FTD and ALS--translating mouse studies into clinical trials.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are related neurodegenerative disorders, which are characterized by a rapid decline in cognitive and motor functions, and short survival. Although the clinical and neuropathological characterization of these diseases has progressed--in part--through animal studies of pathogenetic mechanisms, the translation of findings from rodent models to clinical practice has generally not been successful. This article discusses the gap between preclinical animal studies in mice and clinical trials in patients with FTD or ALS. We outline how to better design preclinical studies, and present strategies to improve mouse models to overcome the translational shortfall. This new approach could help identify drugs that are more likely to achieve a therapeutic benefit for patients.


Never getting to zero: Elementary school students' understanding of the infinite divisibility of number and matter.
Clinical interviews administered to third- to sixth-graders explored children's conceptualizations of rational number and of certain extensive physical quantities. We found within child consistency in reasoning about diverse aspects of rational number. Children's spontaneous acknowledgement of the existence of numbers between 0 and 1 was strongly related to their induction that numbers are infinitely divisible in the sense that they can be repeatedly divided without ever getting to zero. Their conceptualizing number as infinitely divisible was strongly related to their having a model of fraction notation based on division and to their successful judgment of the relative magnitudes of fractions and decimals. In addition, their understanding number as infinitely divisible was strongly related to their understanding physical quantities as infinitely divisible. These results support a conceptual change account of knowledge acquisition, involving two-way mappings between the domains of number and physical quantity.


The mutagenicity of urine fractions from patients administered antineoplastic therapy.
A concern among hospital personnel is their exposure to mutagenic drugs and in the incidental exposures that could occur in caring for the patients. In a recent published study the mutagenicity of urine from patients administered antineoplastic drugs was determined and techniques were developed to chemically inactivate the mutagenicity. A question still remained as to what components of the excreted urine were mutagenic. Urine samples from patients receiving mutagenic drugs were fractionated by high pressure liquid chromatography (HPLC) to then assay by the Ames test the collected and concentrated fractions to determine what were the mutagenic compounds in the urine. Urine samples from patients on single agent cancer treatment with cisplatin, cyclophosphamide, doxorubicin and mitomycin C were assayed. In general, all urine samples containing the cytotoxic agents studied were mutagenic because of the presence of the parent compound, except cyclophosphamide which requires activation and therefore an active metabolite was the major mutagenic constituent in the urine sample. This data indicates that the mutagenicity of urine from patients receiving these antineoplastic agents is the result of the parent compound or a single major metabolite.


An investigation of the relation between tumor-to-liver ratio (TLR) and tumor-to-blood standard uptake ratio (SUR) in oncological FDG PET.
The standardized uptake value (SUV) is the nearly exclusive means for quantitative evaluation of clinical [18F-]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) whole body investigations. However, the SUV methodology has well-known shortcomings. In this context, it has been recognized that at least part of the problems can be eliminated if tumor SUV is normalized to the SUV of a reference region in the liver (tumor-to-liver [TLR] ratio). In recent publications, we have systematically investigated the tumor-to-blood SUV ratio (SUR) for normalization of tumor SUVs which in our view offers principal advantages in comparison to TLR. The aim of this study was a comprehensive comparison of TLR and SUR in terms of quantification of tumor lesions. 18F-FDG PET/CT was performed in 424 patients (557 scans) with different tumor entities prior to radio(chemo)therapy. In the PET images, SUVmax of the primary tumor was determined. SUVliver was calculated in the inferior right lobe of the liver. SUVblood was determined by manually delineating the aorta in the low-dose CT. TLR and SUR were computed and scan time corrected to 60 min p.i. (TLRtc and SURtc). Correlation analysis was performed for SUVliver vs. SUVblood, TLR vs. SUR, SUVliver/SUVblood vs. SUVblood,SURtc/TLR vs. SURtc, and SURtc/TLRtc vs. SURtc. Variability of the respective ratios was assessed via histogram analysis. The prognostic value of TLR and TLRtc for distant metastases-free survival (DM) was investigated with univariate Cox regression in a homogeneous subgroup (N = 130) and compared to previously published results for SUV and SURtc. Correlation analysis revealed a linear correlation of SUVliver vs. SUVblood (R (2)=0.83) and of TLR vs. SURtc (R (2)=0.92). The SUVliver/SUVblood ratio (mean ± s.d.) was 1.47 ± 0.18. For the SURtc/TLR ratio, we obtained 1.14 ± 0.21 and for the SURtc/TLRtc ratio 1.38 ± 0.17. Survival analysis revealed TLR and TLRtc as significant prognostic factors for DM (hazard ratio [HR] = 3.3 and HR = 3, respectively). Both hazard ratios are lower than that of SURtc (HR = 4.1) although this reduction does not reach statistical significance for the given limited group size. HRs of TLR and SURtc are both significantly higher than HR of SUV (HR = 2.2). Suitability of the liver as surrogate of arterial tracer supply for SUV normalization via TLR computation is limited. Further studies in sufficiently large patient groups are required to better characterize the relative performance of SUV, TLR, and SUR in different settings.


Inhibition of alpha-globin gene expression by RNAi.
RNA interference (RNAi), a process by which target messenger RNA (mRNA) is cleaved by small interfering complementary RNA (siRNA), is widely used for investigations of regulation of gene expression in various cells. In this study, siRNA complementary to 5' region of exon II of alpha-globin mRNA was examined for its role in erythroid colony forming cells (ECFCs) isolated from normal peripheral blood donor. On day 6 of cell culture, 1x10(6) ECFCs were transfected with lipofectamine-containing alpha-globin specific siRNA. After 48h of transfection, alpha-globin specific siRNA produced significantly reduction of alpha-globin mRNA level in a dose-dependent manner, but it did not affect the level of beta-globin mRNA. Significantly, decreased numbers of hemoglobinized erythroid cells relative to the control were observed supporting the inhibitory effect of this alpha-globin mRNA specific siRNA.


A bipartite function of ESRRB can integrate signaling over time to balance self-renewal and differentiation.
Cooperative DNA binding of transcription factors (TFs) integrates the cellular context to support cell specification during development. Naive mouse embryonic stem cells are derived from early development and can sustain their pluripotent identity indefinitely. Here, we ask whether TFs associated with pluripotency evolved to directly support this state or if the state emerges from their combinatorial action. NANOG and ESRRB are key pluripotency factors that co-bind DNA. We find that when both factors are expressed, ESRRB supports pluripotency. However, when NANOG is absent, ESRRB supports a bistable culture of cells with an embryo-like primitive endoderm identity ancillary to pluripotency. The stoichiometry between NANOG and ESRRB allows quantitative titration of this differentiation, and in silico modeling of bipartite ESRRB activity suggests it safeguards plasticity in differentiation. Thus, the concerted activity of cooperative TFs can transform their effect to sustain intermediate cell identities and allow ex vivo expansion of immortal stem cells. A record of this paper's transparent peer review process is included in the supplemental information.


An efficient in vitro refolding of recombinant bacterial laccase in Escherichia coli.
Laccases (benzenediol oxygen oxidoreductases, EC 22.214.171.124) are important multicopper enzymes that are used in many biotechnological processes. A recombinant form of laccase from Bacillus sp. HR03 was overexpressed in Escherichia coli BL-21(DE3). Inclusion body (IB) formation happens quite often during recombinant protein production. Hence, developing a protocol for efficient refolding of proteins from inclusion bodies to provide large amounts of active protein could be advantageous for structural and functional studies. Here, we have tried to find an efficient method of refolding for this bacterial enzyme. Solubilization of inclusion bodies was carried out in phosphate buffer pH 7, containing 8M urea and 4mM β-mercaptoethanol and refolding was performed using the dilution method. The effect of different additives was investigated on the refolding procedure of denaturated laccase. Mix buffer (phosphate buffer and citrate buffer, 100mM) containing 4mM ZnSO4 and 100mM sorbitol was selected as an optimized refolding buffer. Also Kinetic parameters of soluble and refolded laccase were analyzed.


Magnetic resonance imaging signatures of tissue pathology in frontotemporal dementia.
The pathologic substrates of frontotemporal dementia (FTD) are difficult to predict in vivo. To determine whether different pathologic substrates of FTD have distinct patterns of regional atrophy on magnetic resonance imaging (MRI). Retrospective case study. The Institute of Neurology, University College London, and the Institute of Psychiatry, King's College London. Patients Twenty-one cases of FTD selected on pathologic grounds (9 with ubiquitin-positive [tau- and alpha-synuclein-negative] inclusions [FTD-U], 7 with Pick disease [PiD], and 5 with familial FTD with tau exon 10+16 mutations [tau exon 10+16]) and 20 healthy controls were studied. Patterns of gray matter atrophy in each group as assessed by voxel-based morphometry (VBM) and a blinded visual assessment of each MRI study. All pathologic substrates were associated with atrophy that involved the inferior and medial temporal and inferior frontal lobes. Additionally, specific VBM signatures were identified for each subgroup: FTD-U was associated with asymmetric (left > right) temporal lobe atrophy, PiD was associated with severe dorsolateral bifrontal atrophy, and tau exon 10+16 was associated with asymmetric (right > left) medial temporal lobe atrophy. The VBM findings were supported by blinded visual assessment. These findings suggest that MRI patterns of regional gray matter atrophy constitute signatures of tissue pathology in FTD.


Associations between the urban environment and psychotic experiences in adolescents.
In 2050 two-thirds of the world's population is predicted to live in cities, which asks for a better understanding of how the urban environment affects mental health. Urbanicity has repeatedly been found to be a risk factor, in particular for psychosis. Here, we explored what factors of the urban exposome underlie the association between urban characteristics and psychotic experiences (PE) in adolescents. Participants were 815 adolescents (mean age 14.84 years, SD 0.78) from an at-risk cohort (greater Rotterdam area, the Netherlands) oversampled on their self-reported emotional and behavioral problems. We used linear regression analysis to examine the association with detailed geodata on urbanicity (surrounding address density), green space density (high and low vegetation), and mixed noise levels (road, rail, air, industry, and wind power) with PE in adolescents. Analyses were adjusted for multiple socio-economic and parental confounders. Furthermore, we explored sex-interaction effects. Higher surrounding address density and low greenspace density were each independently associated with more PE (B = 0.18, 95 % CI 0.02; 0.34 and B = 0.17, 95 % CI 0.01; 0.32, respectively). High mixed noise levels were only associated with more PE in boys (B = 0.23, 95 % CI 0.01; 0.46). A sex-interaction effect was found for high urbanicity (B = -0.46, 95 % CI -0.77; -0.14) and low greenspace density (B = -0.49, 95 % CI -0.73; -0.11), illustrating that these associations with PE were specific for boys. Multiple characteristics of living in an urban area are associated with more PE in adolescent boys. Our observations provide leads for prevention of mental health problems via urban designing.


