As a result, the electrode with triple gradients delivers a low overpotential of 35 mV and operates steadily over 400 h at 5 mA cm-2 /2.5 mAh cm-2 and 250 h at 10 mA cm-2 /1 mAh cm-2 , far surpassing the non-gradient, single-gradient and dual-gradient counterparts. The well-tunable materials and structures with the facile fabrication method of the triple-gradient strategy will bring inspiration for high-performance energy storage devices.


Adult Niemann-Pick disease--a case report.
A case is presented of the rare adult form of Niemann-Pick disease occurring in a Cantonese. The diagnosis was verified by biochemical analysis of the affected tissues.


Acetabular fixation in total hip arthroplasty in the previously irradiated pelvis: a review of basic science and clinical outcomes.
Radiation therapy is a common primary, adjuvant, or palliative treatment for many intrapelvic tumors, including primary gastrointestinal, genitourinary, and hematopoietic tumors, as well as metastatic disease to bone. Radiation has well documented microbiologic and clinical effects on bone ranging from radiation osteitis to early degenerative changes of the hip joint and avascular necrosis of the femoral head. Conventional total hip arthroplasty methods have demonstrated high rates of failure in this population, with historical data describing aseptic loosening rates as high as 44-52%, as radiation have been shown to preferentially diminish osteoblast and osteocyte number and function and limit capacity for both cement interdigitation and biologic bony ingrowth. A review of the clinical literature suggests that patients with prior pelvic irradiation are at higher risk for both septic and aseptic loosening of acetabular components, as well as lower postoperative Harris Hip Score (HHS) when compared to historical controls. With limited evidence, trabecular metal shells with multi-screw fixation and cemented polyethene liners, as well as cemented cup-cage constructs both appear to be durable acetabular fixation options, though the indications for each remains elusive. Further prospective data are needed to better characterize this difficult clinical problem.


Renal metabolism of homologous serum interferon.
The metabolic behaviour of homologous native and desialylated serum and urinary interferons has been investigated by using an isolated and perfused rabbit kidney, the performance of which is comparable to that in vivo. Serum native and urinary interferons disappear from the plasma perfusate with a fractional turnover rate of 1.8 and 2% and half-lives of 3 and 35 min, respectively. Serum desialylated interferon disappears much more rapidly in keeping with the finding that the glomerular sieve poses less steric hindrance and electrophysical repulsion to the passage of less anionic proteins. These results confirm and extend our previous findings, which indicated that the kidneys have a predominant catabolic role and can explain to some extent the rapid disappearance of interferon from plasma.


Impact of sustained virologic response on quality of life in chronic HVC carriers.
It is known that patients with chronic hepatitis C have a lower health-related quality of life (HRQOL) than the general population and evidence suggests that the hepatitis C virus (HCV) could exert direct neuropathic action on HRQOL. From this perspective, the virus clearance should be accompanied by improvement in HRQOL. Thus, we sought to review systematically the evidence in the literature and perform a meta-analysis of HRQOL changes caused by sustained virologic response (SVR). The PubMed was searched using the keywords Hepatitis C, Quality of Life and Therapy. The reviewers came to a consensus on articles that were selected to full reading and those that should be included in the study and a meta-analysis was performed of mean change difference between responders and non-responders. Eleven studies were included in the systematic review and four in the metaanalysis. Of these, nine studies showed more favorable outcome for responders, and they had a better outcome even in studies that evaluated only cirrhotic patients, previous non-responders, relapsers, patients in first treatment and patients unaware of treatment response. Moreover, the meta-analysis showed that the general health and vitality domains had statistically significant mean change difference between responders and non-responders, presenting a summary effect of 6.3 (CI 95% 2.5-10.0) and 7.8 (CI 95% 3.4- 12.1) respectively. There is evidence indicating that SVR is accompanied by an improvement in HRQOL and patients reaching SVR have clinically relevant improvement in domains of general health and vitality.


