Response adaptive salvage with KTd and ASCT for functional high-risk multiple myeloma-The Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial.
We evaluated re-induction incorporating carfilzomib-thalidomide-dexamethasone (KTd) and autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) refractory, or demonstrating a suboptimal response, to non-IMID bortezomib-based induction. KTd salvage consisted of thalidomide 100 mg daily and dexamethasone 20 mg orally combined with carfilzomib 56 mg/m2 days 1, 2, 8, 9, 15 and 16, of each 28-day cycle. Following four cycles, patients achieving a stringent complete response proceeded to ASCT whereas those who did not received a further two cycles then ASCT. Consolidation consisted of two cycles of KTd then Td to a total of 12 months post-ASCT therapy. Primary end-point was the overall response rate (ORR) with KTd prior to ASCT. Fifty patients were recruited. The ORR was 78% with EuroFlow MRD negativity of 34% in the intention-to-treat population and 65% in the evaluable population at 12 months post-ASCT. With follow-up >38 months median PFS and OS have not been reached with PFS and OS at 36 months of 64% and 80%, respectively. KTd was well tolerated with grade 3 and grade ≥4 adverse events rates of 32% and 10%, respectively. Response adaptive utilisation of KTd with ASCT is associated with both high-quality responses and durable disease control in functional high-risk NDMM.


Efficacy of two-route chemotherapy using cis-diamminedichloroplatinum(II) and its antidote, sodium thiosulfate, in combination with angiotensin II for rat liver tumor.
To improve the therapeutic effects of conventional TRC using i.a. CDDP plus simultaneous i.v. STS in a rat liver tumor, we made use of the AT-II-induced hypertension method, in combination with TRC. The decrease in tumor area (-15%), measured 8 days after the TRC using CDDP 12 mg/kg i.a. plus i.v. post-administration (5 min later) of STS 1,264 mg/kg, was much greater than that (+ 13%) seen in the conventional TRC, but BUN level was elevated (44.9 mg/dl). AT-II (15 micrograms/kg) administered i.a. simultaneously with CDDP normalized the BUN level (20.3 mg/dl) and further decreased (-15% to -31%) the tumor area (modified TRC). The modified TRC also exhibited a higher anti-tumor effect than did CDDP 3 mg/kg with AT-II i.a. (5%) at a similar BUN level (22.2 mg/dl). Loss of body weight, decrease in WBC count and changes in serum transaminases of rats treated with the modified TRC were tolerable. The improved therapeutic effect of the modified TRC was explained as follows: during AT-II-induced hypertension, (I) CDDP delivery to the tumor was increased by 150% and (2) CDDP delivery to the kidney was decreased by 35%. The latter effect of AT-II made feasible the post-administration of STS to CDDP.


Improved selectivity for high-performance liquid chromatographic determination of clonazepam in plasma of epileptic patients.
We report a high-performance liquid chromatography method for clonazepam determination in plasma. The use of a synthetic silica-based stationary phase markedly improved clonazepam resolution compared to standard reversed-phase columns. A liquid-liquid extraction was used, associated with reversed-phase chromatography, gradient elution and ultraviolet detection. Accuracy and precision were satisfactory at therapeutic concentrations. Selectivity was studied for benzodiazepines or other antiepileptic drugs, with particular attention to newly marketed drugs i.e., gabapentine and vigabatrin. No interfering substance was evidenced. Under the conditions described, it was possible to quantify clonazepam at nanogram level even when carbamazepine was present at therapeutic concentrations.


Tissue-targeted R-spondin mimetics for liver regeneration.
R-spondin (RSPO) proteins amplify Wnt signaling and stimulate regeneration in a variety of tissues. To repair tissue in a tissue-specific manner, tissue-targeted RSPO mimetic molecules are desired. Here, we mutated RSPO (RSPO2 F105R/F109A) to eliminate LGR binding while preserving ZNRF3/RNF43 binding and targeted the mutated RSPO to a liver specific receptor, ASGR1. The resulting bi-specific molecule (αASGR1-RSPO2-RA) enhanced Wnt signaling effectively in vitro, and its activity was limited to ASGR1 expressing cells. Systemic administration of αASGR1-RSPO2-RA in mice specifically upregulated Wnt target genes and stimulated cell proliferation in liver but not intestine (which is more responsive to non-targeted RSPO2) in healthy mice, and improved liver function in diseased mice. These results not only suggest that a tissue-specific RSPO mimetic protein can stimulate regeneration in a cell-specific manner, but also provide a blueprint of how a tissue-specific molecule might be constructed for applications in a broader context.


Reading attainment in hearing-impaired children: a comparison of higher and lower achievers.
The purpose of the present research is to study hearing-impaired children with higher and lower reading attainment in order to suggest why some of these choldren achieve greater competency than others. Sixteen children, ages 8 to 17, from two oral schools for the hearing-impaired in Britain, were given two tests of reading comprehension. These revealed (1) marked differences in the reading levels of the children, and (2) a relationship between the test scores and what school the children attended. Differences were also found when the children's oral language use and reading comprehension levels were compared. Oral language use was shown to be an important skill related to attainment in reading. Differences in the nature of early language experiences of children in the two schools were said to be partly responsible for the disparity in the children's oral language ability and the differences in their later ability to read. Some insights are offered to explain how one school has fostered the development of good reading skills where other schools have failed to do so.


Detection of antibodies to mycobacterium tuberculosis by solid phase radioimmunoassay.
The sandwich solid phase radioimmunoassay procedure has been adapted to the serological diagnosis of tuberculosis by the use of disposable plastic haemagglutination trays in which the wells were sensitized with soluble mycobacterial antigen and the subsequent uptake of globulin from test sera detected with radioiodinated antiglobulin. The influence of time and temperature of the incubation stages, pH, washing times, drying and the efficiency of various non-specific blocking agents have been studied. In an initial survey carried out on 319 sera the results obtained showed a good correlation with the presence or absence of established tuberculous infection.


Comparison of vanadium-rich activity of three species fungi of basidiomycetes.
A comparison of vanadium-rich activity of three species fungi of Basidiomycetes, Ganoderma lucidum, Coprinus comatus, and Grifola frondosa, was studied. By fermentation and atomic absorption spectroscopy analysis, the biomass of G. lucidum and G. frondosa declined rapidly when the concentration of vanadium exceeded 0.3% but the biomass of C. comatus did not decline rapidly until the concentration of vanadium exceeded 0.4% and the content of vanadium accumulated in the mycelia was 3529.3 microg/g. After the mice were administered (intragastrically) with vanadium-rich C. comatus, the blood glucose of alloxan-induced hyperglycemic mice was decreased (p < 0.05) and the body weight of the alloxan-induced hyperglycemic mice was increased gradually. Thus, we selected C. comatus to absorb vanadium and chose 0.4% as the optimal concentration of vanadium for the pharmacological works.


Regulation of mGluR7 trafficking by SUMOylation in neurons.
SUMOylation is a post-translational modification by which Small Ubiquitin-like MOdifier (SUMO) proteins are covalently linked to the lysine residues of target proteins via an enzymatic cascade. SUMOylation at the synapse plays an important regulatory role in a wide variety of neuronal function such as synapse formation and receptor endocytosis. The metabotropic glutamate receptor type 7 (mGluR7), a presynaptic G protein-coupled receptor, modulates excitatory neurotransmission and synaptic plasticity by inhibiting neurotransmitter release. The SUMO conjugation of mGluR7 has been demonstrated from several in vitro studies, however, it has not been successful in identifying SUMOylation of full-length mGluR7 in vivo. In the present study, we find that mGluR7 at Lys889 is a target of SUMO conjugation, which is impeded by SUMO-specific isopeptidase SENP1 in HEK 293T cells. In addition, we identify SUMOylated mGluR7 both in brain and primary cortical neurons, that is reduced by the treatment of L-AP4, mGluR7 agonist. We find that deSUMOylated mutation in mGluR7 or overexpression of SENP-1 markedly increases mGluR7 internalization in hippocampal neurons, indicating that endocytosis of mGluR7 is enhanced by the reduced SUMO conjugation of mGluR7. Furthermore, Ser862 phosphorylation facilitates SUMO conjugation of mGluR7. Together, these results reveal that SUMOylation of mGluR7 at Lys889 is required for stable surface expression of mGluR7 in neurons.


Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media.
Isolates were obtained from 169 middle ear aspirates of 148 children with recently treated acute otitis media (RTOM) and from 123 aspirates of 84 children with previously untreated acute otitis media (UOM). In RTOM Streptococcus pneumoniae and Group A streptococcus (P less than 0.02) were recovered less frequently whereas Staphylococcus aureus (P less than 0.001) and Haemophilus influenzae (P less than 0.02) were recovered more frequently than in UOM. Patients with RTOM had more beta-lactamase-producing organisms and multiple isolates. Bilateral sterile aspirates were more common in RTOM although bilateral otitis media was more common in UOM. In RTOM most Branhamella catarrhalis isolates were co-pathogens whereas Staphylococcus epidermidis were always isolated in pure culture. Amoxicillin was the antimicrobial most frequently (83.9%) received for the recently treated episode of otitis media. In RTOM 62.4% of isolates were susceptible to previously prescribed antibiotics, suggesting that factors other than antimicrobial susceptibility are also important in the occurrence of RTOM.


Overview performance of lanthanide oxide catalysts in methanation reaction for natural gas production.
A rapid growth in the development of power generation and transportation sectors would result in an increase in the carbon dioxide (CO2) concentration in the atmosphere. As it will continue to play a vital role in meeting current and future needs, significant efforts have been made to address this problem. Over the past few years, extensive studies on the development of heterogeneous catalysts for CO2 methanation have been investigated and reported in the literatures. In this paper, a comprehensive overview of methanation research studies over lanthanide oxide catalysts has been reviewed. The utilisation of lanthanide oxides as CO2 methanation catalysts performed an outstanding result of CO2 conversion and improvised the conversion of acidity from CO2 gas to CH4 gas. The innovations of catalysts towards the reaction were discussed in details including the influence of preparation methods, the structure-activity relationships as well as the mechanism with the purpose of outlining the pathways for future development of the methanation process.