[Desflurane and isoflurane in minimal-flow anesthesia. Consumption and costs with forced fresh gas reduction].
In the present investigation we compared the consumption of desflurane (DES) and isoflurane (ISO) using a standardized minimal-flow protocol with a forced reduction of the fresh gas flow (FGF). 54 adult women were examined. After induction of anaesthesia a forced reduction of the FGF was started: 5 min 0.5 l/min O(2) + 1 l/min N(2)O, 10 min 0.5 l/min O(2) + 0.5 l/min N(2)O; finally 0.3 l/min O(2) + 0.2 l/min N(2)O up to the end of surgery. The consumption of DES/ISO was determined with a precision balance. In the DES group the uptake was around 0.3 vol-%, i.e. less than 8% of the target 2/3 MAC value was taken up. For ISO the uptake was around 0.25 vol-%, i.e. the uptake was approximately 30% of the target 2/3-MAC value. The DES consumption was after 60 min 17.0+/-1.1 g, 120 min--27.3+/-1.8 g and 180 min--36.5+/-1.7 g. ISO consumption was significantly lower: 7.6+/-0.8 g, 12.4+/-1.7 g and 15.5+/-1.6 g. The use of DES yielded higher costs, i.e. 2.28 EUR for 60 min, 3.63 EUR for 120 min and 4.97 EUR for 180 min. The consumption of the inhaled anaesthetics can be calculated as: DES (g)=4.84+0.184 x duration (min) (R(2)=0.981), ISO (g)=2.049+0.0826 x duration (R(2)=0.979). The costs are: DES (EUR)=0.85+0.0323 x duration (min); ISO (EUR)=0.19+0.0077 x duration (min). With a forced reduction of the FGF the DES consumption is still higher.


Development and Validation of the B Cell-Associated Fc Receptor-like Molecule-Based Prognostic Signature in Skin Cutaneous Melanoma.
461 patients with CM from The Cancer Genome Atlast- (TCGA-) CM cohort and 290 pateints from the GSE65904 cohort were enrolled. Student's t-test was used to compare the differences, and Pearson's correlation coefficient was employed to evaluate associations. The Kaplan-Meier (K-M) survival analysis was used to evaluate overall survival (OS). The multivariate Cox regression was conducted to generate the FCRL prognostic signature. GSEA analysis and TIMER were employed to study the potential mechanisms. Patients with Breslow's depth high or equal to 3 cm had the lower expression of FCRL1-6 (all, P < 0.05), which indicates poor OS, as well as age, stage, and Breslow's depth subgroups (all, P < 0.001). The overall FCRL1-6 prognostic signature was generated in the TCGA cohort (K-M, P < 0.001; area under the curve (AUC), 0.649 for 3-year OS) and validated in the GSE65904 cohort (K-M, P < 0.001; AUC, 0.659 for 3-year OS). The GSEA results revealed that high expression of FCRLs indicated activated immune-associated pathways, and FCRLs are positively associated with the infiltration of B cells. Highly expressed FCRLs were observed associated with a favourable OS of CM. FCRL1-6-based prediction signature could act as a biomarker to predict the prognosis of patients with CM.


Organ transplantation from living donors, between bioethics and the law.
The lack of cadaver donors and the high requirements for organs cannot be met by present sources, leading to the need for xenoorgans or stem cell-derived tissues/organs. Actually, despite experimental suggestions, scientific and ethical doubts have been raised by both the scientific community and international organizations (World Health Organization, 1998; European Council of Parliamentary Assembly, 1999). Thus, to balance the shortage of organs, laws allowing living organ donations have been issued in several countries, including Italy, where there is an increasingly favorable attention to organ transplantation from living donors. Because of the prohibition of body commercialization issued by the Oviedo Convention (1997), the bioethics and legal debate as well as issued laws concern 2 major closely related aspects: the health-defense of the donor who accepts a decreased well-being and the counterbalanced possibility of an economic advantage/indemnity.


Development of an international core outcome set for peripheral vascular malformations: the OVAMA project.
An important limitation in vascular malformation research is the heterogeneity in outcome measures used for the evaluation of treatment outcome. To reach international consensus on a core outcome set (COS) for clinical research on peripheral vascular malformations: lymphatic (LM), venous (VM) and arteriovenous malformations (AVM). In this consensus study, we determined what domains should constitute the COS. Thirty-six possibly relevant outcome domains were proposed to an international group of physicians, patients and the parents of patients. In a three-round e-Delphi process using online surveys, participants repeatedly rated the importance of these domains on a five-point Likert scale. Participants could also propose other relevant domains. This process was performed for LM, VM and AVM separately. Consensus was predefined as 80% agreement on the importance of a domain among both the physician group and the patient/parent group. Outcomes were then re-evaluated in an online consensus meeting. 167 physicians and 134 patients and parents of patients with LM (n = 50), VM (n = 71) and AVM (n = 29) participated in the study. After three rounds and a consensus meeting, consensus was reached for all three types of vascular malformations on the core domains of radiological assessment, physician-reported location-specific signs, patient-reported severity of symptoms, pain, quality of life, satisfaction and adverse events. Vascular malformation type-specific signs and symptoms were included for LM, VM and AVM, separately. Our recommendation is that therapeutic-efficacy studies on peripheral vascular malformations should measure at least these core outcome domains.


Bowen's disease in multiple nail beds--case report.
Bowen's disease is in situ squamous cell carcinoma of the skin. A histologically confirmed case of Bowen's disease in multiple nail beds in the hands of a 40-year-old is reported. Treatment consisted of multiple operations involving excision, skin grafting, and the use of 5-fluorouracil.


Plasma and urine levels of urinary trypsin inhibitor in patients with acute and fulminant hepatitis.
Urinary trypsin inhibitor (UTI) is synthesized by hepatocytes and excreted into urine. Plasma and urine UTI levels have been measured to evaluate whether these levels may be useful markers in various pathological conditions. However, there has been no study on plasma and urine UTI levels in patients with acute liver diseases. The aim of the present study was to evaluate plasma and urine UTI levels and their relationship with the severity of hepatic damage in patients with acute liver diseases. Plasma and urine UTI levels were measured by newly developed enzyme-linked immunosorbent assay in 15 patients with acute hepatitis (AH), 12 patients with acute severe hepatitis (ASH) and 10 patients with fulminant hepatitis (FH), as assessed on admission. The serial changes in plasma and urine UTI were also observed in some patients with AH and ASH. Plasma UTI levels (U/mL, median [25-75th percentile]) were: 11.0, (9.5-16.1) in patients with AH; 7.8 (5.6-11.5) in those with ASH; 6.5 (4.0-9.5) in patients with FH; and 9.7 (7.3-11.0) in normal controls. Plasma UTI levels in patients with FH were significantly lower than in those with AH. Plasma UTI levels showed significant positive correlations with the levels of prothrombin time (PT), hepaplastin test, antithrombin III, alpha2-plasmin inhibitor, plasminogen (Plg) and fibrinogen. After the recovery of liver dysfunction, increased plasma UTI levels in patients with AH were decreased, whereas previously decreased plasma UTI levels in patients with ASH were increased. Urine UTI levels were significantly increased in patients with AH compared with those of normal controls. In patients with ASH and FH, urine UTI levels were increased but not significantly. Urine UTI levels significantly positively correlated with PT and Plg. After the recovery of liver dysfunction, previously increased urine UTI levels in patients with AH were decreased. The correlation between plasma UTI and urine UTI levels was not significant. The findings of the present study suggested that the levels of plasma and urine UTI changed in patients with AH and were closely related to the abnormalities of coagulo-fibrinolysis, including PT. Further studies are needed to clarify whether these levels may be useful markers to predict the prognosis of acute hepatitis.


Proteomic analysis discovers potential biomarkers of early traumatic axonal injury in the brainstem.
Application of Tandem Mass Tags (TMT)-based LC-MS/MS analysis to screen for differentially expressed proteins (DEPs) in traumatic axonal injury (TAI) of the brainstem and to predict potential biomarkers and key molecular mechanisms of brainstem TAI. A modified impact acceleration injury model was used to establish a brainstem TAI model in Sprague-Dawley rats, and the model was evaluated in terms of both functional changes (vital sign measurements) andstructural changes (HE staining, silver-plating staining and β-APP immunohistochemical staining). TMT combined with LC-MS/MS was used to analyse the DEPs in brainstem tissues from TAI and Sham groups. The biological functions of DEPs and potential molecular mechanisms in the hyperacute phase of TAI were analysed by bioinformatics techniques, and candidate biomarkers were validated using western blotting and immunohistochemistry on brainstem tissues from animal models and humans. Based on the successful establishment of the brainstem TAI model in rats, TMT-based proteomics identified 65 DEPs, and bioinformatics analysis indicated that the hyperacute phase of TAI involves multiple stages of biological processes including inflammation, oxidative stress, energy metabolism, neuronal excitotoxicity and apoptosis. Three DEPs, CBR1, EPHX2 and CYP2U1, were selected as candidate biomarkers and all three proteins were found to be significantly expressed in brainstem tissue 30 min-7 days after TAI in both animal models and humans. Using TMT combined with LC-MS/MS analysis for proteomic study of early TAI in rat brainstem, we report for the first time that CBR1, EPHX2 and CYP2U1 can be used as biomarkers of early TAI in brainstem by means of western blotting and immunohistochemical staining, compensating for the limitations of silver-plating staining and β-APP immunohistochemical staining, especially in the case of very short survival time after TAI (shorter than 30 min). A number of other proteins that also have a potential marker role are also presented, providing new insights into the molecular mechanisms, therapeutic targets and forensic identification of early TAI in brainstem.


