A public-private partnership for malaria control: lessons from the Malarone Donation Programme.
In 1996, Glaxo Wellcome offered to donate up to a million treatment courses annually of Malarone, a new antimalarial, with a view to reducing the global burden of malaria. The Malarone Donation Programme (MDP) was established the following year. Eight pilot sites were selected in Kenya and Uganda to develop and evaluate an effective, locally sustainable donation strategy that ensured controlled and appropriate use of Malarone. The pilot programme targeted individuals who had acute uncomplicated Plasmodium falciparum malaria that had not responded to first-line treatments with chloroquine or sulfadoxine-pyrimethamine. Of the 161 079 patients clinically diagnosed at the pilot sites as having malaria, 1101 (0.68%) met all the conditions for participation and received directly observed treatment with Malarone. MDP had a positive effect at the pilot sites by improving the diagnosis and management of malaria. However, the provision of Malarone as a second-line drug at the district hospital level was not an efficient and effective use of resources. The number of deaths among children and adults ineligible for MDP at the pilot sites suggested that high priority should be given to meeting the challenges of malaria treatment at the community level.


Investigations of the relationship between use of in vitro cell culture-quantitative PCR and a mouse-based bioassay for evaluating critical factors affecting the disinfection performance of pulsed UV light for treating Cryptosporidium parvum oocysts in saline.
Cryptosporidium parvum is an enteric coccidian parasite that is recognised as a frequent cause of water-borne disease in humans. We report for the first time on use of the in vitro HCT-8 cell culture-quantitative PCR (qPCR) assay and the in vivo SCID-mouse bioassay for evaluating critical factors that reduce or eliminate infectivity of C. parvum after irradiating oocysts in saline solution under varying operational conditions with pulsed UV light. Infections post UV treatments were detected by immunofluorescence (IF) microscopy and by quantitative PCR in cell culture, and by IF staining of faeces and by hematoxylin and eosin staining of intestinal villi in mice. There was a good agreement between using cell culture-qPCR and the mouse assay for determining reduction or elimination of C. parvum infectivity as a consequence of varying UV operating conditions. Reduction in infectivity depended on the intensity of lamp discharge energy applied, amount of pulsing and population size of oocysts (P < or = 0.05). Conventional radiometer was unable to measure fluence or UV dose in saline samples due to the ultra-short non-continuous nature of the high-energy light pulses. Incorporation of humic acid at a concentration above that found in surface water (i.e., < or =10 ppm) did not significantly affect PUV disinfection capability irrespective of parameters tested (P < or = 0.05). These observations show that use of this HCT-8 cell culture assay is equivalent to using the 'gold standard' mouse-based infectivity assay for determining disinfection performances of PUV for treating C. parvum in saline solution.


A qualitative case study of the legislative process of the hygienist-therapist bill in a large Midwestern state.
Inequitable access to dental care contributes to oral health disparities. Midlevel dental provider models are utilized across the globe as a way to bridge the gap between preventive and restorative dental professionals and increase access to dental care. The purpose of this study was threefold: to examine lessons learned from the state legislative process related to creation of the hygienist-therapist in a Midwestern state, to improve understanding of the relationship between alternative oral health delivery models and public policy and to inform the development and passage of future policies aimed at addressing the unmet dental needs of the public. This research investigation utilized a qualitative research methodology to examine the process of legislation relating to an alternative oral health delivery model (hygienist-therapist) through the eyes of key stakeholders. Interview data was analyzed and then triangulated with 3 data sources: interviews with key stakeholders, documents and researcher participant field notes. Data analysis resulted in consensus on 3 emergent themes with accompanying categories. The themes that emerged included social justice, partnerships and coalitions, and the legislative process. This qualitative case study suggests that the creation of a new oral health workforce model was a long and arduous process involving multiple stakeholders and negotiation between the parties involved. The creation of this new workforce model was recognized as a necessary step to increasing access to dental care at the state and national level. The research in this case study may serve to inform advocates of access to oral health care as other states pursue their own workforce models.


Thermal stability of water polyhedra with square faces.
The ability to form numerous crystalline modifications of ice and gas hydrate frameworks is a characteristic feature of water. In fact, this structural variety is much wider due to the proton disorder. Configurations with different arrangements of hydrogen atoms (protons) in hydrogen bonds are not equivalent in their properties. Polyhedral water clusters are convenient objects for studying the effect of proton disorder on the properties of ice-like systems. It was previously established that the stability of water polyhedra is determined by the competition of two factors. The geometric factor gives preference to tetrahedrally coordinated structures with a large number of pentagonal faces. The topological factor takes into account the number of energetically most favorable types of H-bonds. This number increases with the number of square faces. It was found that tetrahedrally coordinated structures are not the most stable. However, these calculations were performed without taking thermal effects into account (Kirov M. V., J Phys Chem A, 124:4463 - 4470, 2020). The purpose of the present article is to study the structural stability of various water polyhedra at different temperatures. In the course of modeling, using the Amoeba force field, the advantage of configurations with a large number of square faces is demonstrated. The structure and energetics of surface defects are studied. Several very stable structures of unusual shape were found, including polyhedra which contain 4-coordinated molecules and polyhedra whose O-H groups are directed to the cluster center. The comparative analysis of cluster stability includes the temperature intervals of melting-like transitions.