Relationship between dentifrice fluoride concentration and clinical caries reduction.
To review the published literature on clinical caries trials of fluoride dentifrices and to combine their results in order to evaluate the correlation between fluoride concentration in dentifrice formulations and their anticaries efficacy, i.e., the dose-response relationship. All available dentifrice caries clinical trials reported in the literature of products having at least two fluoride concentrations greater than 0 ppm were reviewed, graphed and statistically analyzed. The evaluation supported a linear correlation between the fluoride concentration of dentifrices between 0 and 5000 ppm F and clinical caries efficacy.


[Synthesis and activation of N-aminopolyacrylamide derivatives as carriers in solid phase degradation of proteins].
N-amino polyacrylamide derivatives were synthesized and their activation by different techniques were examined. The use of these derivatives as solid support in sequential degradation of proteins is proposed. An example is reported.


Ectopic hTERT expression facilitates reprograming of fibroblasts derived from patients with Werner syndrome as a WS cellular model.
The induced pluripotent stem cell (iPSC) technology has provided a unique opportunity to develop disease-specific models and personalized treatment for genetic disorders, and is well suitable for the study of Werner syndrome (WS), an autosomal recessive disease with adult onset of premature aging caused by mutations in the RecQ like helicase (WRN) gene. WS-derived fibroblasts were previously shown to be able to generate iPSCs; however, it remains elusive how WS-derived iPSCs behave and whether they are able to mimic the disease-specific phenotype. The present study was designed to address these issues. Unexpectedly, we found that a specific WS fibroblast line of homozygous truncation mutation was difficult to be reprogrammed by using the Yamanaka factors even under hypoxic conditions due to their defect in induction of hTERT, the catalytic unit of telomerase. Ectopic expression of hTERT restores the ability of this WS fibroblast line to form iPSCs, although with a low efficiency. To examine the phenotype of WRN-deficient pluripotent stem cells, we also generated WRN knockout human embryonic stem (ES) cells by using the CRISPR/Cas9 method. The iPSCs derived from WS-hTERT cells and WRN-/- ESCs are fully pluripotent, express pluripotent markers and can differentiate into three germ layer cells; however, WS-iPSCs and WRN-/- ESCs show S phase defect in cell cycle progression. Moreover, WS-iPSCs and WRN-/- ESCs, like WS patient-derived fibroblasts, remain hypersensitive to topoisomerase inhibitors. Collectively, WS-derived iPSCs and WRN-/- ESCs mimic the intrinsic disease phenotype, which may serve as a suitable disease model, whereas not be good for a therapeutic purpose without gene correction.


Broad neutralization of wild-type dengue virus isolates following immunization in monkeys with a tetravalent dengue vaccine based on chimeric yellow fever 17D/dengue viruses.
The objective of the study was to evaluate if the antibodies elicited after immunization with a tetravalent dengue vaccine, based on chimeric yellow fever 17D/dengue viruses, can neutralize a large range of dengue viruses (DENV). A panel of 82 DENVs was developed from viruses collected primarily during the last decade in 30 countries and included the four serotypes and the majority of existing genotypes. Viruses were isolated and minimally amplified before evaluation against a tetravalent polyclonal serum generated during vaccine preclinical evaluation in monkey, a model in which protection efficacy of this vaccine has been previously demonstrated (Guirakhoo et al., 2004). Neutralization was observed across all the DENV serotypes, genotypes, geographical origins and isolation years. These data indicate that antibodies elicited after immunization with this dengue vaccine candidate should widely protect against infection with contemporary DENV lineages circulating in endemic countries.


Apoptosis induced by glycoprotein (150-kDa) isolated from Solanum nigrum L. is not related to intracellular reactive oxygen species (ROS) in HCT-116 cells.
This study was carried out to investigate the apoptotic effects of glycoprotein [Solanum nigrum L. (SNL) glycoprotein, 150-kDa] isolated from Solanum nigrum L., which has been used as an antipyretic and anticancer agent in folk medicine. With the purified SNL glycoprotein, we evaluated the cytotoxic and apoptotic effects of SNL glycoprotein on HCT-116 cells, DNA fragmentation and nuclear staining assays, respectively. SNL glycoprotein has an apparent cytotoxic and apoptotic effect at a concentration of 40 microg/ml after 4 h. To further verify the apoptotic effect, we investigated the changes in activity of the apoptotic-related proteins [Bid, cytochrome c, caspases and poly(ADP-ribose)polymerase (PARP)] triggered by SNL glycoprotein, using a western blot analysis. The results in this study indicated that SNL glycoprotein has a stimulatory effect on Bid activation, resulting in the release of cytochrome c, the stimulation of caspase-8, -9 and -3 activities, and the cleavage of PARP in HCT-116 cells. However, SNL glycoprotein did not significantly stimulate an increase in levels of intracellular reactive oxygen species (ROS). From the results in this experiment, it is suggested that SNL glycoprotein induces apoptosis through the mitochondrial apoptotic signal pathway in HCT-116 cells, rather than through intracellular ROS.


Therapeutic effect of histidine decarboxylase inhibitor on chronic active hepatitis.
The effect of orally administered histidine decarboxylase inhibitor on liver function tests and histological appearance as well as on plasma histamine level were evaluated in biopsy proven 13 patients with chronic active hepatitis, whose liver function tests were refractory to other measures. Tritoqualine was used as histidine decarboxylase inhibitor and was administered in dose levels of 600 to 1,600 mg per day. Before treatment the average value of SGOT, SGPT and plasma histamine showed 252 +/- 24U, 318 +/- 152U and 15.2 +/- 5.5 microgram/L, respectively. Results obtained at six weeks' treatment, however, gave significantly improved values, indicating SGOP 57 +/- 24 (p less than 0.001), SGOP 40 +/- 28 (p less than 0.001) and plasma histamine 8.6 +/- 0.4 (p less than 0.001). Serum gammaglobulin also tended to fall (p less than 0.1). Marked improvement was noted in reexamined biopsied specimen, representing disappearance of fibrogenesis as well as round cell infiltration in and around the portal tract, together with pericellular fibrosis. Four cases have been proven to be healed. Despite long-term administration, no obvious side effect was observed. Investigation for HBsAg revealed to be positive in 4, however, no conspicuous difference was seen from that of negative cases in the improvement.


PVP-b-PEO block copolymers for stable aqueous and ethanolic graphene dispersions.
The ability to disperse pristine (unfunctionalized) graphene is important for various applications, coating, nanocomposites, and energy related systems. Herein we report that amphiphilic copolymers of poly(4-vinyl pyridine)-block-poly(ethylene oxide) (PVP-b-PEO) are able to disperse graphene with high concentrations about 2.6mg/mL via sonication and centrifugation. Ethanolic and aqueous highly-ordered pyrolytic graphite (HOPG) dispersions with block copolymers were prepared and they were compared with the dispersions stabilized by P-123 Pluronic® (P123) and poly(styrene)-block-poly(ethylene oxide) (PS-b-PEO) synthesized. Transmission electron microscopy, scanning electron microscopy, atomic force microscopy, X-ray diffraction, Raman and UV-visible spectroscopic studies confirmed that PVP-b-PEO block copolymers are better stabilizers for HOPG graphene than P123 and PS-b-PEO. X-ray photoelectron spectroscopy and force-distance (F-d) curve analyses revealed that the nitrogen of vinyl pyridine plays a vital role in better attractive interaction with surface of graphene sheet. Thermogravimetric analysis showed that larger amount of PVP-b-PEO was adsorbed onto graphene with longer poly(4-vinyl pyridine) (PVP) block length and in aqueous medium, respectively, and which was consistent with electrical conductivity decreases. This study presents the dispersion efficiency of graphene using PVP-b-PEO varies substantially depending on the lengths of their hydrophobic (PVP) domains.


Increased urinary Smad3 is significantly correlated with glomerular hyperfiltration and a reduced glomerular filtration rate and is a new urinary biomarker for diabetic nephropathy.
Diabetic nephropathy is one of the major microvascular complications of diabetes. We investigated the association between urinary Smad3 (usmad3) levels, glomerular hyperfiltration, and the development of nephropathy in patients with type 2 diabetes mellitus (T2DM). The usmad3 level was determined by enzyme-linked immunosorbent assay in 245 well-characterised patients with T2DM and 82 healthy control subjects. The associations of the usmad3 level with glomerular hyperfiltration, glucose and lipid profiles, and renal function were evaluated. The usmad3 level was significantly higher in patients with diabetes than in the control group. The level in the hyperfiltration group was higher than that in the normofiltering group, regardless of whether patients were in the normoalbuminuric or the proteinuria groups. Pearson's correlation analysis suggested that the usmad3 level was significantly correlated with age, systolic blood pressure, fasting plasma glucose, insulin, C-peptide, glycated haemoglobin, and estimated glomerular filtration rate (eGFR). A multiple linear stepwise regression analysis revealed that usmad3 levels in patients with T2DM and an eGFR ≥ 90 ml/min/1.73 m(2) were independently and positively correlated with eGFR, whereas in patients with T2DM and eGFR <90 ml/min/1.73 m(2), the levels were independently and negatively correlated with eGFR. The usmad3 level was significantly correlated with biphasic changes in the GFR (both glomerular hyperfiltration and reduced eGFR) in patients with T2DM. Usmad3 may serve as a novel marker for hyperfiltration and for screening patients with T2DM for nephropathy.


Event-triggered adaptive dynamic programming for decentralized tracking control of input constrained unknown nonlinear interconnected systems.
This paper addresses decentralized tracking control (DTC) problems for input constrained unknown nonlinear interconnected systems via event-triggered adaptive dynamic programming. To reconstruct the system dynamics, a neural-network-based local observer is established by using local input-output data and the desired trajectories of all other subsystems. By employing a nonquadratic value function, the DTC problem of the input constrained nonlinear interconnected system is transformed into an optimal control problem. By using the observer-critic architecture, the DTC policy is obtained by solving the local Hamilton-Jacobi-Bellman equation through the local critic neural network, whose weights are tuned by the experience replay technique to relax the persistence of excitation condition. Under the event-triggering mechanism, the DTC policy is updated at the event-triggering instants only. Then, the computational resource and the communication bandwidth are saved. The stability of the closed-loop system is guaranteed by implementing event-triggered DTC policy via Lyapunov's direct method. Finally, simulation examples are provided to demonstrate the effectiveness of the proposed scheme.