Comparability Considerations and Challenges for Expedited Development Programs for Biological Products.
Expedited development programs for biological products to be used in the treatment of serious conditions bring about challenges because of the compressed clinical development timeframes. As expedited development does not lessen the quality expectations, one challenge is providing adequate chemistry, manufacturing, and control (CMC) information required to support approval of a biological product. In particular, the analytical comparability and, in some cases, pharmacokinetic comparability studies needed to bridge the clinical material to the commercial material could delay submission of applications for life-saving medicines. While there is the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Topic Q5E guidance on assessing comparability of biological products before and after manufacturing changes, specific guidance on the emerging issue of conducting comparability exercises in the face of expedited drug development is lacking. In July 2019, clinical pharmacologists and product quality chemists from the US FDA and industry representatives convened an FDA workshop for a scientific exchange about considerations and challenges around conducting comparability exercises for expedited programs for biological products. This article highlights discussions from the workshop.


Abdominal wound dehiscence.
Abdominal wound dehiscence is a surgical complication with a high morbidity rate but which is associated with predictable and preventable factors. During a 10 year period (1966 to 1975) at the New York Lying-In Hospital, 70 cases were found on the obstetric-gynecologic service, and these cases were analyzed to see why dehiscence remains a problem. Those factors contributing to dehiscence include obesity, pre-existing pulmonary and cardiovascular problems, vertical incisions, the triad of ileus, vomiting, and coughing, and, to a lesser extent, hypoproteinemia, fluid and electrolyte imbalance, and wound infection. The incidence of abdominal wound dehiscence would be much lower if high-risk patients were identified, adequate pulmonary toilet was used, ileus was promptly treated with abdominal decompression, and strict attention was paid to electrolyte and protein balance in the pre- and post-operative period. The management of abdominal wound dehiscence is also discussed.


Is the formation of fibrin a necessary event for the initiation of angiogenic responses in the chick chorioallantoic membrane?
Millipore filters belong to number of solid materials which interact with the chorioallantoic membrane (CAM) and frequently initiate local edemas sometimes accompanied by vascular responses. We observed that such reactions can completely be prevented by coating Millipore filter pieces with hydrophilic polymers (e.g. polyvinylpyrrolidone dextran) or by hydrophobic substances as liquid paraffin and vaseline. Protease inhibitors (Contrikal, epsilon-aminocaproic acid) did not prevent such reactions but increased the incidence of vascular responses. By assaying several blood components we found a relationship between the initiation of vascular responses in the CAM and the process of blood clotting. If small amounts (5 to 10 microliter) of citrated bovine or human plasma arae dropped on the CAM angiogenic responses occur as good as regularly. They are also initiated if the plasmas are recalified and small fibrin fragments are placed on the CAM. Chicken plasma, however, regularly induced such responses only in combination with bovine serum or following application of (or treatment with) fibrinolysis inhibitors. We conclude that the formation of a stable extravascular plasma clot with reduced susceptibility to fibrinolysis could be the most important precondition for the initiation of vascular responses, and that all materials, substances or biofactors capable of activating the clotting cascade should also have the capacity to induce angiogenic responses.


Use of Saccharomyces cerevisiae expressing beta-galactosidase to screen for antimycotic agents directed against yeast cell wall biosynthesis and possible application to pathogenic fungi.
Saccharomyces cerevisiae expressing beta-galactosidase was used to develop a screen for compounds active against formation of the yeast cell wall. The screen detailed here is based on the release of beta-galactosidase from cells which had received an osmotic shock.


Characterization of a spontaneously occurring mutant of the TOL20 plasmid in Pseudomonas putida MT20: possible regulatory implications.
Pseudomonas putida MT20 carries a plasmid (TOL20) that codes for the enzymes responsible for the catabolism of toluene, m- and p-xylene to benzoate, and m- and p-toluate, respectively, followed by meta cleavage of the aromatic ring. Growth on 5 mM benzoate selects very strongly for (i) strains that have been cured of the plasmid and (ii) strains with an intermediate growth pattern (the B3 phenotype) that retain the ability to grow on toluene, m-xylene, and benzoate but are unable to grow on m-toluate. Both types of strains were selected because they are no longer able to oxidize benzoate by the plasmid pathway but instead use an alternative route, the ortho or beta-ketoadipate pathway, which is chromosomally coded and supports faster growth. Evidence that one strain with the B3 phenotype, MT20-B3, has a regulatory mutation that prevents induction of the meta-pathway enzymes by benzoate and m-toluate, but which enables them to be induced by toluene and m-xylene, is presented. The plasmid in this strain, as in most of the others with the same phenotype, is nonconjugative. Analysis of MT20-B3, together with revertants of it and other noninducible mutants, has led to a model for the regulation of the plasmid-coded enzymes in MT20, in which it is proposed that the early enzymes for degradation of m-toluate and benzoate are positively controlled by two regulator molecules, one of which interacts with toluene and m-xylene as inducers and the other of which interacts with benzoate and m-toluate. It is argued that MT20-B3 and strains with a similar phenotype arose as a result of a deletion of the gene coding for the second regulator molecule.


Spouse concordance of plasma cholesterol and triglyceride.
Spouse concordance for plasma cholesterol and triglyceride was studied in 1971 spouse pairs including 545 spouse pairs married 40 or more years. Both lipids showed modest but statistically significant age corrected Kendall Tau-B correlations; 0.046 (P = 0.005) for cholesterol and 0.070 (P = 0.0001) for triglycerides. Concordance was not explained by season of sampling or by selective mortality. Relative weight was positively correlated in spouse pairs and appeared to explain much of the observed correlations in cholesterol and triglycerides. Spouse pairs also showed positive correlations for cigarette smoking and egg and milk consumption, though these behavioral variables explained little of the concordance for cholesterol and triglycerides. Lipid concordance was highest in marriages of the shortest (1-9 yr) and longest (40 + yr) durations, as was relative weight concordance, suggesting an interaction between duration of marriage and environmental and/or selective factors affecting plasma lipids.


Naturally occurring leukemia viruses in H-2 congenic C57BL mice. III. Characterization of C-type viruses isolated from lymphomas induced by milk transmission of B-ecotropic virus.
The prevalence of different host-range classes of murine leukemia virus (MuLV) was studied in C57BL mice with (V+) and without (V-) milk transmission of a naturally occurring B-tropic ecotropic MuLV. Virus isolates were studied with respect to growth properties, XC-plaque formation, antigen profiles of their envelope proteins (gp70 and P15(E)), gp70 tryptic-peptide maps, and their potential to induce lymphomas after inoculation into newborn mice. B-tropic ecotropic MuLV with the capacity to cause plaques in XC cells was isolated from almost all lymphomas of both V+ and V- sublines. The reaction patterns of these ecotropic isolates with monoclonal antibodies reactive with MuLV-env proteins and the tryptic-peptide maps of the gp70 molecule indicate that they are similar to each other and differ only slightly from the ecotropic MuLV in the spleens of young V+ animals, which is identical to the milk-transmitted virus. XC-, B-tropic dualtropic mink cell focus-inducing (MCF) viruses were isolated from the majority of different types of lymphoma (B cell, T cell, or neither B nor T cell derived), but not from the spleens or milk of young V+ or V- animals. The env proteins of the MCF isolates are highly heterogeneous, but most isolates originating from B10.AV + T-cell lymphomas share MCF-related epitopes in their gp85 envelope precursor with AKR MCF-247 virus. Most MCF viruses isolated from non-T lymphomas do not possess these epitopes. The results indicate that also in this model the generation of dualtropic MCF viruses might be important in lymphoma induction, although only some of the cloned MCF viruses show enhanced oncogenic properties in comparison with ecotropic isolates. A cloned oncogenic MCF virus induced different lymphoma types in C57BL/10 (= B10, H-2b) and B10.A (H-2a) mice, similar to what was found earlier with the milk-transmitted virus. Hence, the lymphoma-type differences are not due to differences in the B-tropic ecotropic viruses transmitted through the milk in these strains, but reflect an influence of the H-2 complex on the phenotype of the virus-induced lymphomas.


trans-Bis[8-(benzyl-sulfan-yl)quinoline-κ2 N,S]di-chlorido-cobalt(II).
The title di-chloro-cobalt(II) complex, trans-[CoCl2(1)2] [1 = 8-(benzyl-sulfanyl)-quinoline, C16H13NS], has a central CoII atom (site symmetry ) that exhibits a distorted octa-hedral coordination geometry and is coordinated by two N and two S atoms from the bidentate N,S-ligand (1) situated in an equatorial plane and two Cl atoms in the axial positions. Complexes are linked by weak inter-molecular C-H⋯π inter-actions between the 8-(benzyl-sulfanyl)-quinoline ligands, forming a chain extending along the a-axis direction.


Curcumin Treatment Identifies Therapeutic Targets within Biomarkers of Liver Colonization by Highly Invasive Mesothelioma Cells-Potential Links with Sarcomas.
Investigations of liver metastatic colonization suggest that the microenvironment is preordained to be intrinsically hospitable to the invasive cancer cells. To identify molecular determinants of that organotropism and potential therapeutic targets, we conducted proteomic analyses of the liver in an aggressive model of sarcomatoid peritoneal mesothelioma (M5-T1). The quantitative changes between SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra) proteotype patterns of the liver from normal rats (G1), adjacent non-tumorous liver from untreated tumor-bearing rats (G2), and liver from curcumin-treated rats without hepatic metastases (G3) were compared. The results identified 12 biomarkers of raised immune response against M5-T1 cells in G3 and 179 liver biomarker changes in (G2 vs. G1) and (G3 vs. G2) but not in (G3 vs. G1). Cross-comparing these 179 candidates with proteins showing abundance changes related to increasing invasiveness in four different rat mesothelioma tumor models identified seven biomarkers specific to the M5-T1 tumor. Finally, analysis of correlations between these seven biomarkers, purine nucleoside phosphorylase being the main biomarker of immune response, and the 179 previously identified proteins revealed a network orchestrating liver colonization and treatment efficacy. These results highlight the links between potential targets, raising interesting prospects for optimizing therapies against highly invasive cancer cells exhibiting a sarcomatoid phenotype and sarcoma cells.


Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease.
To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. NCT02511418.


ABVD as the treatment option in advanced Hodgkin's lymphoma patients older than 45 years.
Advanced age is considered an unfavourable prognostic factor for Hodgkin's lymphoma (HL). The optimal treatment for these patients is not yet defined, especially for the advanced stages. We analysed the outcome and prognostic relevance of patient and disease characteristics in 46 advanced stage HL patients who were older than 45 years, treated with ABVD. Elderly patients (>60 year) had a significantly higher rate of comorbidities (p < 0.05). The complete remission rate was significantly lower in elderly patients and in patients with an IPS ≥ 3 (p < 0.05, p < 0.05, respectively). Elderly patients had significantly shorter event-free survival (p < 0.01) and overall survival (p < 0.01) compared to patients of 45-60 year. Extranodal disease, an IPS ≥ 3, bulky disease, an ESR > 50 and the presence of a large mediastinal tumour mass didn't have an influence on survival (p > 0.05). The multivariate Cox regression analysis identified the age of >60 year as an independent prognostic factor. The prospective clinical trials seem to be needed for defining the optimal therapeutic approach in elderly patients.


[External validity of clinical trials for treatment of dementia with ginkgo biloba extracts].
Ginkgo bilobaextracts have been applied in the treatment of dementia of vascular origin and Alzheimer disease for a long time. However, in the most elaborated systematic review to date, Birks and colleagues drew quite a moderate conclusion in spite of the overall positive results. The reason for such a moderate interpretation often lies in the preference of internal validity such as randomisation and blinding, sometimes at the expense of external validity (conditions of everyday practice). Because of this, we analysed the clinical trials evaluated by Birks et al. in the light of the following questions: 1) To what extent are criteria of external validity considered? 2) Does the additional evaluation of external validity lead to differences in the estimation of efficacy? 3) What are the results of our analysis in regard to the efficacy of ginkgo biloba extract? The selection of the clinical trials was based upon those included in the review carried out by Birks et al. (2002). The criteria for evaluating external validity were developed by consulting physicians specialised in geriatrics, experts in herbal pharmaceutics and affected/ related individuals (patients and relatives). We analysed 34 placebo-controlled clinical trials with a total of 37 comparisons. 21 trials showed significant results in favour of the ginkgo application in more than 50% of investigated outcome parameters, eight were significant for less than 50% of the parameters, four showed a trend in favour of ginkgo, and only two studies (with 4 comparisons) found no advantage for ginkgo. One of these negative studies used daily doses far below the usual dose range [corrected] We found no evidence for publication bias. None of the studies considered all criteria of external validity. Out of the seven studies with relatively high external validity and good overall quality, five showed a significant result in more than 50% of parameters, two in < or = 50%. Severe adverse effects were not mentioned in the studies. 1) In the clinical studies analysed external validity was taken into account only moderately, especially with respect to additional non-pharmaceutical interventions and selection of participants. 2) The evaluation according to external validity led to a different selection of studies that were used for estimation of the ginkgo efficacy without effects on the overall result. 3) Sufficient evidence of the efficacy of ginkgo bilobaextracts in the treatment of dementia of vascular origin and Alzheimer disease is provided in spite of methodological limitations. Further studies should focus on effectiveness, ginkgo-sensitive subgroups, more individualised therapeutic goals and corresponding outcome measurements.


Carbohydrate metabolism in hypothyroid myopathy.
The carbohydrate metabolism in hypothyroid patients was investigated. After an overnight fast, the blood glucose level was 24% lower and the blood lactate level was 35% lower in the untreated hypothyroid patients than that observed in the treated hypothyroid patients or in the normal subjects. There was no difference in the blood alanine or plasma free fatty acid values between the subject groups. Skeletal muscle biopsied from two hypothyroid patients with marked myopathy showed normal glycogen content, 0.83%-0.86% (normal 1.06%), but reduced activity of acid maltase, 32-50 nmoles/min/g (normal 97). Forearm ischemic stimulation applied to hypothyroid patients failed to elevate the level of lactate. The results are compatible with impaired glycogenolysis from the skeletal muscle, which may be a contributory factor in the myopathy in hypothyroidism.


Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase.
CCAAT-enhancer binding proteins (C/EBPs) are transcription factors that play a central role in the differentiation of myeloid cells and adipocytes. Tribbles pseudokinases govern levels of C/EBPs by recruiting them to the COP1 ubiquitin ligase for ubiquitination. Here, we present the first crystal structure of a Tribbles protein, which reveals a catalytically inactive TRIB1 pseudokinase domain with a unique adaptation in the αC helix. A second crystal structure and biophysical studies of TRIB1 with its C-terminal extension, which includes the COP1-binding motif, show that the C-terminal extension is sequestered at a site formed by the modified TRIB1 αC helix. In addition, we have identified and characterized the TRIB1 substrate-recognition sequence within C/EBPα, which is evolutionarily conserved in C/EBP transcription factors. Binding studies indicate that C/EBPα recruitment is weaker in the presence of the C-terminal COP1-binding motif, but the magnitude of this effect suggests that the two bind distinct rather directly overlapping binding sites.


Quality of life in patients with cisplatin-resistant urothelial cancer: Typical ailments and effect of paclitaxel-based salvage therapy.
Efficacy of palliative second-line treatment in patients suffering from advanced urothelial cancer (aUC) is limited. Accordingly, careful observation of patient-reported and treatment-related changes of quality of life (QoL) is mandatory. Therefore, we evaluated "typical" ailments and treatment related QoL changes in these patients. Results of the EORTC QLQ-C30 questionnaire were reviewed in 129 patients included in 2 prospective trials on paclitaxel-based treatment of cisplatin-resistant aUC (gemcitabine/paclitaxel: 102 patients [AB 20/99]; paclitaxel/everolimus: 27 patients [AB 35/09]). Eligible patients had completed EORTC QLQ-C30 questionnaire questionnaire before treatment start and available data on response. Global health status (QL), functional scales (FuSc) and symptom scales (SySc) were compared with published normative data for patients suffering from metastatic/recurrent cancers. Treatment related changes of QoL were evaluated. For statistical evaluation 2-way analysis of variance was used. A total of 87 patients were eligible (63 men and 24 women, median age = 65 [interquartile range: 60-71]y, AB 20/99: 63 patients [72%], AB 35/09: 24 patients [28%]). Compared with metastatic/recurrent cancers normative data, impaired emotional FuSc (-11.6 [95% CI:-21.0 to-2.1] points, P<0.01) and higher pain SySc (+12.9 [CI: 3.7-22.1] points, P<0.001) were the most relevant differences. QL and further FuSc/SySc were comparable. Pain SySc was significantly lower after 3 (-15.8 [CI:-31.4 to-0.7] points, P<0.01] and 4 cycles (-13.6 [CI:-29.2-2.1] points, P<0.05). Further changes of QL, FuSc or SySc during treatment were not observed. QL, FuSc, and SySc at baseline and during treatment did not differ between responders and nonresponders. Patients with aUC who received additional treatment demonstrated QoL changes similar to persons with other recurrent/metastatic cancers. Special emphasis should be attributed to pain and emotional problems. Despite treatment related side effects, patients did not report impairment of QoL.


A New Test for Achilles Tendinopathy Based on Kager's Fat Pad Clinical Assessment Predictive Values.
Background This study aimed to check the diagnostic accuracy of a new test to identify Achilles tendinopathy. Observational study. Seventy patients recruited from a private medical centre met the diagnostic criteria for unilateral Achilles tendinopathy (age, 45.1 ± 12.7 years; weight, 75.00 ± 10 kg; height, 1.75 ± 0.1 m) and were tested based on both Achilles tendons. Seventy patients with a unilateral Achilles tendinopathy ultrasound diagnosis were tested using David's test. Most (86%) subjects demonstrated Kager's fat pad asymmetry in relation to the Achilles tendon in the complete passive dorsiflexion in the prone position (David's sign). No healthy tendons had David's sign. The presence of asymmetry in Kager's fat pad in relation to the Achilles tendon during complete passive dorsiflexion is strongly indicative of ultrasound-diagnosed tendinopathy. David's test demonstrated a sensitivity of 85.71% (95% CI, 77.51% to 93.91%) and a specificity of 100% (95% CI, 100% to 100%), while noting the lack of blinding of the assessors and the uncertainty of the diagnostic measures (95% CI). Asymmetry of the fat pad could potentially serve as a characteristic marker for patients with Achilles tendinopathy.


In vitro correction of disorders of lysosomal transport by microvesicles derived from baculovirus-infected Spodoptera cells.
Infection of Spodoptera frugiperda (Sf9) cells by baculovirus (BV) is well established for transgene expression of soluble proteins, but few correctly folded transmembrane proteins have been so produced. We here report the use of the BV/Sf9 (BVES) method for the expression and transfer, via microvesicles, of the exclusive lysosomal exporters for cystine and sialic acid, human cystinosin and sialin. These proteins and their mRNA are released into the culture medium as very low-density microvesicles (~1.05 g/ml), which do not label for lysobisphosphatidic acid. The presence of the human transgene proteins in the vesicles was confirmed by western blotting and confirmed and quantified by mass spectrometry. Addition of vesicles to cultures of human fibroblast lines deficient in either cystinosin or sialin produced a progressive depletion of stored lysosomal cystine or sialic acid, respectively. The depletion effect was slow (T1/2 ~48 h), saturable (down to ~40% of initial after 4 days) and stable (>one week). Surprisingly, BV infection of Spodoptera appeared to induce expression and release into microvesicles of the insect orthologue of cystinosin, but not of sialin. We conclude that BVES is an effective method to express and transfer functional transmembrane proteins so as to study their properties in mammalian cells, and has a generic potential for transport protein replacement therapy.