Validation of Psoas Muscle Index as a predictor of successful extubation in elderly intensive care patients: a retrospective cohort study.
Extubation failure-associated factors have not been investigated in elderly patients. We hypothesized that psoas cross-sectional area, an emerging indicator of frailty, can be a predictor of extubation outcomes. This retrospective study analyzed data from patients admitted between January and April 2016 at the mixed medical intensive care unit (ICU) of the Tokyo Medical University Hospital. Patients were considered eligible if aged 65 years or older, required intubation at the emergency room, and were admitted to ICU for over 24 h. Overall, 39 ICU patients were eligible and categorized into two groups: extubation success (n = 24) and extubation failure (n = 15) groups. The psoas cross-sectional area was measured at the third lumbar level on computer tomography images. Psoas Muscle Index (PMI) was defined as the psoas cross-sectional area/height2. Primary outcome was to evaluate differences between the psoas cross-sectional area and f(PMI) between the groups, if any. Both groups were comparable in terms of demographic characteristics. Psoas cross-sectional area (extubation success group, 1,776.5 ± 498.2 mm2, extubation failure group, 1,391.2 ± 589.4 mm2; P = 0.022) and PMI (extubation success group, 1,089 ± 270.7 mm2/m2, extubation failure group, 889 ± 338.5 mm2/m2; P = 0.032) were significantly greater in the extubation success group than in the extubation failure group. The psoas cross-sectional area and PMI can predict extubation outcomes in elderly intensive care patients.


Generalized matched filtering for time-resolved MR angiography of pulsatile flow.
Generating flow-specific images (arteriograms, venograms) with optimal signal-to-noise ratios for time-resolved MR angiography is a conditional maximum problem, and its solutions are generalized matched filters. We have investigated six matched filters, corresponding to all possible combinations of three flow suppression conditions and two signal-to-noise ratio maximization procedures. Four of these matched filters correspond to previously described methods: the subtractive matched filter, the standard deviation, the global venous eigenimage and the global arterial eigenimage. The two others are referred to here as the local venous eigenimage and the local arterial eigenimage. These six matched filters have been applied to 2D time-resolved phase contrast angiographic data. The local arterial eigenimage is found to be the most effective in suppressing undesired venous flow and preserving desired arterial flow.


Ingesting microplastics or nanometals during development harms the tropical pollinator Partamona helleri (Apinae: Meliponini).
The disposal of plastics and metal-derived compounds results in the contamination of the environment with nano/microparticles, leading to the exposure of various organisms to these harmful particles. However, the impacts of these particles on pollinating insects, which provide relevant ecosystem services, are not well understood. The aim of this study was to assess the effects of microscopic particles on the tropical pollinator Partamona helleri (Apinae: Meliponini), specifically evaluating the toxicity of plastic microparticles (polystyrene - PS, and polyethylene terephthalate - PET) and nanoparticles of a metal oxide (titanium dioxide - TiO2) via larval ingestion by bees reared in vitro. The survival rate of P. helleri larvae was not affected by the ingestion of particles of PS (500 ng/bee), PET (500 ng/bee), or TiO2 (10 μg/bee) compared to the non-treated diet (control or diet without the particles). Adults derived from treated larvae had increased body weight compared to the control, and the walking behavior of adults was altered by the ingestion of particles. Adults that ingested PET or TiO2 as larvae tended to rest for a longer time and interact more with other bees than the control. Hemocyte counts also changed, with a shift in the proportion of plasmatocytes and prohemocytes in treated individuals. Our findings suggest that even levels considered low for honey bees of exposure to plastic microparticles or metal nanoparticles can harm the health and behavior of stingless bees.