Ocular albinism 1 protein: trafficking and function when expressed in Saccharomyces cerevisiae.
The ocular albinism 1 (Oa1) protein is believed to be involved in the biogenesis of melanosomes, but its cellular localization is controversial and its function is unknown. Based upon sequence homology, it has been predicted that Oa1 belongs to the G protein coupled receptor (GPCR) superfamily. We used the yeast Saccharomyces cerevisiae as a genetically amenable system to study the localization and function of Oa1. Sucrose gradient and immunofluorescence studies revealed that when expressed in yeast, Oa1 localizes to the prevacuolar compartment, the functional equivalent of the mammalian late endosome. Oa1 behaved as G protein coupled receptor in a yeast-based GPCR signalling assay. Extracts of cultured melanocytes, and, in particular, a particulate fraction from cultured melanocytes, stimulated Oa1-mediated GPCR signalling.


Differences in game-related statistics of basketball performance by game location for men's winning and losing teams.
The aim of the present study was to identify game-related statistics that differentiate winning and losing teams according to game location. The sample included 306 games of the 2004-2005 regular season of the Spanish professional men's league (ACB League). The independent variables were game location (home or away) and game result (win or loss). The game-related statistics registered were free throws (successful and unsuccessful), 2- and 3-point field goals (successful and unsuccessful), offensive and defensive rebounds, blocks, assists, fouls, steals, and turnovers. Descriptive and inferential analyses were done (one-way analysis of variance and discriminate analysis). The multivariate analysis showed that winning teams differ from losing teams in defensive rebounds (SC = .42) and in assists (SC = .38). Similarly, winning teams differ from losing teams when they play at home in defensive rebounds (SC = .40) and in assists (SC = .41). On the other hand, winning teams differ from losing teams when they play away in defensive rebounds (SC = .44), assists (SC = .30), successful 2-point field goals (SC = .31), and unsuccessful 3-point field goals (SC = -.35). Defensive rebounds and assists were the only game-related statistics common to all three analyses.


Astigmatism of the mammalian cornea: evolutionary and perceptive significance.
Astigmatism enables spatial, linear and directional discrimination. These faculties are demonstrated by astigmatic photographic experiments. Comparative anatomic deductions lead to the assumption that the eyes of early mammals were astigmatic. Thereby these animals, lacking binocularity and accommodation, could achieve visual spatial information. This assumption is supported by the fact that features of astigmatic refraction, specially straight linearity, have been adopted by various intra-ocular structures, and by the neuronal structuralisation of receptive fields in the visual cortex of mammals.


Ictal EEG source localization in focal epilepsy: Review and future perspectives.
Electroencephalographic (EEG) source imaging localizes the generators of neural activity in the brain. During presurgical epilepsy evaluation, EEG source imaging of interictal epileptiform discharges is an established tool to estimate the irritative zone. However, the origin of interictal activity can be partly or fully discordant with the origin of seizures. Therefore, source imaging based on ictal EEG data to determine the seizure onset zone can provide precious clinical information. In this descriptive review, we address the importance of localizing the seizure onset zone based on noninvasive EEG recordings as a complementary analysis that might reduce the burden of the presurgical evaluation. We identify three major challenges (low signal-to-noise ratio of the ictal EEG data, spread of ictal activity in the brain, and validation of the developed methods) and discuss practical solutions. We provide an extensive overview of the existing clinical studies to illustrate the potential clinical utility of EEG-based localization of the seizure onset zone. Finally, we conclude with future perspectives and the needs for translating ictal EEG source imaging into clinical practice.


Development and biological evaluation of 99mTc-BAT-tropane esters.
Two (99m)Tc-BAT-tropane conjugates, i.e., technetium(V)-oxo-3-[N-(2-mercaptoethyl), N-(N'-(2-mercaptoethyl)-2-aminoethyl)]-aminopropyl 3beta-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]octane-2beta-carboxylate and the corresponding norchloro derivative, were prepared and evaluated as potential imaging agents for the central nervous dopamine transporter (DAT) system. In these compounds, a tropane and a (99m)Tc-BAT moiety were linked through an ester bond. Both compounds were formed as a mixture of two diastereomers which could be purified and isolated using reversed-phase high-performance liquid chromatography (HPLC). Radio-LC-MS analysis supported the hypothesised structure of the synthesised technetium complexes. After intravenous injection in mice and rats, the compounds were stable in vivo, and no important metabolites were found in plasma or urine. In vitro testing suggested specific competitive binding to the DAT system, but in vivo experiments in rats showed no significant brain uptake for the diastereomers of both compounds; neither was there any specific uptake in the striatum. The results suggest that replacement of a methylene linker by an ester does not seriously affect the binding properties of the tropane conjugates to the dopamine transporter but results in a drastic reduction of passage over the blood-brain barrier (BBB).


Current status of rotavirus vaccines.
Rotaviruses remain the major cause of childhood diarrheal disease worldwide and of diarrheal deaths of infants and children in developing countries. The huge burden of childhood rotavirus-related diarrhea in the world continues to drive the remarkable pace of vaccine development. Research articles were searched using terms "rotavirus" and "rotavirus vaccine" in MEDLINE and PubMed. Articles not published in the English language, articles without abstracts, and opinion articles were excluded from the review. After preliminary screening, all articles were reviewed and synthesized to provide an overview of current vaccines and vaccination programs. In this review of the global rotavirus vaccines and vaccination programs, the principles of rotavirus vaccine development and the efficacy of the currently licensed vaccines from both developed and developing countries were summarized. Rotavirus is a common cause of diarrhea in children in both developed and developing countries. Rotavirus vaccination is a cost-effective measure to prevent rotavirus diarrhea.


Aggresomes do not represent a general cellular response to protein misfolding in mammalian cells.
Aggresomes are juxtanuclear inclusion bodies that have been proposed to represent a general cellular response to misfolded proteins in mammalian cells. Yet, why aggresomes are not a pathological characteristic of protein misfolding diseases is unclear. Here, we investigate if a misfolded protein inevitably forms aggresomes in mammalian cells. We show that a cytoplasmic form of the prion protein may form aggresomes or dispersed aggregates in different cell lines. In contrast to aggresomes, the formation of dispersed aggregates is insensitive to histone deacetylase 6 inhibitors and does not result in cytoskeleton rearrangements. Modulation of expression levels or proteasome inhibitors does not alter the formation of dispersed aggregates. Our results establish that aggresomes are not obligatory products of protein misfolding in vivo.


Cytokines, thyroid autoantibody synthesis and thyroid cell survival in culture.
In autoimmune thyroid disease lymphoid cells infiltrating the thyroid gland occur in conspicuous aggregates or as a diffusely distributed population invading the thyroid follicles. Consequently cytokines secreted by activated T cells or macrophages could influence neighbouring thyroid cells as well as other lymphocytes. We have investigated this possibility using recombinant cytokines. Thyroid cell survival was assessed in terms of mitochondrial dehydrogenase activity in monolayers exposed to tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 (IL-1 alpha and beta) and interleukin-2 (IL-2) in the presence or absence of thyroid-stimulating hormone (TSH). Neither TNF-alpha nor IL-2 affected thyroid cell survival, IFN-gamma was usually inhibitory and IL-1 alpha slightly enhanced cell survival in some experiments. However, the effects were small and variable and were not enhanced by potentially synergistic combinations of cytokines, longer periods of exposure, or different culture conditions. In contrast, IFN-gamma, IL-2 and TNF-alpha inhibited the ability of thyroid lymphocytes from patients with Graves' disease and Hashimoto's thyroiditis to synthesize autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg). Comparison of lymphoid populations isolated by digestion and/or mechanical disaggregation indicated that a population of activated B cells, plasma cells and T cells, intimately associated with thyroid cells since they could only be extracted by digestion, was influenced by cytokines. Our studies suggest that in addition to its well-recognized ability to induce MHC class II antigens on thyroid cells, IFN-gamma may inhibit thyroid cell proliferation and TNF-alpha, IFN-gamma and IL-2 may down-regulate thyroid autoantibody synthesis.


Endocrine emergencies.
Several potentially fatal endocrine emergencies in relation to obstetrics and gynecology are discussed in the article. Rates of case fatality vary in different series, but range from 10% to 30%. Rapid recognition, prompt supportive care, and intervention likely maximize maternal and fetal outcomes.


Nitrogen dioxide prediction in Southern California using land use regression modeling: potential for environmental health analyses.
We modeled the intraurban distribution of nitrogen dioxide (NO(2)), a marker for traffic pollution, with land use regression, a promising new exposure classification technique. We deployed diffusion tubes to measure NO(2) levels at 39 locations in the fall of 2003 in San Diego County, CA, USA. At each sample location, we constructed circular buffers in a geographic information system and captured information on roads, traffic flow, land use, population and housing. Using multiple linear regression, we were able to predict 79% of the variation in NO(2) levels with four variables: traffic density within 40-300 m of the sampling location, traffic density within 300-1000 m, length of road within 40 m and distance to the Pacific coast. Applying this model to validation samples showed that the model predicted NO(2) levels within, on average, 2.1 p.p.b for 12 training sites initially excluded from the model. Our evaluation of this land use regression model showed that this method had excellent prediction and robustness in a North American context. These models may be useful tools in evaluating health effects of long-term exposure to traffic-related pollution.


Expansion of Invasive Group A Streptococcus M1UK Lineage in Active Bacterial Core Surveillance, United States, 2019‒2021.
From 2015-2018 to 2019‒2021, hypertoxigenic M1UK lineage among invasive group A Streptococcus increased in the United States (1.7%, 21/1,230 to 11%, 65/603; p<0.001). M1UK was observed in 9 of 10 states, concentrated in Georgia (n = 41), Tennessee (n = 13), and New York (n = 13). Genomic cluster analysis indicated recent expansions.


Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: a putative mechanism of antiseizure action.
Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (beta-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. We found that PUFAs at concentrations down to 21microM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels.