Saliva as a biomarker for dental caries: A systematic review.
The aim of the present review article is to establish a systematic review to describe the role of various salivary components such as pH, buffering capacity, proteins, electrolyte, antioxidant, enzymes, and minerals in occurrence and initiation of dental caries in participants with and without dental caries. An electronic search was conducted in the PubMed, Scopus, Web of Science, and Google Scholar databases. The MESH terms (Medical Subject Headings) were "dental caries susceptibility," "caries risk assessment, "Salivary Biomarker," "saliva," "Proteins," "electrolytes," "biomarker," "Anti-oxidant's." The database search was limited to the studies published between 2008 and 2018 and only human studies were included. Furthermore, the STROBE criteria checklist was used to analyze the studies which had to be included in the systematic review. A total of 150 articles were retrieved through electronic database. After evaluating the title, abstract, and full text of these articles, only 11 were selected for the present systematic review. However, two articles were excluded because they were classified as high risk of bias according to the STROBE criteria. Out of 9 studies selected, 5 were classified as low-risk bias and 4 were classified as moderate-risk bias. Based on the results of the systematic review, out of 11 studies, 7 found to have a statistically significant difference between individuals with and without caries experience. Hence, it can be concluded that there is an association between various components of saliva and dental caries.


Right care, first time: a highly personalised and measurement-based care model to manage youth mental health.
Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change. Consequently, the effects of adolescent-onset mood and psychotic syndromes can have long term consequences. A key clinical challenge for youth mental health is to develop and test new systems that align with current evidence for comorbid presentations and underlying neurobiology, and are useful for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. Our highly personalised and measurement-based care model includes three core concepts: ▶ A multidimensional assessment and outcomes framework that includes: social and occupational function; self-harm, suicidal thoughts and behaviour; alcohol or other substance misuse; physical health; and illness trajectory. ▶ Clinical stage. ▶ Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on proposed pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). The model explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within this highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care as well as utilisation of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality, mental health care for young people. CHAPTER 1: MULTIDIMENSIONAL OUTCOMES IN YOUTH MENTAL HEALTH CARE: WHAT MATTERS AND WHY?: Mood and psychotic syndromes present one of the most serious public health challenges that we face in the 21st century. Factors including prevalence, age of onset, and chronicity contribute to substantial burden and secondary risks such as alcohol or other substance misuse. Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change; thus, effects can have long term consequences. We propose five key domains which make up a multidimensional outcomes framework that aims to address the specific needs of young people presenting to health services with emerging mental illness. These include social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Impairment and concurrent morbidity are well established in young people by the time they present for mental health care. Despite this, services and health professionals tend to focus on only one aspect of the presentation - illness type, stage and trajectory - and are often at odds with the preferences of young people and their families. There is a need to address the disconnect between mental health, physical health and social services and interventions, to ensure that youth mental health care focuses on the outcomes that matter to young people. CHAPTER 2: COMBINING CLINICAL STAGE AND PATHOPHYSIOLOGICAL MECHANISMS TO UNDERSTAND ILLNESS TRAJECTORIES IN YOUNG PEOPLE WITH EMERGING MOOD AND PSYCHOTIC SYNDROMES: Traditional diagnostic classification systems for mental disorders map poorly onto the early stages of illness experienced by young people, and purport categorical distinctions that are not readily supported by research into genetic, environmental and neurobiological risk factors. Consequently, a key clinical challenge in youth mental health is to develop and test new classification systems that align with current evidence on comorbid presentations, are consistent with current understanding of underlying neurobiology, and provide utility for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. This chapter outlines a transdiagnostic framework for classifying common adolescent-onset mood and psychotic syndromes, combining two independent but complementary dimensions: clinical staging, and three proposed pathophysiological mechanisms. Clinical staging reflects the progression of mental disorders and is in line with the concept used in general medicine, where more advanced stages are associated with a poorer prognosis and a need for more intensive interventions with a higher risk-to-benefit ratio. The three proposed pathophysiological mechanisms are neurodevelopmental abnormalities, hyperarousal and circadian dysfunction, which, over time, have illness trajectories (or pathways) to psychosis, anxious depression and bipolar spectrum disorders, respectively. The transdiagnostic framework has been evaluated in young people presenting to youth mental health clinics of the University of Sydney's Brain and Mind Centre, alongside a range of clinical and objective measures. Our research to date provides support for this framework, and we are now exploring its application to the development of more personalised models of care. CHAPTER 3: A COMPREHENSIVE ASSESSMENT FRAMEWORK FOR YOUTH MENTAL HEALTH: GUIDING HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE USING MULTIDIMENSIONAL AND OBJECTIVE MEASURES: There is an urgent need for improved care for young people with mental health problems, in particular those with subthreshold mental disorders that are not sufficiently severe to meet traditional diagnostic criteria. New comprehensive assessment frameworks are needed to capture the biopsychosocial profile of a young person to drive highly personalised and measurement-based mental health care. We present a range of multidimensional measures involving five key domains: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Objective measures include: neuropsychological function; sleep-wake behaviours and circadian rhythms; metabolic and immune markers; and brain structure and function. The recommended multidimensional measures facilitate the development of a comprehensive clinical picture. The objective measures help to further develop informative and novel insights into underlying pathophysiological mechanisms and illness trajectories to guide personalised care plans. A panel of specific multidimensional and objective measures are recommended as standard clinical practice, while others are recommended secondarily to provide deeper insights with the aim of revealing alternative clinical paths for targeted interventions and treatments matched to the clinical stage and proposed pathophysiological mechanisms of the young person. CHAPTER 4: PERSONALISING CARE OPTIONS IN YOUTH MENTAL HEALTH: USING MULTIDIMENSIONAL ASSESSMENT, CLINICAL STAGE, PATHOPHYSIOLOGICAL MECHANISMS, AND INDIVIDUAL ILLNESS TRAJECTORIES TO GUIDE TREATMENT SELECTION: New models of mental health care for young people require that interventions be matched to illness type, clinical stage, underlying pathophysiological mechanisms and individual illness trajectories. Narrow syndrome-focused classifications often direct clinical attention away from other key factors such as functional impairment, self-harm and suicidality, alcohol or other substance misuse, and poor physical health. By contrast, we outline a treatment selection guide for early intervention for adolescent-onset mood and psychotic syndromes (ie, active treatments and indicated and more specific secondary prevention strategies). This guide is based on experiences with the Brain and Mind Centre's highly personalised and measurement-based care model to manage youth mental health. The model incorporates three complementary core concepts: ▶A multidimensional assessment and outcomes framework including: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness trajectory. ▶Clinical stage. ▶Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on three underlying pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). These core concepts are not mutually exclusive and together may facilitate improved outcomes through a clinical stage-appropriate and transdiagnostic framework that helps guide decisions regarding the provision of appropriate and effective care options. Given its emphasis on adolescent-onset mood and psychotic syndromes, the Brain and Mind Centre's model of care also respects a fundamental developmental perspective - categorising childhood problems (eg, anxiety and neurodevelopmental difficulties) as risk factors and respecting the fact that young people are in a period of major biological and social transition. Based on these factors, a range of social, psychological and pharmacological interventions are recommended, with an emphasis on balancing the personal benefit-to-cost ratio. CHAPTER 5: A SERVICE DELIVERY MODEL TO SUPPORT HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE IN YOUTH MENTAL HEALTH: Over the past decade, we have seen a growing focus on creating mental health service delivery models that better meet the unique needs of young Australians. Recent policy directives from the Australian Government recommend the adoption of stepped-care services to improve the appropriateness of care, determined by severity of need. Here, we propose that a highly personalised approach enhances stepped-care models by incorporating clinical staging and a young person's current and multidimensional needs. It explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within a highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care and use of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality of, mental health care for young people.


Characterization of Orodispersible Films: An Overview of Methods and Introduction to a New Disintegration Test Apparatus Using LDR - LED Sensors.
Orodispersible Film (ODF) is a promising and progressive dosage form that offers exceptional drug delivery benefits to patients. Indeed, they are the most transformational alternatives to traditional/conventional dosage forms such as tablets and capsules. ODFs are portable and highly comfortable for self-administration by patients with swallowing problems. The key to gain end-user acceptance is to have an ODF with outstanding quality. Poor quality may lead to choking or spitting, accordingly leading to a lack of compliance. It is vital to employ suitable experimental methodologies that facilitate characterization or determination of the quality of ODF. Nonetheless, there are no standard techniques prescribed in official compendia of any country. But, there is a consensus in the thin-film research community about the characterization techniques that one relies on deciding the quality of an ODF. We review various experimental techniques and highlight its importance in determining the performance and quality of an ODF. We provide a relatively novel and inventive disintegration test apparatus, which works using 'Light Dependent Resistor (LDR) and Light Emitting Diode (LED) sensors' for clear and accurate determination of start and end disintegration time of an ODF.


Rupture of ectopic pregnancy after medical therapy with methotrexate: a case series.
Medical treatment of ectopic pregnancy with methotrexate has become the standard of care in many areas of the U.S. Rupture of ectopic pregnancy after medical treatment presents a diagnostic challenge to the Emergency Physician. We review a series of 11 patients with ectopic pregnancy treated with methotrexate who then required surgical treatment for rupture.


Neutralization potential of the plasma of HIV-1 infected Indian patients in the context of anti-V3 antibody content and antiretroviral therapy. [corrected].
We assessed the anti-V3 antibody content and viral neutralization potential of the plasma of 63 HIV-1-infected patients (antiretroviral naïve=39, treated=24) against four primary isolates (PIs) of clade C and a tier 1 clade B isolate SF162. Depletion and inhibition of anti-V3 antibodies in the plasma of five patients with high titers of anti-V3 antibodies led to modest change in the neutralization percentage against two PIs (range 0-21%). The plasma of antiretroviral-treated patients exhibited higher neutralization potential than that of the drug-naïve plasmas against the four PIs tested which was further evidenced by a follow-up study.