Evaluation of live trivalent vaccine of measles AIK-C strain, mumps Hoshino strain and rubella Takahashi strain, by virus-specific interferon-gamma production and antibody response.
A trivalent measles-mumps-rubella live virus vaccine, containing measles AIK-C strain, mumps Hoshino strain, and rubella Takahashi strain, was evaluated in 229 children, aged 1 to 5 years. The vaccine induced a high seroconversion rate: 221 (98.7%) out of 224 subjects initially seronegative for measles virus, 167 (93.3%) out of 179 initially seronegative for mumps virus, and 212 (99.1%) out of 214 initially seronegative for rubella virus. It also induced a sufficient cellular immunity against each of the three viruses in over 90% of the subjects, as judged by virus-specific interferon-gamma (IFN-gamma) production. Virus-specific IFN-gamma production was observed 10 days after vaccination by stimulation with measles virus and rubella virus and 14 days after vaccination by stimulation with mumps virus. Mumps-virus-specific IFN-gamma production was observed in 7 out of 12 recipients without seroconversion for mumps virus. And measles-virus-specific IFN-gamma production was demonstrated in one out of three recipients without seroconversion for measles virus. A significant correlation was observed between the serum antibody and IFN-gamma production six weeks after vaccination for measles virus (r = 0.201, P less than 0.01) and for mumps virus (r = 0.174, P less than 0.05) but not for rubella virus (r = -0.045, P less than 0.05). The incidence of febrile reactions of greater than or equal to 37.5 C was quite low, 14.4%, and that of greater than or equal to 39 C occurred in only 1.3% of the recipients. These results suggested that the trivalent vaccine induced sufficient humoral and cellular immunity and yet resulted in no more untoward reaction than observed from the measles vaccine alone.


Optimal staffing for a good quality inpatient diabetes service.
Increasing numbers of people admitted to hospital have diabetes and need specialist support. To date, there is no mechanism which can help teams estimate the number of health care professionals they need to provide optimal care for people with diabetes in hospitals. The Joint British Diabetes Societies (JBDS) for Inpatient Care Group organised a survey of specialist inpatient diabetes teams in the UK for current staffing and the perception of optimal staffing using mailing lists available through their representative organisations. The results were verified and confirmed by one-to-one conversations with individual respondents and discussed in multiple expert-group meetings to agree on the results. Responses were received from 17 Trusts covering 30 hospital sites. Current diabetes specialist staffing level per 100 people with diabetes in hospital (Median, IQR) for consultants was 0.24 (0.22-0.37), diabetes inpatient specialist nurses was 1.94 (1.22-2.6), dieticians was 0.00 (0.00-0.00), podiatrists was 0.19 (0.00-0.62), pharmacists was 0.00 (0.00-0.37), psychologists was 0.00 (0.00-0.00). The teams also reported that for optimal care the total staff needed for each group (Median, IQR) was much higher; consultants 0.65 (0.50-0.88), specialist nurses 3.38 (2.78-4.59), dieticians 0.48 (0.33-0.72), podiatrists, 0.93 (0.65-1.24), pharmacists, 0.65 (0.40-0.79) and psychologists 0.33 (0.27-0.58). Based on the results of the survey, the JBDS expert group produced an Excel calculator to estimate staffing needs of any hospital site in question just by populating a few of the cells. Current inpatient diabetes staffing is much lower than needed in most Trusts who responded to the survey. The JBDS calculator can provide an estimate of the staffing needs of any hospital.


Hospital Dermatology: analysis of dermatological consultations in a tertiary teaching hospital.
In hospital settings, dermatology can offer substantial clinical support for the diagnosis and management of skin conditions, reducing morbidity and mortality. Thus, the study aimed to analyze the profile of referrals and consultations performed by the Dermatology Service of the Santa Casa de Misericordia de Porto Alegre, from August 2018 to January 2020. This study is descriptive, quantitative, and retrospective, conducted through data collection and review of medical records and referrals. The variables included were clinical data of referrals, in-patients profiles, dermatological diagnoses, complementary exams, therapeutic conduct, and recommended follow-ups. A total of 1020 referrals were analyzed, which resulted in 641 consultations (328 men, 313 women). The most prevalent skin disease groups were 'Dermatitis and Eczema' (33.1%) and 'Other infectious skin diseases (21.8%), while the most frequent ICD-10 were 'Drug eruptions - L27' (9.9%) and 'Other and unspecified dermatitis - L30' (6.6%). Corticoids were the most recommended treatments (27.7%), followed by antifungals (13.1%). 'Consultation Discharge' (44%) and 'Outpatient' Dermatology follow-up (27%) were the most frequent causes for ending consultation. Among the study limitations, the authors highlight its retrospective nature, with data analysis based on referrals and medical records, which may present inaccurate or incomplete information. In addition to this, the study may demonstrate a certain degree of subjectivity due to the review and interpretation process conducted by the researchers. However, the definition of objective criteria based on previous studies attenuates such possible bias. Furthermore, considering that the Dermatology teams are composed of a preceptor dermatologist and residents, the established diagnoses were not submitted to third-party verification, except in the cases of skin biopsies and cultures. Thus, the professional's experience and skills may have influenced the dermatological diagnoses. These findings underlie the importance of Dermatology in hospital assistance, contributing to the management of a wide range of skin conditions.