Radiotherapy for brainstem gliomas in children and adults: A single-institution experience and literature review.
To evaluate the treatment results of radiotherapy (RT) in children and adults with brainstem gliomas (BSGs) and review the previous literature. Thirty patients (14 children, 16 adults) with BSG treated using RT were retrospectively evaluated. The median ages of the children and adults were 8 years (range: 2-16 years) and 49 years (range: 19-75 years), respectively. A histological diagnosis was obtained in 11 patients. The median total radiation dose was 56 Gy (range: 50-70 Gy) with a single fraction size of 1.8-2.0 Gy. Temozolomide was administered concurrently with RT in 14 patients. Tumor progression after RT occurred in 26 patients (14 children and 12 adults). Four adults survived without tumor progression. The median survival times for children and adults were 8.5 and 39 months, respectively. The 1-, 2- and 3-year overall survival rates for children/adults were 29%/75%, 14%/68% and 0%/53%, respectively (P = 0.001), and the 1-, 2- and 3-year progression-free survival rates for children/adults were 14%/69%, 0%/49% and 0%/35%, respectively (P < 0.001). Grade 3 or higher acute and late toxicities did not occur. In this study, the prognosis of children with BSGs was considerably poorer than that of adults, and our results are consistent with those of previous studies. Efforts should be made to improve the survival outcomes of patients with BSGs, especially children.


Efficacy of ivermectin against benzimidazole-resistant Nematodirus spathiger in sheep.
Eighteen helminth-free lambs were randomly allocated to six groups of three. Each lamb was dosed with 3300 infective larvae pooled from two isolates of Nematodirus spathiger known to be benzimidazole resistant. One lamb from each group was treated with oral ivermectin, one with oral oxfendazole and one left untreated 21 days after infection. All lambs were humanely killed 14 days later and small intestine worm counts performed. No Nematodirus were found in the ivermectin-treated lambs. Nematodirus numbers were reduced by 13% in oxfendazole-treated lambs relative to the control lambs.


Urinary urea excretion in idiopathic hypercalciuria of children.
In adults, it is well known that high protein intake may increase the risk of nephrolithiasis through increased urinary calcium excretion and other mechanisms. We aimed to assess the role of protein intake on urinary calcium excretion in children with idiopathic hypercalciuria (HC). The 24-h urinary urea excretion as a reflection of protein intake was evaluated in 65 children with HC and in 76 normocalciuric control children. All of them were on a free diet and did not receive any specific drug. Urinary urea excretion was 18.9+/-6.6 (SD) mmol/kg/day in the HC group and 14.2+/-4.9 in controls (P<0.0001). Urinary urea excretion significantly decreased with age, as well as with body weight and height gain in both groups. Calcium excretion significantly increased with increasing sodium and urea excretion in the HC but not the control group. There was a significant (P=0.005) interaction between urinary sodium and urea excretion in the rising calciuria of the HC group. Multiple regression analysis showed that, in the HC group, variations in urinary urea explained 11.4% of the entire variability of urinary calcium excretion, whereas adding the urinary sodium effect increased this relation only to 16%. Children with HC have a higher dietary protein intake than normocalciuric children. The decrease in urea excretion with increasing age and body mass may reflect the relatively higher protein intake of young growing individuals. Salt and protein have a cumulative effect on rising calcium excretion in HC children, but the role of protein intake is outstanding.


Alterations in plasma volume, electrolytes and protein during incremental exercise at different pedal speeds.
We investigated the effects of pedal speed on changes in plasma volume, electrolytes and protein during incremental exercise. Ten adult males participated in two, 30 minute incremental cycle ergometer exercise tests at room temperature (22 degrees C, rh = 56%). Exercise load was increased from 20 to 70% of peak VO2. Five minutes were spent at each of six stages which were equally spaced in exercise intensity. Subjects pedaled at 50 (50 RPM) and 90 (90 RPM) rev.min-1. Venous blood samples were drawn prior to exercise and during the last minute of each stage. Relative plasma volume changes showed a progressive hemoconcentration during the exercise. There were no significant differences due to pedal speed as plasma volume loss averaged -7.3% during exercise. [Na+], [Cl-], and [K+] increased significantly during exercise but were not influenced by pedal speed. Changes in plasma protein and albumin concentrations indicated that there was a loss of globulin from the vascular volume in both conditions and an addition of albumin to the plasma in 50 RPM. The difference in plasma albumin dynamics was possibly related to an effect of pedal speed on movement of fluid in the lymphatic vessels of the legs.


High expression of p21 Waf1 in sarcoid granulomas: a putative role for long-lasting inflammation.
In sarcoid granulomas, apoptotic events are reduced, which explains their characteristic long-lasting inflammation. We have described that interferon-gamma (IFN-gamma) inhibits apoptosis in macrophages through the expression of p21(Waf1). Here, we explore the molecular mechanisms involved in the inhibition of apoptosis in sarcoid granulomas. We analyzed skin biopsies from 19 sarcoidosis patients and 16 controls. Total RNA was subjected to semiquantitative reverse transcriptase-polymerase chain reaction analysis. There was no difference found in the expression of proapoptotic (Bax and Bcl-X(s)) or antiapoptotic (Bcl-2 and Bcl-X(L)) genes nor in the expression of the tumor suppressor gene p53. Furthermore, the expression of IFN-gamma and the cdk inhibitors p21(Waf1) and p27(Kip1) were analyzed. IFN-gamma was detected in 37% of the sarcoidosis patients, and controls were negative (P<0.02). In addition, a higher proportion of patients expressing p21(Waf1) (58%) versus controls (12%) was found (P<0.005). There was a significant correlation between the expression of IFN-gamma and p21(Waf1) (r=0.69) and between p21(Waf1) and fibronectin (r=0.65). Finally, using immunohistochemistry, high p21(Waf1) reactivity was observed inside the granuloma. We conclude that the high levels of p21(Waf1) in sarcoidosis may explain the absence of apoptosis in the granuloma and the persistence of inflammation.


Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant.
The epidermal growth factor receptor (EGFR) T790M mutant is found in approximately 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). Here, a series of novel aminopyrimidines bearing a hydrazone moiety were identified as potent and selective EGFR inhibitors. Compounds 14a, 15g, and 15i potently inhibited all EGFR mutants including EGFR T790M/L858R, EGFR T790M/delE746_A750, and EGFR T790M while they showed weak effects on the wild type (WT) EGFR. In addition, these compounds effectively suppressed proliferation of gefitinib-resistant H1975 (EGFR T790M/L858R) cells but were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. Therefore, 14a, 15g, and 15i might be promising candidates to overcome drug resistance mediated by the EGFR T790M mutant.


A 'retro-inverso' PNA: structural implications for DNA and RNA binding.
'Retro-inverso' peptide nucleic acid (PNA) monomers of thymine (T*: N-(amidomethyl)-N-(N1-thyminyl-acetyl)-beta-alanyl) (and adenine) have been prepared and introduced in PNA oligomers. A homo 'retro-inverso' T*8 PNA was found not to hybridize to a complementary DNA or RNA oligonucleotide, whereas introduction of one retro-inverso thymine unit into the middle of a normal PNA 15-mer resulted in a c.a. 8 degrees C destabilization of the complex of this oligomer with a complementary DNA or RNA oligomer. In an effort to compensate for the structural nucleobase 'phase-shift' caused by the T* monomer by also introducing a beta-alanine monomer it is concluded that the effect of the T* backbone is -7 degrees C when hybridizing to DNA and -4.5 degrees C when hybridizing to RNA. Nonetheless, the T* unit shows good sequence discrimination comparable to that of normal PNA. Molecular dynamics simulations indicate an unfavourable conformation of the backbone amide carbonyl group resulting in reduced interaction with the aqueous medium and an 'electrostatic clash' with the carbonyl of the nucleobase linker. These results show that a simple inversion of an amide bond in the PNA backbone has a dramatic, and hardly predictable, effect on the DNA mimicking properties of the oligomer.


The functional universe of membrane contact sites.
Organelles compartmentalize eukaryotic cells, enhancing their ability to respond to environmental and developmental changes. One way in which organelles communicate and integrate their activities is by forming close contacts, often called 'membrane contact sites' (MCSs). Interest in MCSs has grown dramatically in the past decade as it is has become clear that they are ubiquitous and have a much broader range of critical roles in cells than was initially thought. Indeed, functions for MCSs in intracellular signalling (particularly calcium signalling, reactive oxygen species signalling and lipid signalling), autophagy, lipid metabolism, membrane dynamics, cellular stress responses and organelle trafficking and biogenesis have now been reported.


Small ocean temperature increases elicit stage-dependent changes in DNA methylation and gene expression in a fish, the European sea bass.
In natural fish populations, temperature increases can result in shifts in important phenotypic traits. DNA methylation is an epigenetic mechanism mediating phenotypic changes. However, whether temperature increases of the magnitude predicted by the latest global warming models can affect DNA methylation is unknown. Here, we exposed European sea bass to moderate temperature increases in different periods within the first two months of age. We show that increases of even 2 °C in larvae significantly changed global DNA methylation and the expression of ecologically-relevant genes related to DNA methylation, stress response, muscle and organ formation, while 4 °C had no effect on juveniles. Furthermore, DNA methylation changes were more marked in larvae previously acclimated to a different temperature. The expression of most genes was also affected by temperature in the larvae but not in juveniles. In conclusion, this work constitutes the first study of DNA methylation in fish showing that temperature increases of the magnitude predicted by the latest global warming models result in stage-dependent alterations in global DNA methylation and gene expression levels. This study, therefore, provides insights on the possible consequences of climate change in fish mediated by genome-wide epigenetic modifications.


A placental cause of intra-uterine fetal death depends on the perinatal mortality classification system used.
Different classification systems for the cause of intra-uterine fetal death (IUFD) are used internationally. About two thirds of these deaths are reported as unexplained and placental causes are often not addressed. Differences between systems could have consequences for the validity of vital statistics, for targeting preventive strategies and for counselling parents on recurrence risks. Our objective was to compare use of the Tulip classification with other currently used classification systems for causes of IUFD. We selected the extended Wigglesworth classification, modified Aberdeen and the classifications by Hey, Hovatta, de Galan-Roosen and Morrison. We also selected the ReCoDe system for relevant conditions, comparable to contributing factors in the Tulip classification. Panel classification for 485 IUFD cases in the different systems was performed by assessors after individual investigation of structured patient information. Distribution of cases into cause of death groups for the different systems varied, most of all for the placental and unknown groups. Systems with a high percentage of cases with an unknown cause of death and death groups consisting of clinical manifestations only are not discriminatory. Our largest cause of death group was placental pathology and classification systems without placental cause of death groups or minimal subdivision of this group are not useful in modern perinatal audit as loss of information occurs. The most frequent contributing factor was growth restriction. This illustrates the vital role of the placenta in determination of optimal fetal development. In the Tulip classification, mother, fetus and placenta are addressed together. The system has a clear defined subclassification of the placenta group, a low percentage of unknown causes and is easily applied by a multidisciplinary team. A useful classification aids future research into placental causes of IUFD.