[Chemical form of the radioactive excretion products after intravenous application of 125I-orthoiodohippurate to rats (author's transl)].
100 muCi 125I-Orthoiodohippurate were injected i. v. to 2 Wistar rats. Urine and faeces were analysed by means of thin-layer chromatography and high-pressure liquid chromatography. The combined metabolic balance resulted in the following findings: Rat 1: 15% 125I-Orthoiodobenzoic acid, 66% 125I-Orthoiodohippuric acid and 12,5% 125I-iodide. Rat 2: 18,5% 125I-Orthoiodobenzoic acid, 67,5% 125I-Orthoiodohippuric acid and 10,2% 125I-iodide.


A Systematic Review of Posttraumatic Growth in Survivors of Interpersonal Violence in Adulthood.
This review critically evaluates the literature on posttraumatic growth in survivors of interpersonal violence, integrating the findings from 12 quantitative and 4 qualitative studies. The following databases were searched using predetermined terms: AMED, EMBASE, MEDLINE, PsycINFO, BNI, CINAHL, and Web of Knowledge. The review's findings suggest that the mean prevalence of growth in interpersonal violence survivors is around 71% (range 58-99%). The highest level of growth was consistently experienced in the "appreciation of life" domain. However, survivors reported growth in the four remaining domains: "personal strength," "new possibilities," "experience of relationships with others," and "outlook on life." The nature of the relationship between growth and distress was inconsistent across studies. A combination of pretrauma, peritrauma, and posttrauma variables were found to be related to the degree of growth survivors experienced. Methodological weaknesses of the quantitative studies included the predominant use of retrospective, cross-sectional, correlational designs, discrepancy in the measurement of growth, insufficient sample sizes for power calculations in five studies and limited external validity. Qualitative findings were limited by sampling methods, insufficient information about interview schedules, the lack of credibility checks, and evidence of reflexivity demonstrated by some studies. Implications for practice, policy, and future research are discussed.


Simultaneous quantification of four active schisandra lignans from a traditional Chinese medicine Schisandra chinensis(Wuweizi) in rat plasma using liquid chromatography/mass spectrometry.
A simple, rapid and sensitive method was developed for the simultaneous quantification of four active schisandra lignans (schisandrin, schisantherin A, deoxyshisandrin and gamma-schisandrin) from a traditional Chinese medicine Schisandra chinensis(Wuweizi) in rat plasma using a high-performance liquid chromatography system coupled to a positive ion electrospray mass spectrometric analysis. The plasma sample preparation was a simple deproteinization by the addition of three volumes of methanol followed by centrifugation. The analytes and internal standard (IS) bicyclol were separated on a Zorbax SB-C18 column (3.5 microm, 2.1 mm x 100 mm) with mobile phase of methanol/water (70:30, v/v) containing 0.1% formic acid at a flow rate of 0.2 mL/min with an operating temperature of 25 degrees C. Detection was performed on a Trap XCT mass spectrometer equipped with an electrospray ionization (ESI) source operated in selected ion monitoring (SIM) mode. Positive ion ESI was used to form sodium adduct molecular ions at m/z 455 for schisandrin, m/z 559 for schisantherin A, m/z 439 for deoxyshisandrin, m/z 423 for gamma-schisandrin, and m/z 413 for the internal standard bicyclol. Linear detection responses were obtained for the four test compounds ranging from 0.010 to 2.0 microg/mL and the lower limits of quantitation (LLOQs) for four lignans were 0.010 microg/mL. The intra- and inter-day precisions (R.S.D.%) were within 12.5% for all analytes, while the deviation of assay accuracies was within +/-13.0%. The average recoveries of analytes were greater than 80.0%. All analytes were proved to be stable during all sample storage, preparation and analytic procedures. The method was successfully applied to the pharmacokinetic study of the four lignans after oral administration of Schisandra chinensis extraction to rats.


The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis.
While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical phases prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis.


Airbag induced facial and bilateral ocular injuries in a 14-year-old child.
Although air bags have reduced the incidence of fatal and severe injuries in automobile collisions, they have been shown to carry a risk of injury themselves. Ocular injury in particular can often be a direct consequence of air bag deployment. We report a 14-year-old child who sustained facial burn and bilateral ocular injuries affecting both the anterior and posterior segments due to an inflated air bag in a low speed motor vehicle accident.


trans-6-Aminocyclohept-3-enols, a new designed polyfunctionalized chiral building block for the asymmetric synthesis of 2-substituted-4-hydroxypiperidines.
trans-6-Aminocyclohept-3-enols 18 and ent-18 are new designed polyfunctionalized chiral building blocks for piperidine alkaloids synthesis and are prepared in high yields from the enzymatically derived cyclohept-3-ene-1,6-diol monoacetate (-)-8. Efficient highly enantioselective syntheses of cis-4-hydroxypipecolic acid (1) and piperidines 3 and 4, in both enantiomeric forms, are described. [reaction: see text]


Hospital Phenotypes in the Management of Patients Admitted for Acute Myocardial Infarction.
To characterize hospital phenotypes by their combined utilization pattern of percutaneous coronary interventions (PCI), coronary artery bypass grafting (CABG) procedures, and intensive care unit (ICU) admissions for patients hospitalized for acute myocardial infarction (AMI). Using the Premier Analytical Database, we identified 129,138 hospitalizations for AMI from 246 hospitals with the capacity for performing open-heart surgery during 2010-2013. We calculated year-specific, risk-standardized estimates of PCI procedure rates, CABG procedure rates, and ICU admission rates for each hospital, adjusting for patient clinical characteristics and within-hospital correlation of patients. We used a mixture modeling approach to identify groups of hospitals (ie, hospital phenotypes) that exhibit distinct longitudinal patterns of risk-standardized PCI, CABG, and ICU admission rates. We identified 3 distinct phenotypes among the 246 hospitals: (1) high PCI-low CABG-high ICU admission (39.2% of the hospitals), (2) high PCI-low CABG-low ICU admission (30.5%), and (3) low PCI-high CABG-moderate ICU admission (30.4%). Hospitals in the high PCI-low CABG-high ICU admission phenotype had significantly higher risk-standardized in-hospital costs and 30-day risk-standardized payment yet similar risk-standardized mortality and readmission rates compared with hospitals in the low PCI-high CABG-moderate ICU admission phenotype. Hospitals in these phenotypes differed by geographic region. Hospitals differ in how they manage patients hospitalized for AMI. Their distinctive practice patterns suggest that some hospital phenotypes may be more successful in producing good outcomes at lower cost.


Anthrax sub-unit vaccine: the structural consequences of binding rPA83 to Alhydrogel®.
An anthrax sub-unit vaccine, comprising recombinant Protective Antigen (rPA83) and aluminium hydroxide adjuvant (Alhydrogel®) is currently being developed. Here, a series of biophysical techniques have been applied to free and adjuvant bound antigen. Limited proteolysis and fluorescence identified no changes in rPA83 tertiary structure following binding to Alhydrogel and the bound rPA83 retained two structurally important calcium ions. For adsorbed rPA83, differential scanning calorimetry revealed a small reduction in unfolding temperature but a large decrease in unfolding enthalpy whilst urea unfolding demonstrated unchanged stability but a loss of co-operativity. Overall, these results demonstrate that interactions between rPA83 and Alhydrogel have a minimal effect on the folded protein structure and suggest that antigen destabilisation is not a primary mechanism of Alhydrogel adjuvancy. This study also shows that informative structural characterisation is possible for adjuvant bound sub-unit vaccines.


Techniques in recurrent giant cell tumour of the first metatarsal in adolescents - A rare report of 2 cases.
Giant cell tumour of the foot is very rare. Very few cases of first metatarsal giant cell tumour were reported. We report two cases of recurrent giant cell tumour in adolescent patients. One was treated with wide excision and fibula grafting. The second patient underwent Boyd's amputation because of superceded infection. Both had no pain, recurrence at the end of final follow up. Recurrent giant cell tumour of the first metatarsal in adolescents and its management is not described in English literature to the best of our knowledge.


[The Maugeri Stress Index: a questionnaire to assess work-related psychological stress].
The European directives concerning the evaluation of work-related stress were absorbed into Italian law by means of Legislative Decree No. 81 of 9 April 2008. To develop a new questionnaire to assess the impact of work-related psychological distress and to validate it by testing its factorial structure, its content, its construct and discriminant validity. After critically reviewing the literature, we generated an initial item set to identify the items to be used in a preliminary version of the questionnaire, and then used a focus group to test the comprehensibility of the items. The questionnaire was administered to 329 subjects working in state and private organisation and a small sample of 29 subjects complaining of vexation at work. The Maugeri Stress Index (MSI) is reliable (Cronbach alpha: 0.93). Factorial analysis indicated five factors: Well-being, Adaptation, Support, Irritability and Avoidance. The total and subscale scores were significantly different when comparing subjects with and without vexation at work. The MSI has a multi-factorial structure, good internal reliability and sufficient discriminant power.


Threats to Feminist Identity and Reactions to Gender Discrimination.
The aim of this research was to examine conditions that modify feminists' support for women as targets of gender discrimination. In an experimental study we tested a hypothesis that threatened feminist identity will lead to greater differentiation between feminists and conservative women as victims of discrimination and, in turn, a decrease in support for non-feminist victims. The study was conducted among 96 young Polish female professionals and graduate students from Gender Studies programs in Warsaw who self-identified as feminists (Mage = 22.23). Participants were presented with a case of workplace gender discrimination. Threat to feminist identity and worldview of the discrimination victim (feminist vs. conservative) were varied between research conditions. Results indicate that identity threat caused feminists to show conditional reactions to discrimination. Under identity threat, feminists perceived the situation as less discriminatory when the target held conservative views on gender relations than when the target was presented as feminist. This effect was not observed under conditions of no threat. Moreover, feminists showed an increase in compassion for the victim when she was portrayed as a feminist compared to when she was portrayed as conservative. Implications for the feminist movement are discussed.