Persistence to anti-CGRP monoclonal antibodies and onabotulinumtoxinA among patients with migraine: a retrospective cohort study.
To date, real-world evidence on persistence to anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies (mAbs) or onabotulinumtoxinA have excluded eptinezumab. This retrospective cohort study was performed to compare treatment persistency among patients with migraine on anti-CGRP mAbs (erenumab, fremanezumab, galcanezumab, or eptinezumab) or onabotulinumtoxinA. This retrospective study used IQVIA PharmMetrics data. Adult patients with migraine treated with an anti-CGRP mAb or onabotulinumtoxinA who had 12 months of continuous insurance enrollment before starting treatment were included. A "most recent treatment episode" analysis was used in which the most recent episode was defined as the latest treatment period with the same drug (anti-CGRP mAb or onabotulinumtoxinA) without a ≥ 15-day gap in medication supply on/after June 25, 2020, to December 31, 2021. Patients were indexed at the start of their most recent episode. Patients were considered non-persistent and discontinued the therapy associated with their most recent episode if there was ≥ 15-day gap in medication supply. A Cox proportional-hazards model estimated the discontinuation hazard between treatments. The gap periods and cohort definition were varied in sensitivity analyses. The study included 66,576 patients (median age 46 years, 88.6% female). More eptinezumab-treated patients had chronic migraine (727/1074), ≥ 3 previous acute (323/1074) or preventive (333/1074) therapies, and more prior treatment episodes (3) than other treatment groups. Based on a 15-day treatment gap, patients on subcutaneous anti-CGRP mAbs had a 32% (95% CI: 1.19, 1.49; erenumab), 42% (95% CI: 1.27, 1.61; galcanezumab), and 58% (95% CI: 1.42, 1.80; fremanezumab) higher discontinuation hazard than those receiving eptinezumab, with this relationship attenuated, but still statistically significant based on 30-day and 60-day treatment gaps. There was no significant difference in the discontinuation hazard between eptinezumab and onabotulinumtoxinA. Based on a 15-day treatment gap among patients who newly initiated therapy, the discontinuation hazard of subcutaneous anti-CGRP mAbs remained significantly higher compared to eptinezumab and onabotulinumtoxinA. Patients treated with eptinezumab demonstrated persistency that was higher than subcutaneous anti-CGRP mAbs and similar to onabotulinumtoxinA.


Molecular dynamics study of membrane permeabilization by wild-type and mutant lytic peptides from the non-enveloped Flock House virus.
Flock House virus (FHV) serves as a model system for understanding infection mechanisms utilized by non-enveloped viruses to transport across cellular membranes. During the infection cycle of FHV, a fundamental stage involves disruption of the endosomal membrane by membrane active peptides, following externalization of the peptides from the capsid interior. The FHV lytic agents are the 44 C-terminal amino acids residues of the capsid protein, which are auto-catalytically cleaved during the capsid maturation process. The cleaved peptides are termed γ peptides. In this study, we perform multi-scale molecular dynamics simulations including 40 μs all-atom molecular dynamics simulations to study the behavior of pre-inserted transmembrane lytic peptides at a high concentration in a neutral membrane. We study the dynamical organization among peptides to form oligomeric bundles in four systems including the wild-type γ peptide and three mutant forms; namely, a truncation mutant in which the 23 C-terminal residues are deleted (γ1), a construct where the 8 C-terminal residues of γ are fused to γ1 (Δ385-399 γ) and a single-point mutant (F402A γ), all of which have been experimentally shown to drastically affect infectivity and lytic activity compared to the wild-type γ. Our results shed light on the actions of varied forms of the FHV lytic peptide including membrane insertion, trans-membrane stability, peptide oligomerization, water permeation activity and dynamic pore formation. Findings from this study provide detailed structural information and rationale for the differences in lytic activity among variants of FHV γ.