Nodular-type muscle sarcoidosis developing after a dog bite.
We report a 46-year-old woman who experienced swelling of the right thigh around the wound caused by a dog bite. Physical findings, laboratory findings, imaging studies, and muscle biopsy showed that this was nodular-type muscle sarcoidosis. This is an unusual case of sarcoidosis, and the possibility is discussed that a dog bite may serve as a trauma to trigger sarcoidosis in genetically predisposed individuals.


Preparation of molecularly imprinted resin/polydopamine nanofibers mat for the highly efficient extraction and determination of sulfonamides in environmental water.
With polyacrylonitrile nanofibers mat (PAN NFsM) as a template, molecularly imprinted resin/polydopamine nanofibers mat (MIR/PDA NFsM) was synthesized for the extraction of sulfonamides (SAs) in water. The specific surface area and pore volume were increased obviously due to the functionalization of MIR. The adsorption efficiencies of MIR/PDA NFsM under optimized conditions for SAs were 92.3-99.3%. Possible adsorption mechanisms of imprinting recognition and hydrogen bond interactions were also put forward. Compared with MIR particles, the MIR/PDA NFsM exhibited much superior adsorption performance. Particularly, the outstanding mass transfer efficiency of MIR/PDA NFsM was much higher than the other reported adsorbents for SAs. Finally, a new method based on the solid-phase extraction (SPE) of MIR/PDA NFsM was successfully developed for the detection of five SAs in environmental water with HPLC-MS/MS and applied to the analysis of actual samples. Under the selected conditions, the enrichment factors of MIR/PDA NFsM of SCP, SMT, SMZ, SMR, and SMX were between 23.0 and 25.0. Low detection limits (0.26-0.76 ng L-1), broad linear range (1.0 ng L-1 to 10.0 μg L-1), and satisfactory recoveries (82.8-115.6%) and precisions (RSDs < 7.2%) were obtained. Moreover, the excellent reusability properties and storage stability endowed MIR/PDA NFsM with great value for practical applications.


Traumatic pulmonary artery--left atrial fistula: an unusual case of cyanosis in an adult.
Eighteen months after sustaining a stab wound to the left upper chest, a 59-year-old man presented with cyanosis and extertional dyspnea. Arterial desaturation due to a central 22 per cent right-to-left shunt was present. A selective pulmonary arteriogram demonstrated a fistula between the main pulmonary artery and the left atrium. At operation the fistula was closed. A laceration of the pulmonic valve and healed pericarditis were present. Marked symptomatic improvement followed the operation, but a murmur of pulmonic valvular regurgitation persisted. The fistula and laceration of the pulmonic valve were probably traumatic in origin.


Association of polymorphisms in translesion synthesis genes with prognosis of advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy.
Translesion synthesis (TLS) polymerases enable cells to bypass or overcome DNA damage during DNA replication and contributes to genomic instability and cancer. Inhibition of the expression of TLS genes enhances the sensitivity of cancer cells to cisplatin. This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) in the TLS genes and clinical outcome of advanced non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. A total of 16 SNPs were genotyped and analyzed in 302 advanced NSCLC patients (discovery set), and the results were further validated in additional 428 NSCLC patients (validation set). Analyses revealed significant associations of two SNPs, rs3213801 and rs3792136, with overall survival, with the lowest combined P values of 0.003 and 0.016, respectively. These effects also remained in stratification analyses by clinical variables. Furthermore, the number of risk genotypes of the two SNPs showed a cumulative effect on overall survival (P = 0.03). Genetic polymorphisms in the TLS genes might serve as potential predictive biomarkers of prognosis of advanced NSCLC patients treated with platinum-based chemotherapy.


Expression of Tie-1 and 2 receptors, and angiopoietin-1, 2 and 4 in gastric carcinoma; immunohistochemical analyses and correlation with clinicopathological factors.
There is strong evidence that tyrosine kinases are involved in the regulation of tumour progression, cellular growth and differentiation. Recently, many kinds of tyrosine kinase receptors have been reported, and among them Tie-1 and 2 constitute a major class. Angiopoietin (Ang)-1 is known as a ligand of the Tie-2 tyrosine kinase receptor. The aim of this study was to determine the expression profile of Tie-1 and 2 and Ang-1, 2 and 4 in gastric adenocarcinoma. Eighty-nine cases of surgically resected human gastric adenocarcinoma were studied by immunohistochemistry. Of these, 60 (67.4%), 61 (68.5%), 69 (77.5%), 75 (84.3%), and 47 cases (52.8%) showed positive staining in the cytoplasm of carcinoma cells for the Tie-1 and 2 and Ang-1, 2 and 4 proteins, respectively. The expression of Ties and Angs was significantly correlated with several type of histological differentiation and several clinicopathological factors. Ties and Angs were highly expressed in human gastric adenocarcinoma cells. These findings suggest that the Tie-Ang receptor-ligand complex is one of the factors involved in the cellular differentiation and progression of human gastric adenocarcinoma.


Cecal volvulus associated with intestinal malrotation presenting as postoperative intestinal obstruction.
To report a case of intestinal malrotation predisposing to cecal volvulus following nonabdominal surgery in an adult. A 23-year-old male with known anorectal malformation developed a postoperative intestinal obstruction following percutaneous nephrolithotomy for left renal calculus. Computed tomography of the abdomen revealed a grossly dilated cecum (9 cm) with ileocecal junction on the left side and small bowel loops on the right side of the abdomen. The patient underwent emergency exploratory laparotomy and retroperitonealization cecopexy. Bowel functions were normal at the follow-ups. This case highlights the importance of suspecting cecal volvulus even following nonabdominal surgery in the presence of predisposing factors.


Biochemical Data and Metabolic Profiles of Male Exclusive Narghile Smokers (ENSs) Compared With Apparently Healthy Nonsmokers (AHNSs).
Studies evaluating the metabolic profiles of ENSs are scarce and presented controversial conclusions. This study aimed to compare the metabolic profiles of ENSs' and AHNSs' groups. Males aged 25-45 years and free from a known history of metabolic and/or cardiovascular diseases were included. According to the smoking status, two groups of ENSs and AHNSs were identified. Body mass index (BMI, kg/m2), waist circumference (WC, cm), systolic and diastolic blood pressures (SBP, DBP, mmHg), fasting blood data in mmol/L (blood glycemia [FBG], triglycerides [TG], total cholesterol [TC], high- and low- density lipoprotein cholesterol [HDL-C, LDL-C]) and obesity status were evaluated. The metabolic syndrome (MetS) was defined according to the 2006 International Diabetes Federation (IDF) recommendations. Data were expressed as mean ± standard deviation ( SD) or percentages. Compared to the AHNSs' group ( n = 29), the ENSs' one ( n = 29) had (a) higher values of BMI (26.5 ± 2.3 vs. 28.2 ± 3.6), WC (95 ± 7 vs. 100 ± 10), and TG (1.22 ± 0.40 vs. 1.87 ± 0.85); and (b) included a lower percentage of males having low HDL-C (82.7% vs. 62.0%), and higher percentages of males having obesity (6.9% vs. 37.9%) or hypertriglyceridemia (10.7% vs. 51.7%). Both the ENSs' and AHNSs' groups: (a) had similar values of FBG (5.38 ± 0.58 vs. 5.60 ± 0.37), TC (4.87 ± 1.16 vs. 4.36 ± 0.74), HDL-C (0.92 ± 0.30 vs. 0.82 ± 0.21), LDL-C (3.09 ± 0.98 vs. 2.92 ± 0.77), SBP (117 ± 9 vs. 115 ± 8), and DBP (76 ± 6 vs. 73 ± 7); and (b) included similar percentages of males having normal weight (17.2% vs. 31.0%); overweight (44.8% vs. 62.1%); android obesity (79.3% vs. 59.6%), hypertension (10.3% vs. 10.3%), hyperglycemia (37.9% vs. 48.2%), and MetS (51.7% vs. 34.5%). There is a need to monitor narghile use among male metabolic patients since it alters some components of the MetS.


Evaluation of two herd-level diagnostic tests for Streptococcus agalactiae using a latent class approach.
Streptococcus agalactiae mastitis persists as a significant economic problem for the dairy industry in many countries. In Denmark, the annual surveillance programme for this mastitis pathogen initially based only on bacteriological culture of bulk tank milk (BTM) samples, has recently incorporated the use of the real-time PathoProof Mastitis PCR assay with the goal of improving detection of infected herds. The objective of our study was to estimate the herd sensitivity (Se) and specificity (Sp) of both tests of BTM samples using latent class models in a Bayesian analysis while evaluating the effect of herd-level covariates on the Se and Sp of the tests. BTM samples were collected from all 4258 Danish dairy herds in 2009 and screened for the presence of S. agalactiae using both tests. The highest Se of PCR was realized at a cycle threshold (Ct) cut-off value of 40. At this cut-off, the Se of the PCR was significantly higher (95.2; 95% posterior credibility interval [PCI] [88.2; 99.8]) than that of bacteriological culture (68.0; 95% PCI [55.1; 90.0]). However, culture had higher Sp (99.7; 95% PCI [99.3; 100.0]) compared to PCR (98.8; 95% PCI [97.2; 99.9]). The accuracy of the tests was unaffected by the herd-level covariates. We propose that screenings of BTM samples for S. agalactiae be based on the PCR assay with Ct readings of <40 considered as positive. However, for higher Ct values, confirmation of PCR test positive herds by bacteriological culture is advisable especially when the between-herd prevalence of S. agalactiae is low.


Transcriptional silencing of RFXAP in MHC class II-deficiency.
MHC-II deficiency is recognized by defects in components of the RFX complex or CIITA. In this study, we have characterized at the molecular level the putative defect in MHC-II regulatory factors of a recently identified MHC-II deficiency patient (FGK). We found that this patient lacked detectable levels of mRNA and protein of the RFX complex subunit RFXAP. It was subsequently established that the RFXAP gene in FGK differed from wild type RFXAP by a homozygous 75bp insertion in the 5'-UTR, which impaired the activity of the FGK RFXAP promoter. The transcriptional silent state of RFXAP correlated with reduced recruitment of RNA polymerase II to FGK RFXAP chromatin. Together, this insertion in the promoter region represents a novel type of MHC-II gene silencing in MHC-II deficiency patients.


Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death.
Currently, there is no effective treatment for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Thus, a major focus of neuroscience research is to examine the mechanisms involved in neuronal loss in order to identify potential drug targets. Recent results indicate that DNA damage and re-entry into the cell cycle may constitute a common pathway in apoptosis in neurological diseases. The role of the cell cycle in such disorders is supported by data on the brain of patients who showed an increase in cell-cycle protein expression. Indeed, studies performed in neuronal cell preparations indicate that oxidative stress could be the main mechanism responsible for cell cycle re-entry. DNA damage and repair after oxidative stress may activate the enzyme ataxia telangiectasia mutated, which is a cell-cycle regulator. Once the cell cycle is activated, the increase in the expression of transcription factor E2F-1 could induce neuronal apoptosis. Furthermore, the potential routes involved in E2F-1 induced apoptosis could be p53-dependent or p53-independent. Under this E2F-1 hypothesis of cell death, multiple mitochondria-dependent pathways may be activated, including caspase and caspase-independent signaling cascades. Finally, given that cyclin-dependent kinase inhibitory drugs have neuroprotective and anti-apoptotic effects in experimental models, their potential application for the treatment of neurological disorders should be taken into account.


Measles vaccines: a review of adverse events.
A great deal of controversy has recently been generated over the publication of several articles implicating measles vaccine in the induction of Crohn's disease and autism. The publication of this work has already had a negative impact on measles vaccine acceptance in the UK. These allegations are particularly troubling because they arise in the context of increased use of measles vaccine as global control of measles nears and the international community considers strategies for a drive towards eradication. In 1994, the US Institute of Medicine reviewed the world literature and published a comprehensive review of adverse events associated with measles-containing vaccines. Reviewing the literature published between 1994 and the present day, reveals that there is considerable new data suggesting that modified gelatin rather than egg proteins is responsible for most episodes of anaphylaxis following measles vaccination. New work weakens the possible links between measles vaccine and subacute sclerosing panencephalitis and Guillain-Barré syndrome, but strengthens the rare association of measles-containing vaccines with post infectious encephalomyelitis. The alleged associations between measles vaccination and Crohn's disease and autism are based upon weak science and have largely been refuted by a large volume of stronger work. A review of the data generated in the last 4 years amply demonstrates the continued efforts of the scientific community to monitor and understand true measles vaccine-associated adverse events. The rapidity and clarity of this same community's debunking of the spurious associations with Crohn's disease and autism suggests that those charged with vaccination programmes have learned from past mistakes. During 30 years of worldwide use, measles vaccination has proven to be one of the safest and most successful health interventions in the history of mankind. It is not a 'perfect' vaccine, but the benefits of measles vaccination far outweigh the risks even in countries with low incidence of measles and high rates of measles vaccine coverage.


The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology.
Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the "writers", "readers", and "erasers" of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer.


First isolation of West Nile virus from a dromedary camel.
Although antibodies against West Nile virus (WNV) have been detected in the sera of dromedaries in the Middle East, North Africa and Spain, no WNV has been isolated or amplified from dromedary or Bactrian camels. In this study, WNV was isolated from Vero cells inoculated with both nasal swab and pooled trachea/lung samples from a dromedary calf in Dubai. Complete-genome sequencing and phylogenetic analysis using the near-whole-genome polyprotein revealed that the virus belonged to lineage 1a. There was no clustering of the present WNV with other WNVs isolated in other parts of the Middle East. Within lineage 1a, the dromedary WNV occupied a unique position, although it was most closely related to other WNVs of cluster 2. Comparative analysis revealed that the putative E protein encoded by the genome possessed the original WNV E protein glycosylation motif NYS at E154-156, which contained the N-linked glycosylation site at N-154 associated with increased WNV pathogenicity and neuroinvasiveness. In the putative NS1 protein, the A70S substitution observed in other cluster 2 WNVs and P250, which has been implicated in neuroinvasiveness, were present. In addition, the foo motif in the putative NS2A protein, which has been implicated in neuroinvasiveness, was detected. Notably, the amino-acid residues at 14 positions in the present dromedary WNV genome differed from those in most of the closely related WNV strains in cluster 2 of lineage 1a, with the majority of these differences observed in the putative E and NS5 proteins. The present study is the first to demonstrate the isolation of WNV from dromedaries. This finding expands the possible reservoirs of WNV and sources of WNV infection.


Central manipulation of dopamine receptors attenuates the orexigenic action of ghrelin.
Recent evidence suggests that ghrelin, a peptidic hormone stimulating food intake, interacts with the dopamine signaling. This interaction has been demonstrated to modulate several effects of ghrelin, such as locomotor activity, memory, and food intake. Ghrelin increases dopamine levels in the shell of the nucleus accumbens stimulating food intake, while ablation of the ghrelin receptor attenuates the hypophagia caused by the activation of dopamine receptor 2. However, it is not known whether the orexigenic action of ghrelin is due to changes in central dopamine receptors. We used Sprague-Dawley rats injected with different dopamine receptor agonists, antagonists, and ghrelin. We demonstrate that the specific central blockade of dopamine receptor 1, 2, and 3 (D1, D2, and D3, respectively) reduces the orexigenic action of ghrelin. Similarly, specific central stimulation, either singly of dopamine receptor 1 or dopamine receptors 2 and 3 simultaneously, causes a significant decrease in ghrelin-induced food intake. Co-stimulation of all three receptors (D1, D2, and D3) also led to a marked attenuation in ghrelin-induced food intake. Importantly, the reduction in ghrelin-induced feeding was not caused by malaise or any type of behavioral alteration. Taken together, these data indicate that dopamine receptors play an important role in acute stimulation of feeding behavior induced by central injection of ghrelin.


A new approach to high sensitivity differential hybridization.
We describe a new approach to differential hybridization, designed to identify cDNA clones representing rare mRNA species. Duplicate filters carrying a library of cDNA from phorbolmyristate acetate (PMA)-induced EL-4 cells in lambda gt11 were hybridized with high concentrations of unlabeled, cloned, single-stranded cDNA from induced and control EL-4 cells, respectively. Plaques binding single-stranded cDNA were revealed by a second round of hybridization with 35S-labeled DNA complementary to the vector moiety of the single-stranded cDNA. Plaques corresponding to PMA-induced mRNAs occurring at a level of about 1 part in 15,000 were isolated. We believe the method is at least ten times more sensitive than conventional differential hybridization.


Ventrolateral medullary pressor area: site of hypotensive action of clonidine.
Intravenous injections of clonidine produce an initial transient increase in blood pressure followed by a long-lasting hypotension and bradycardia. The initial pressor response is due to activation of vascular alpha 1-adrenergic receptors while the hypotension and bradycardia are caused by the central actions of clonidine. Although, hypothalamus, nucleus tractus solitarius (NTS), ventrolateral medulla and the intermediolateral cell column of the thoracolumbar spinal cord (IML) have been implicated, the exact site of these actions of clonidine in the central nervous system is not established. The results of this investigation suggest that the pressor area in the ventrolateral medulla (VLPA) is the site of hypotensive and bradycardic actions of intravenously administered clonidine. This conclusion is based on the observation that microinjections of idazoxan, a specific alpha 2-adrenergic receptor blocker, into the VLPA prevented and reversed the hypotension and bradycardia despite the fact that other proposed sites of these actions (NTS, hypothalamus and IML) were intact and accessible to intravenously administered clonidine.


Analysis of transgenic grapevine (Vitis rupestris) and Nicotiana benthamiana plants expressing an Arabis mosaic virus coat protein gene.
A disarmed LBA4404 strain of Agrobacterium tumefaciens harboring a binary vector which contained chimeric genes encoding the neomycin phosphotransferase (npt II) and the coat protein (CP) of Arabis mosaic nepovirus (ArMV) was used in co-cultivation experiments with leaf discs of Nicotiana benthamiana and somatic embryos of the grapevine rootstock cultivar Vitis rupestris. Transgenic N. benthamiana expressing the ArMV CP gene were regenerated and six independent lines were characterized. Enzyme-linked immunosorbent assay (ELISA) performed on leaf tissue demonstrated the accumulation of the ArMV CP in five of the six lines analyzed. Immunosorbent electron microscopy (ISEM) studies revealed the presence of virion-like isometric particles (VLPs) reacting to a rabbit antiserum specific to ArMV virions. ArMV-CP expressing transgenic N. benthamiana lines showed protection against ArMV expressed as a delay in infection and a reduction of the percentage of infected plants. Four independent transgenic lines of V. rupestris transformed with the ArMV CP gene were regenerated and characterized. In contrast to N. benthamiana, transgenic V. rupestris did not accumulate the ArMV CP at levels detectable by ELISA and no VLPs could be observed by ISEM. Northern blot analysis showed that the ArMV CP mRNA was expressed at lower level in V. rupestris compared with N. benthamiana. The reason for this difference in transgene expression and/or mRNA stability between grapevine and N. benthamiana is unclear, but the genetic state of the transgene(s) (homozygous in N. benthamiana versus hemizygous in V. rupestris) may have an effect on gene expression.


Student preferences and perceptions of learning from vSIM for Nursing™.
This study explored BSN students' perceptions of learning with vSim for Nursing™. Using a mixed methods design with 99 students, key points of learning were medication administration and respiratory interventions. Qualitative data demonstrated learning of assessment, prioritization, and emergency management. The top student preferences of how to use virtual simulation were as a clinical makeup or to enhance lecture. The findings support the use of virtual simulation and provide data to guide nurse educators to more strategically integrate virtual simulation exercises.