Integrated Health Care Management of Moderate to Severe TBI in Older Patients-A Narrative Review.
Traumatic brain injuries are common, especially within the elderly population, which is typically defined as age 65 and older. This narrative review aims at summarizing and critically evaluating important aspects of their health care management in covering the entire pathway from prehospital care to rehabilitation and beyond. The number of older patients with traumatic brain injury (TBI) is increasing, and there seem to be differences in all aspects of care along their pathway when compared to younger patients. Despite a higher mortality and a generally less favorable outcome, the current literature shows that older TBI patients have the potential to make significant improvements over time. More research is needed to evaluate the most efficient and integrated clinical pathway from prehospital interventions to rehabilitation as well as the optimal treatment of older TBI patients. Most importantly, they should not be denied access to specific treatments and therapies only based on age.


Diversification of the Islamic stock market, Bitcoin, and Bullions in response to the Russia-Ukraine conflict and the COVID-19 outbreak.
This study investigates the interconnectedness of the Islamic stock market, Bullion, and Bitcoin as diversifiers for portfolios, exploring their role as hedges and safe havens. The analysis covers the period from January 2015 to December 2022, with a particular focus on the influence of the COVID-19 pandemic and the Russia-Ukraine War on the MSCI World Islamic Index, bullions (Gold, Silver, Platinum, Nickel, Palladium, and Aluminium), and Bitcoin, employing a time-varying parameter vector autoregression (TVP-VAR) model. During crisis periods, our findings reveal that the transmission and reception of shocks among these assets varied, with a heightened level of co-movement observed during the pandemic and war periods. These results emphasise the importance of considering the dynamic nature of financial assets' connectedness in asset investment decisions, particularly in times of crisis. Furthermore, the findings suggest that Bullion can serve as a hedge for both Bitcoin and the Islamic stock market. The study also explores the optimal diversification of investment portfolios and highlights the importance of adhering to Islamic principles in portfolio diversification. By integrating Islamic rules into the diversification process, investors can enhance the effectiveness and relevance of their investment strategies.


A quantitative analysis of the afferent and extrinsic efferent innervation of specific regions of the bladder and urethra in the cat.
Using the fluorescent tracer dyes bisbenzimide, nuclear yellow and fast blue, the possibility of differential innervation of various regions of the bladder and urethra was tested in cats. The dyes were injected into the lateral detrusor, bladder base, and urethra. Fluorescent cell bodies were counted in serial 48 micron sections of dorsal root, inferior mesenteric, sympathetic chain and pelvic plexus ganglia. Several dorsal root ganglia, primarily S2, were the principal source of afferent innervation to all locations injected. The bladder and urethra received significant efferent innervation from both the inferior mesenteric ganglia and sympathetic chain ganglia (particularly L7 to S2) however, pelvic plexus ganglia made only small contribution to the innervation of these areas. The sympathetic chain and inferior mesenteric ganglia contributed equally to the innervation of the detrusor and bladder base but the sympathetic chain made double the contribution of the inferior mesenteric ganglia to the innervation of the urethra. There was a very low incidence (less than 1%) of neurons which projected to more than one injection site.


Corrigendum: Cultural lenses of the utility of the ICD-11-PD model: Integrating the Peruvian context.
[This corrects the article DOI: 10.3389/fpsyt.2022.1016471.].


Differences in Plaque Characteristics and Myocardial Mass: Implications for Physiological Significance.
The mechanism of the fractional flow reserve (FFR) difference according to sex has not been clearly understood. This study sought to evaluate sex differences in coronary stenosis, plaque characteristics, and left ventricular (LV) mass and their implications for physiological significance. This was a post hoc analysis of a pooled population of multicenter, international prospective cohorts. Patients (166 women and 489 men) underwent coronary computed tomography angiography (CCTA) within 90 days before invasive FFR measurements were included. The minimal lumen area, percent of plaque burden, whole vessel plaque volume by composition, high-risk plaque characteristics, and LV mass were analyzed from CCTA images. Among 1,188 vessels analyzed, the FFR value was higher in women than that in men (0.85 ± 0.13 vs 0.82 ± 0.14; P = 0.001) despite a similar percentage of diameter stenosis between the sexes (45.9% ± 18.9% vs 46.1% ± 17.7%; P = 0.920). The composition of fibrofatty plaque + necrotic core (13.1% ± 16.9% vs 21.2% ± 19.9%; P < 0.001) and frequencies of low attenuation plaque (12.7% vs 24.5%; P < 0.001) and positive remodeling (33.8% vs 45.5%; P = 0.001) were lower in women than in men. Vessel, plaque, and lumen volumes were significantly smaller in women than that in men (all P < 0.001); however, no sex difference was observed in any of these parameters after adjustment for LV mass (all P > 0.10). Sex was not an independent predictor of the FFR value after adjustment for stenosis severity, plaque characteristics, and LV mass. Higher FFR values for the same stenosis severity in women can be explained by fewer high-risk plaque characteristics and smaller myocardial mass in women than that in men. (CCTA-FFR Registry for Risk Prediction; NCT04037163).


COVID-19 and the Sikh Community in the UK: A Qualitative Study.
The COVID-19 pandemic has had, and continues to have, a significant effect on individuals worldwide, and it is clear that minority communities including the Sikh community have been particularly affected by the virus. The current study assessed the impact of the pandemic in a sample of 44 British Sikhs across 11 virtual focus groups. Three main themes emerged including making meaningful connections, struggling to adjust and the organisation of gurdware (Sikh places of worship) in coping with the COVID-19 pandemic. Findings highlight that faith may promote collective action for collective healing especially during mass trauma, with specific insight into what this may entail for the Sikh community.


Discrete Choice Experiment Attribute Selection Using a Multinational Interview Study: Treatment Features Important to Patients with Type 2 Diabetes Mellitus.
Methods for discrete choice experiment (DCE) attribute and attribute-level selection have not yet been firmly established and are rarely reported in detail. This paper describes a qualitative study designed to inform the development of a DCE survey designed to examine preferences for glucagon-like peptide-1 receptor agonist (GLP-1RA) treatments among patients with type 2 diabetes mellitus. The study involved a literature review, interviews with clinical experts, and interviews with GLP-1RA-experienced (i.e., exenatide once weekly, liraglutide once daily) and injection-naïve type 2 diabetes patients from Brazil, China, Germany, Japan, and the UK. Interviews followed a semi-structured guide including open-ended questions, and probes to capture the patients' perspective on important aspects of GLP-1RAs and concerns with injectable treatments. Qualitative analyses were performed utilizing MAXQDA version 11. Descriptive statistics were used to summarize the sample. Thirty-two articles were reviewed, including 13 DCE studies. Thirty-one attributes were identified from the DCE studies, and 61 different attributes were identified in the non-DCE studies. Fifty patients completed interviews: 28 (56%) GLP-1RA-experienced and 22 (44%) injection-naïve, 54% were male, and they had a mean age of 52.8 years. Patients considered efficacy, adverse effects, and dosing frequency as the most important treatment-related attributes. From a list of five pre-defined device- or regimen-related attributes, patients considered dosing frequency, needle size, and injection preparation as the three most important attributes. This study adds to the DCE literature to inform researchers on attribute selection methodology in an international setting as there is limited published information to guide researchers on best practices for selecting and defining attributes for DCE surveys.


Coexpression of a mutant beta-actin and the two normal beta- and gamma-cytoplasmic actins in a stably transformed human cell line.
HUT 14 is a cloned transformed cell line derived from normal diploid human KD fibroblasts. HUT 14 cells have an altered actin phenotype. In addition to the two nonmuscle actins beta and gamma, also present in the parent KD cells, they show the stable expression of a novel actin species (Ax-actin). Amino acid sequence analysis has been used to identify the three actins of HUT 14 cells. beta- and gamma-actins are identified as normal mammalian nonmuscle actins whereas Ax-actin is characterized as a beta-actin mutant revealing a single amino acid substitution at position 244. The results obtained are compatible with a simple mutational event involving a point mutation in one of the two beta-nonmuscle actin genes assumed to be present in proliferating human diploid fibroblasts. Certain emerging principles of nonmuscle actin gene expression in higher vertebrates are discussed.


The endometrial nucleolar channel system as an indicator of progestin potency in HRT.
A quantitative assessment has been made of nucleolar channel systems (NCS) in the endometrial glands of postmenopausal women receiving hormone replacement therapy. The women were taking conjugated equine oestrogen and one of five progestins. The number of NCS induced was related to the dose of progestin administered. The minimum doses of progestin inducing a comparable response to premenopausal secretory phase endometria were found to be 1-2.5 mg norethindrone, 150 micrograms norgestrel and 20 mg dydrogesterone. Progesterone and medroxyprogesterone acetate were inadequate at the doses tested. The results show that the quantification of endometrial gland NCS would be a useful addition to the biochemical and morphological assessments made of any new progestin treatment.


Role of Forkhead Box Class O proteins in cancer progression and metastasis.
It is now widely accepted that several gene alterations including transcription factors are critically involved in cancer progression and metastasis. Forkhead Box Class O proteins (FoxOs) including FoxO1/FKHR, FoxO3/FKHRL1, FoxO4/AFX and FoxO6 transcription factors are known to play key roles in proliferation, apoptosis, metastasis, cell metabolism, aging and cancer biology through their phosphorylation, ubiquitination, acetylation and methylation. Though FoxOs are proved to be mainly regulated by upstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt signaling pathway, the role of FoxOs in cancer progression and metastasis still remains unclear so far. Thus, with previous experimental evidences, the present review discussed the role of FoxOs in association with metastasis related molecules including cannabinoid receptor 1 (CNR1), Cdc25A/Cdk2, Src, serum and glucocorticoid inducible kinases (SGKs), CXCR4, E-cadherin, annexin A8 (ANXA8), Zinc finger E-box-binding homeobox 2 (ZEB2), human epidermal growth factor receptor 2 (HER2) and mRNAs such as miR-182, miR-135b, miR-499-5p, miR-1274a, miR-150, miR-34b/c and miR-622, subsequently analyzed the molecular mechanism of some natural compounds targeting FoxOs and finally suggested future research directions in cancer progression and metastasis.


Casein phosphopeptides drastically increase the secretion of extracellular proteins in Aspergillus awamori. Proteomics studies reveal changes in the secretory pathway.
The secretion of heterologous animal proteins in filamentous fungi is usually limited by bottlenecks in the vesicle-mediated secretory pathway. Using the secretion of bovine chymosin in Aspergillus awamori as a model, we found a drastic increase (40 to 80-fold) in cells grown with casein or casein phosphopeptides (CPPs). CPPs are rich in phosphoserine, but phosphoserine itself did not increase the secretion of chymosin. The stimulatory effect is reduced about 50% using partially dephosphorylated casein and is not exerted by casamino acids. The phosphopeptides effect was not exerted at transcriptional level, but instead, it was clearly observed on the secretion of chymosin by immunodetection analysis. Proteomics studies revealed very interesting metabolic changes in response to phosphopeptides supplementation. The oxidative metabolism was reduced, since enzymes involved in fermentative processes were overrepresented. An oxygen-binding hemoglobin-like protein was overrepresented in the proteome following phosphopeptides addition. Most interestingly, the intracellular pre-protein enzymes, including pre-prochymosin, were depleted (most of them are underrepresented in the intracellular proteome after the addition of CPPs), whereas the extracellular mature form of several of these secretable proteins and cell-wall biosynthetic enzymes was greatly overrepresented in the secretome of phosphopeptides-supplemented cells. Another important 'moonlighting' protein (glyceraldehyde-3-phosphate dehydrogenase), which has been described to have vesicle fusogenic and cytoskeleton formation modulating activities, was clearly overrepresented in phosphopeptides-supplemented cells. In summary, CPPs cause the reprogramming of cellular metabolism, which leads to massive secretion of extracellular proteins.


Excimer laser photorefractive keratectomy (PRK) in myopic astigmatism.
To assess the visual and refractive results of excimer laser photorefractive keratectomy (PRK) in myopic astigmatism. Excimer laser PRK was performed using an Aesculap Meditec MEL 60 laser in 46 myopic astigmatic eyes. Preoperative corneal astigmatism was -1.50 D. (+/- 0.50) in 7 eyes (15.2%); -2.50 D. (+/- 0.50 in 14 eyes (30.5%); -3.50 D. (+/- 0.50) in 13 eyes (28.3%); -4.50 D. (+/- 0.50) in 8 eyes (17.4%); and -5.50 D. (+/- 0.50) in 4 eyes (8.6%). Mean preoperative cylinder was -3.50 D. (+/- 2.50). Mean preoperative sphere was -4.50 D. (+/- 2.25). Pre and post-operative visual acuity, refraction, keratometer readings, corneal topography, intraocular pressure, and slit lamp findings were recorded. By one year of follow-up, postoperative cylinder was between +0.50 and -0.50 D. in 31 eyes (67.4%); between -0.50 and -1.50 D. in 11 eyes (23.9%); between -1.50 and -2.50 D. in 4 eyes (8.7%). Mean post-operative cylinder was -1.21 D. (+/- 1.70). Mean postoperative sphere was -1.09 D. (+/- 1.25). Myopic and astigmatic improvement was achieved in each patient (100%). Topography analysis showed 69.4% were within 0.5 mm, 96.8% within 1 mm, 97.8% within 1.5 mm of centration; 55% of the patients achieved uncorrected visual acuity of 10/10 (Snellen). One patient (2.2%) lost one line of best corrected vision due to decentration and change of axis. These preliminary results of myopic astigmatic excimer laser PRK procedures compare favorably in efficiency and safety with reports of PRK for myopia.


X⋅⋅⋅X Halogen Bond-Induced Supramolecular Helices.
The halogen bond is the attractive interaction between the electrophilic region of a halogen atom and the nucleophilic region of another molecular entity, emerging as a favorable manner to manipulate supramolecular chirality in self-assemblies. Engineering halogen bonded helical structures remains a challenge due to its sensitivity to solvent polarity and competitive forces like hydrogen bonds. Herein, we report a X⋅⋅⋅X (X=Cl, Br, I) type weak halogen bond that induces the formation and evolution of supramolecular helical structures both in solid and solution state. The π-conjugated phenylalanine derivatives with F, Cl, Br and I substitution self-assembled into 21 helical packing driven by hydrogen bond and halogen bond, respectively. The specific molecular geometries of π-conjugated amino acids gave rise to multiple noncovalent forces to stabilize the X⋅⋅⋅X halogen bond with small bond energies ranging from -0.69 to -1.49 kcal mol-1 . Halogen bond induced an opposite helicity compared to the fluorinated species, accompanied by the inversed circularly polarized luminescence.


Classification of electrocardiogram signals with waveform morphological analysis and support vector machines.
Electrocardiogram (ECG) indicates the occurrence of various cardiac diseases, and the accurate classification of ECG signals is important for the automatic diagnosis of arrhythmia. This paper presents a novel classification method based on multiple features by combining waveform morphology and frequency domain statistical analysis, which offer improved classification accuracy and minimise the time spent for classifying signals. A wavelet packet is used to decompose a denoised ECG signal, and the singular value, maximum value, and standard deviation of the decomposed wavelet packet coefficients are calculated to obtain the frequency domain feature space. The slope threshold method is applied to detect R peak and calculate RR intervals, and the first two RR intervals are extracted as time-domain features. The fusion feature space is composed of time and frequency domain features. A combination of support vector machine (SVM) with the help of grid search and waveform morphological analysis is applied to complete nine types of ECG signal classification. Computer simulations show that the accuracy of the proposed algorithm on multiple types of arrhythmia databases can reach 96.67%.


Differential stringent control of the tandem E. coli ribosomal RNA promoters from the rrnA operon expressed in vivo in multicopy plasmids.
The tandem P1, P2 promoter region of the rrnA ribosomal operon has been fused to the t1, t2 terminator region of the rrnB operon in pBR322 plasmid derivatives. This deletes most internal RNA structural elements ordinarily processed out of ribosomal operon transcripts. In vivo as well as in vitro transcripts arising from both promoters terminate predominantly in the t1 terminator region about 40 base pairs beyond the mature rrnB 5S RNA gene. Stringent control of the P1 and P2 promoted transcripts has been assessed in vivo. In these plasmid fusions, the upstream (P1) promoter activity was subject to stringent control, while the downstream (P2) promoter activity was inhibited by amino acid starvation in both stringent and relaxed hosts. A plasmid with an additional deletion of the P2 region also showed stringent regulation of the P1 promoter.


P5A ATPase controls ER translocation of Wnt in neuronal migration.
The Wnt family contains conserved secretory proteins required for developmental patterning and tissue homeostasis. However, how Wnt is targeted to the endoplasmic reticulum (ER) for processing and secretion remains poorly understood. Here, we report that CATP-8/P5A ATPase directs neuronal migration non-cell autonomously in Caenorhabditis elegans by regulating EGL-20/Wnt biogenesis. CATP-8 likely functions as a translocase to translocate nascent EGL-20/Wnt polypeptide into the ER by interacting with the highly hydrophobic core region of EGL-20 signal sequence. Such regulation of Wnt biogenesis by P5A ATPase is common in C. elegans and conserved in human cells. These findings describe the physiological roles of P5A ATPase in neural development and identify Wnt proteins as direct substrates of P5A ATPase for ER translocation.


Clinical methods for evaluating implant framework fit.
Passive fit of implant-supported-prosthesis frameworks has been suggested as a prerequisite for successful long-term osseointegration. However, there are no scientific guidelines as to what is passive fit and how to achieve and measure it. The purpose of this article is to discuss passive fit and to review the various clinical methods that have been suggested for evaluating implant framework fit.Methods. The dental literature was reviewed to identify the clinical methods that have been used to evaluate implant framework fit. The suggested levels of passive fit are empirical. Numerous techniques have been advocated to evaluate the prosthesis-implant interface, but none individually provides objective results. It is suggested that clinicians use a combination of the available methods to minimize misfits.


[Anxiety and substance abuse disorders-Focus on alcohol and cannabis].
Anxiety disorders are frequent, with a 12-month prevalence of 14%, tend to be chronic, and display a high comorbidity with substance abuse disorders. Anxiety and substance abuse disorders are associated with a pronounced individual as well as socioeconomic burden. This article reviews the epidemiological, etiological, and clinical aspects of the dual diagnosis of anxiety and substance abuse disorders, with a particular focus on alcohol and cannabis. The treatment comprises nonpharmacological strategies, mainly cognitive behavioral therapy combined with elements of motivational interviewing (MI) and pharmacological management with antidepressants; however, the use of selective serotonin reuptake inhibitors (SSRI)/serotonin and noradrenaline reuptake inhibitors (SNRI) is not unreservedly recommended. The use of gabapentinoids requires careful risk-benefit consideration because of their potential for abuse and dependence in substance abuse disorders. Benzodiazepines are reserved exclusively for crisis management. Rapid diagnosis and treatment initiation targeting both disorders are essential for successful treatment of comorbid anxiety and substance abuse disorders.


Transcranial alternating stimulation in a high gamma frequency range applied over V1 improves contrast perception but does not modulate spatial attention.
Spatial visual attention enhances information processing within its focus. Vision at an attended location is faster, more accurate, of higher spatial resolution, and has an enhanced sensitivity for fine changes. Earlier hypotheses suggest that the neuronal mechanisms of these processes are based on the interactions among different neuronal groups by means of cortical oscillations in the gamma range. The aim of the current study was to modulate these oscillations externally, using a new technique called transcranial alternating current stimulation (tACS). We investigated the effect of covert spatial attention within and outside its focus by probing contrast sensitivity and contrast discrimination at high resolution across the visual field of 20 healthy human subjects. While applying 40, 60, and 80 Hz tAC stimulation over the primary visual cortex (V1), subjects' contrast-discrimination thresholds were obtained using two different conditions: in the first condition we presented a black disc as a peripheral cue that automatically attracted the subject's attention, whereas there was no cue in the second condition. We found that the spatial profile of contrast sensitivity was not affected by the stimulation. Contrast-discrimination thresholds on the other hand decreased significantly during 60 Hz tACS, whereas there was no effect of 40 and 80 Hz stimulation. These results suggest that attention plays an important role in contrast discrimination based on V1 activities that are influences by gamma range tACS stimulation.