Survival of Salmonella spp. under varying temperature and soil conditions.
Soils can serve as suitable reservoirs for or barriers against microbial contamination of water resources and plant produce. The magnitude of water or food contamination risks through soil depends on several factors, including the survival potential of microorganisms in the soil. This study assessed and compared the survival/persistence of 14 Salmonella spp. strains in loam and sandy soils at 5, 10, 20, 25, 30, 35, 37 °C and under uncontrolled ambient temperature conditions in Campinas Sao Paulo. The ambient temperature ranged from 6 °C (minimum) to 36 °C (maximum). Bacterial population densities were determined by the conventional culture method (plate counts) and monitored for 216 days. Statistical differences among the test parameters were determined by Analysis of Variance, while relationships between temperature and soil type were evaluated using Pearson correlation analysis. Similarly, relationships between time and temperature for survival of the various strains were evaluated using Pearson correlation analysis. Results obtained indicate that temperature and soil type influence the survival of Salmonella spp. in soils. All 14 strains survived for up to 216 days in the organic-rich loam soil under at least three of the temperature conditions evaluated. However, comparatively lower survival rates were recorded in sandy soil, especially at lower temperature. The optimum temperature for survival varied among the strains, where some survived best at 5 °C and others between 30 and 37 °C. Under uncontrolled temperature conditions, the Salmonella strains survived better in loam than in sandy soils. Bacterial growth over post inoculation storage period was overall more impressive in loam soil. In general, the results indicate that temperature and soil type can interact to influence the survival of Salmonella spp. strains in soil. For the survival of some strains, there were significant correlations between soil type and temperature, while for some others, no significant relationship between soil and temperature was determined. A similar trend was observed for the correlation between time and temperature.


Phage P1 Cre-loxP site-specific recombination. Effects of DNA supercoiling on catenation and knotting of recombinant products.
Bacteriophage P1 contains a site-specific recombination system consisting of a site, loxP, and a recombinase protein Cre. We have shown that with purified Cre protein we can carry out recombination between two loxP sites in vitro. When that recombination occurs between two sites in direct orientation on the same DNA molecule, we observed the production of free and catenated circular molecules. In this paper we show that recombination between sites in opposite orientation leads to both knotted and unknotted circular products. We also demonstrate that the production of catenanes and knots is influenced by two factors: (1) supercoiling in the DNA substrate, supercoiled DNA substrates yield significantly more catenated and knotted products than nicked circular substrates; and (2) mutations in the loxP site, a class of mutations have been isolated that carry out recombination but result in a distribution of products in which the ratio of catenanes to free circles is increased over that observed with a wild-type site. A more detailed analysis of the products from recombination between wild-type sites indicates: (1) that the catenanes or knots produced by recombination are both simple and complex; (2) that the ratio of free products to catenanes is independent of the distance between the two directly repeated loxP sites; and (3) that for DNA substrates with four loxP sites significant recombination between non-adjacent sites occurs to give free circular products. These observations provide insights into how two loxP sites are brought together during recombination.


A compact 7-cell Si-drift detector module for high-count rate X-ray spectroscopy.
A new Si-drift detector module for fast X-ray spectroscopy experiments was developed and realized. The Peltier-cooled module comprises a sensor with 7 × 7-mm2 active area, an integrated circuit for amplification, shaping and detection, storage, and derandomized readout of signal pulses in parallel, and amplifiers for line driving. The compactness and hexagonal shape of the module with a wrench size of 16mm allow very short distances to the specimen and multi-module arrangements. The power dissipation is 186mW. At a shaper peaking time of 190 ns and an integration time of 450 ns an electronic rms noise of ~11 electrons was achieved. When operated at 7 °C, FWHM line widths around 260 and 460 eV (Cu-Kα) were obtained at low rates and at sum-count rates of 1.7 MHz, respectively. The peak shift is below 1% for a broad range of count rates. At 1.7-MHz sum-count rate the throughput loss amounts to 30%.


Potassium-stimulated release of GABA, glycine, and taurine from the chick retina.
The effect of depolarizing potassium concentration on the release of [14C]glycine, [3H]GABA, and [3S]taurine was investigated in the whole chick retina and in a synaptosomal fraction prepared from the chick retina. In the whole retina, increasing potassium concentration above 40 mM resulted in an increased release of the three amino acids. The release of glycine was the most stimulated and that of taurine, the least. The potassium-evoked release of glycine and GABA was calcium dependent. In the synaptosomal fraction, 68.5 mM potassium significantly stimulated the efflux of GABA and glycine by a calcium-dependent mechanism. The release of taurine from this fraction was unaffected by high potassium.


Glycemic control in the critically ill - 3 domains and diabetic status means one size does not fit all!
Hyperglycemia, hypoglycemia, and increased glucose variability have each been shown to be independently associated with increased risk of mortality in the critically ill. Sechterberger and colleagues have completed a large observational cohort study that demonstrates that diabetic status modulates these relationships in clinically meaningful ways. These findings corroborate, in a strikingly consistent manner, those of another very recently published large observational study.


Introduction: understanding mechanisms of the actions of rifaximin in selected gastrointestinal diseases.
Historically, the beneficial effects of the nonsystemic oral agent rifaximin on various gastrointestinal (GI) disorders have been attributed to direct antibiotic activity on gut microbiota. However, data are accumulating to suggest that other nonantibacterial effects may be involved in rifaximin efficacy. To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis complications, inflammatory bowel diseases, and irritable bowel syndrome with diarrhoea. Gastroenterology experts convened a round-table discussion to address clinical and pre-clinical rifaximin data pertaining to select GI diseases and the potential mechanisms of action that underlie rifaximin efficacy profiles. As preparation, the literature was searched for publications related to rifaximin, its mechanisms of action, and its efficacy in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis-related complications, inflammatory bowel diseases and irritable bowel syndrome. Gut microbiota dysbiosis and proinflammatory activities are thought to significantly contribute to disease pathophysiology of these conditions. Rifaximin may resolve gut microbiota dysbiosis by promoting GI colonisation of beneficial bacterial species without drastic alterations in overall diversity. Rifaximin-induced changes in the production and metabolism of bacteria-produced agents (e.g. deoxycholic acid, lipopolysaccharides) also may help preserve normal gut microbiota. Rifaximin may suppress local and systemic inflammatory processes by preserving epithelial function (e.g. limiting bacterial translocation), modulating bacterial virulence and reducing proinflammatory cytokine production. The commonality of pathological mechanisms underlying multiple GI diseases and the ability of rifaximin to modulate the gut microenvironment (i.e. gut microenvironment modulator) may explain its diverse efficacy profile.


Solution structure of homology region (HR) domain of type II secretion system.
The type II secretion system of Gram-negative bacteria is important for bacterial pathogenesis and survival; it is composed of 12 mostly multimeric core proteins, which build a sophisticated secretion machine spanning both bacterial membranes. OutC is the core component of the inner membrane subcomplex thought to be involved in both recognition of substrate and interaction with the outer membrane secretin OutD. Here, we report the solution structure of the HR domain of OutC and explore its interaction with the secretin. The HR domain adopts a β-sandwich-like fold consisting of two β-sheets each composed of three anti-parallel β-strands. This structure is strikingly similar to the periplasmic region of PilP, an inner membrane lipoprotein from the type IV pilus system highlighting the common evolutionary origin of these two systems and showing that all the core components of the type II secretion system have a structural or sequence ortholog within the type IV pili system. The HR domain is shown to interact with the N0 domain of the secretin. The importance of this interaction is explored in the context of the functional secretion system.


Post-transcriptional regulation in budding yeast meiosis.
The precise regulation of gene expression is essential for developmental processes in eukaryotic organisms. As an important post-transcriptional regulatory point, translational control is complementary to transcriptional regulation. Sporulation in the budding yeast Saccharomyces cerevisiae is a developmental process controlled by a well-studied transcriptional cascade that drives the cell through the events of DNA replication, meiotic chromosome segregation, and spore assembly. Recent studies have revealed that as cells begin the meiotic divisions, translational regulation of gene expression fine tunes this transcriptional cascade. The significance and mechanisms of this translational regulation are beginning to emerge. These studies may also provide insights into translational regulation in germ cell development of multicellular organisms.


Validity and Reliability Evidence of the Munro Scale for Perioperative Patients Part II: Construct Validity.
Background and Purpose: The Munro Pressure Injury Risk Assessment Scale for Perioperative Patients (Munro Scale) is the first three-phase risk instrument designed specifically for perioperative patients. The purpose of this study was to establish validity and reliability evidence for the Munro Scale. This study also had a goal to reduce the data into more manageable constructs with fewer items. Methods: Exploratory and confirmatory factor analyses were used to test the hypothesized model for risk assessment using the Munro Scale to identify latent variables. A retrospective review of charts from 630 risk assessments was analyzed from two community acute care hospital settings. Results: The model explained 95% of the variance in the cumulative final risk level, R2 = .95, F(20, 588) = 501.88, p < .001. Six latent variables emerged in the model with a cumulative contribution rate of 56% of the variance. Similar results were obtained in studies with Chinese and Turkish translations of the Munro Scale. Conclusions: The validity and reliability evidence obtained in this study supports the implementation of the Munro Scale for clinical practice in the perioperative setting.


Some physical characteristics of NIDA marijuana cigarettes.
Marijuana cigarettes of three different potencies (0.0%, 1.4% and 2.7% delta-9-tetrahydrocannabinol (THC) content) provided by the National Institute on Drug Abuse (NIDA) were compared on a variety of characteristics, including physical appearance, weight, burn rate, and deliveries of total particulate matter and carbon monoxide. Significant differences between the different potency cigarettes were obtained on most measures. These differences could be relevant to the design and interpretation of pharmacologic/toxicologic and behavioral studies conducted with these cigarettes. The possible basis for these observed differences, methods for minimizing some of them, and other potential problems related to the use of NIDA marijuana cigarettes are discussed.


Shifting product spectrum by pH adjustment during long-term continuous anaerobic fermentation of food waste.
Anaerobic fermentation is widely used to recover different products from food waste, and in this study, the evolution of fermentation products and microbial community along with pH variation was investigated thoroughly using four long-term reactors. Lactic fermentation dominated the system at pH 3.2-4.5 with lactic acid concentration of 5.7-13.5 g/L, and Lactobacillus was the superior sort. Bifidobacteria increased significantly at pH 4.5, resulting in the increase of acetic acid. Butyric acid fermentation was observed at pH 4.7-5.0. Bifidobacterium, Lactobacillus, and Olsenella were still dominant, but the lactic acid produced by them was converted to volatile fatty acids (VFAs) rapidly by Megasphaera, Caproiciproducens, Solobacteria, etc. Mixed acid fermentation occurred at pH 6.0 with the highest concentration 14.2 g/L of VFAs, and the dominant Prevotella and Megasphaera converted substrates to VFAs directly. On the whole, pH 4.5 and 4.7 led to the highest hydrolysis rate of 50% and acidification rate of 45%.


Drug susceptibility patterns of rapidly growing mycobacteria isolated from skin and soft tissue infections in Venezuela.
To our knowledge, this is the first work on drug susceptibility patterns of rapid growing mycobacteria from Latin America. The susceptibility patterns for 14 antimicrobial agents of the three most important species that cause skin infections in Venezuela were determined as follows: 63 strains belonging to Mycobacterium abscessus group, 66 strains of the Mycobacterium fortuitum group, and 13 Mycobacterium chelonae strains. The M. abscessus group strains were resistant to most antibiotics tested while M. fortuitum strains were relatively susceptible to a large number of antibiotics. We demonstrate the presence of an inducible and truncated erm(41) gene in M. abscessus group, namely M. abscessus subsp. massiliense. We show the variations in susceptibility to antimicrobial agents within and between the mycobacterial species and compare our susceptibility patterns with those reported from other countries. We conclude that the identification of mycobacteria to the species level can guide the antibiotic treatment, but that it is always important to consider drug susceptibility testing when rapidly mycobacteria are isolated.


Two-year study of relapse prevention by a new education program in schizophrenic patients treated with the same antipsychotic drug.
It is not clear whether patient's psycho-education enhances compliance to antipsychotic treatments and reduces the number of relapses. Here we investigated the impact of a new psycho-educational program (SOLEDUC) on the one- and two-years rate of relapse (primary outcome measure) and a number of clinical assessments (secondary outcome measures). This was a multicentric French clinical trial (51 centers) of Phase IV, open, controlled, randomized, consisting in two parallel groups: the Soleduc group (N=111) and the control group (N=109). All subjects received a variable dose over the 2-year period of the same antipsychotic drug (amisulpride). Soleduc consisted of a 7-session program (1h per session), presented three times (at baseline, 6-months and 12-months). Patients in the control group received a non-specific psychosocial training for an equivalent period of time. The models of Andersen-Gill (AG) and Prentice, Williams and Peterson (PWP) were used to analyze relapses. Patients in the Soleduc group attended 14.8+/-6.1 sessions (mean+/-SD), including 17 patients who never attended a session. Intent to treat analysis showed less patients relapsing in the Soleduc group as compared to the control group (21.6% versus 28.4% after 1 year and 84.4% versus 90.8% after 2years), but the differences were not statistically significant. Relapse risk was significantly reduced for patients who followed at least 7 modules (p=0.015 AG-test; p<0.001 PWP-test). In conclusion, no significant differences in relapse rates were found between patients attending the Soleduc program and the control group. Attendance of at least 7 out of 21 program sessions was required to see a modest, but significant two-year relapse prevention in schizophrenia. Other well designed studies are required to evaluate the medical impact of patient's education programs.


Systemic and local cytokine kinetics in musculoskeletal injury: a prospective study in patients with ankylosing spondylitis.
Back surgery in patients with ankylosing spondylitis is a major trauma in individuals with tissue inflammation and joint destruction along the spine; we used surgery in these patients as a model in the study of systemic and local cytokine profiles in complicated trauma situations. Blood was sampled before, during and after surgery in 10 patients operated on with extending osteotomy of the lumbar spine. Samples of arterial blood and local wound blood were analysed for proinflammatory and anti-inflammatory cytokines. Surgery induced no significant changes in systemic values of TNFalpha and IL-1beta. There were significant increments in systemic values of IL-6, IL-8 and sTNF-R1. A systemic increase in values of IL-10 was only noticed after 24 h. There were increments in local values of TNFalpha at 24 h and in local values of IL-1beta, IL-6, Il-8 and IL-10 at both 4 and 24 h postoperatively. The local values were in general significantly higher than the systemic values. This study indicates that a major musculoskeletal trauma principally is followed by significant increases in systemic levels of IL-6 with only modest systemic reactions in TNFalpha and IL-1beta, even in patients with an inflammatory disease. However, there are in general significantly increased local levels of IL-1beta, IL-6, IL-8 and IL-10, and our conclusion is that systemic cytokine levels might not reflect local reactions.


Enterovesical cystoplasty for bladder closure in cloacal exstrophy.
Successful bladder closure was accomplished in 4 infants with cloacal exstrophy by enterocystoplasty. Two patients were operated upon as newborns, and 2 were 3 and 8 months old, respectively. Three patients are alive and all are incontinent awaiting secondary bladder neck reconstruction. The surgical technique and results are described.


Photophysical characterization of new 3-amino and 3-acetamido BODIPY dyes with solvent sensitive properties.
The structural, electronic and photophysical properties of three new asymmetric, highly fluorescent difluoroborondipyrromethene (BODIPY) dyes, bearing an amino or an acetamido group at position 3 of the chromophoric core, have been studied in different apolar, polar and polar/protic solvents. The presence of the 3-amido group extents the delocalization of the pi-system, leading to bathochromic shifts in the absorption and fluorescence bands, as predicted by quantum mechanic calculations. The 3-amino dye shows photophysical properties highly dependent on the solvent polarity and acidity, and is characterized by a hypsochromic shift of its absorption band, with regard to the corresponding acetylated dye, as well as a low fluorescence quantum yield in acid media with proton concentration lower than 4 x 10(-4) M. In media with higher proton concentration, the BF(2) bridge group of the 3-amino dye is removed, yielding the corresponding non-fluorescent dipyrromethene precursor. These results suggest that the 3-amino dye could be used as a fluorescence probe for the study of the acidity of different environments.


Correlation of adenosine receptor affinities and cardiovascular activity.
Binding affinities of 28 adenosine analogs at A1 adenosine receptors (rat whole brain membranes, [3H]N6-cyclohexyladenosine, CHA), and at A2 adenosine receptors (rat striatal membranes, [3H]NECA) were compared to their EC25 values for decreasing heart rate and increasing coronary flow in the isolated rat heart. Heart rate (an A1 response) correlated with A1 binding affinity (r2 = 0.71, p less than 0.0001) but not with A2 binding affinity (r2 = 0.007, n.s.); conversely, coronary flow (an A2 response) correlated with A2 binding affinity (r2 = 0.83, p less than 0.0001) but not with A1 binding affinity (r2 = 0.05, n.s.). These results confirm that the brain A1 and A2 receptors, studied by binding methods, bear close similarities to their respective counterparts in the heart, studied by means of functional responses.


An Algorithm for the Management of Explantation Surgery.
Creating pleasing breast aesthetics after an explantation can be challenging, especially when performed with a total capsulectomy. The necessity of a capsulectomy for a variety of breast issues is not completely agreed on and can increase adverse events, patient morbidity, and cost of the operation and often impairs the final aesthetic result. In this article, an algorithm for the management of explantation patients provides a framework for treatment of the capsule and the breast to optimize outcomes.


Anxiety, coping style and hopelessness during COVID-19 pandemic: An Iranian population-based study.
The COVID-19 pandemic has caused new conditions such as nationwide quarantine, a dramatic decrease in-person interaction and an increase in death anxiety for governments and people. The pandemic of an unpredictable disease with no definite treatment can pose physical and psychological risks to individuals. The present study aimed to investigate the state of anxiety, coping styles, and hopelessness of people in the lockdown period and reopening in Iran. In this national population-based cross-sectional study, a total of 1191 people who had access to social networks from all over Iran completed the anxiety, hopelessness, and coping style questionnaires online using the snowball sampling method. Analysis was conducted using Stata software version 12 (Stat Corp). The significance level was set at 0.05. The results of the study suggested that women experienced higher levels of anxiety than men, and, in stressful situations, women were more likely to use emotion-focused coping styles, while men frequently used problem-focused coping styles. The majority of participants reported moderate levels of anxiety and low levels of hopelessness (64.04%). The results of multiple linear regression show any level of anxiety mild (ß = 0.59, 95% confidence interval [CI]: 0.32-0.85), moderate (ß = 0.72, 95% CI: 1.36-1.08), and severe (ß = 2, 95% CI: 1.36-2.56) relative to the none anxiety significantly increase the hopelessness, Furthermore, showing a negative significant adjusted association with the problem-focused coping style (ß = -0.06, 95% CI: -0.07 to -0.04), and a significant positive association with the emotion-focused coping style (ß = 0.04, 95% CI: 0.02-0.06). Our findings could be used to prevent psychological damage in societies and suggested addressing problem-focused coping style, especially during a crisis, and providing people with preprepared mental health protocols at this pandemic.


Response of metastatic adenoid cystic carcinoma and Merkel cell tumor to high-dose melphalan with autologous bone marrow transplantation.
Two patients with metastatic spread of unusual tumors responded to treatment with high-dose Melphalan and autologous bone marrow transplant. One patient had adenoid cystic carcinoma of a minor salivary gland and the other had Merkel cell tumor of the scalp. Both patients had undergone prior surgery and radiotherapy, but later relapsed with distant metastases. Both patients had progression of their disease despite conventional and salvage chemotherapy. Treatment with high-dose Melphalan and autologous bone marrow transplant resulted in partial responses for both patients. High-dose Melphalan should be considered for therapy earlier in the course of patients with these unusual cancers.


Bradykinin stimulates prepubertal rat germ cell proliferation in vitro.
The effect of bradykinin on germ cell proliferation was studied by using in vitro organ cultures of testicular fragments from 3.5- and 4.5-day-old rats in the presence of 3H-thymidine. Bradykinin in tested concentrations of 10(-8), 10(-6) and 10(-4) M manifested a significant stimulation of rat prespermatogonial cell proliferation. The percentage of labeled germ cells increased up to 3-fold in comparison with the control value especially in 3.5-day-old rat testicular explants. Two kininase inhibitors: phosphoramidon and captopril were also used in combination with bradykinin. The percentage of labeled germ cells was slightly increased as compared to the samples treated with bradykinin only. Experiments with two agonists and two antagonists of B1 and B2 receptors for kinins showed that the rat prespermatogonial cell proliferation response to bradykinin is probably mediated via B2 receptors. The present findings suggest that bradykinin may be an important local testicular factor with paracrine or autocrine role in the regulation of spermatogonial cell proliferation and germ cell number.