Impact of acupuncture on vasomotor rhinitis: a randomized placebo-controlled pilot study.
Chronic rhinitis without an allergic or infectious etiology (vasomotor rhinitis) is a common disease for which there are only few and not very effective therapeutic treatment options. The current placebo-controlled, partially double-blinded pilot study evaluated the effects of acupuncture on the symptoms of vasomotor rhinitis. A total of 24 patients with confirmed diagnosis of vasomotor rhinitis were randomly allocated to either acupuncture or sham laser acupuncture treatment. The sham laser was a deactivated laser pen beaming normal red light. The main outcome measure was the alteration of the nasal sickness score (NSS; score(max) 27 points). Secondary outcome measures were the evaluation of a subjective symptoms score by patients' diaries and of their quality of life (SF-12 health survey). A credibility assessment regarding the respective treatment was performed. The study is registered as an International Standard Randomised Controlled Trial, number NCT00682162. NSS of patients treated by acupuncture was significantly reduced from 9.3 +/- 3.89 to 4.1 +/- 3.20 points (p < 0.001), whereas NSS declined from 5.6 +/- 2.74 to 3.7 +/- 2.61 points after sham treatment (p < 0.05). Comparison between the groups revealed a significant change of NSS (Mann-Whitney, p < 0.01), an analysis that also considers the significant difference between the baseline values of both groups (p < 0.05). Secondary outcome measures did not show significant differences between both groups. The credibility assessment was comparable for both treatments. This pilot study showed significant effects of acupuncture compared to a sham treatment in the NSS on symptoms of vasomotor rhinitis. These results may justify the performance of a large randomized trial to strengthen our understanding of the therapeutic value of acupuncture in the treatment of vasomotor rhinitis.


Identification of Constituents and Exploring the Mechanism for Toutongning Capsule in the Treatment of Migraine.
Toutongning capsule (TTNC) is an effective and safe traditional Chinese medicine used in the treatment of migraine. In this present study, a multiscale strategy was used to systematically investigate the mechanism of TTNC in treating migraine, which contained UPLC-UESI-Q Exactive Focus network pharmacology and experimental verification. First, 88 compounds were identified by the UPLC-UESI-Q Exactive Focus method for TTNC. Then, the target fishing for these compounds was performed by means of an efficient drug similarity search tool. Third, a series of network pharmacology experiments were performed to predict the key compounds, targets, and pathways. They were protein-protein interaction (PPI), KEGG pathway enrichment analysis, and herbs-compounds-targets-pathways (H-C-T-P) network construction. As a result, 18 potential key compounds, 20 potential key targets, and 6 potential signaling pathways were obtained for TTNC in treatment with migraine. Finally, molecular docking and experimental were carried out to verify the key targets. In short, the results showed that TTNC is able to treat migraine through multiple components, multiple targets, and multiple pathways. This work may provide a theoretical basis for further research on the molecular mechanism of TTNC in the treatment of migraine.


Further chromosomal mapping of a blood pressure QTL in Dahl rats on chromosome 2 using congenic strains.
Both linkage and use of congenic strains have shown that a region on rat chromosome 2 (Chr 2) of Dahl salt-sensitive rats (S) contained a quantitative trait locus (QTL) for blood pressure (BP). A congenic strain was made by replacing a segment of the S rat by the homologous region of the Milan normotensive (MNS) rat. Since the region was roughly 80 cM in size, a further reduction is required toward the final identification of the QTL. Currently, three congenic substrains were made by replacing smaller sections within the 80 cM. Each strain contains a specific region of MNS in the S genetic background. Two of the three congenic strains shared a segment in common, and both showed a BP-lowering effect. One of the three congenic strains carried a unique segment and had the same BP as S. Deducing the fragment shared in the two substrains having an effect, the BP QTL has to be present in a region of roughly 15 cM. In contrast to BP, heart rates of all the congenic rats were the same as that of the S rat. Thus BP and the heart rate are under the control of independent genetic determinants.


Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A.
The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.


Nickel-Catalyzed Site-Selective C-H Bond Difluoroalkylation of 8-Aminoquinolines on the C5-Position.
A simple and efficient protocol for nickel-catalyzed regioselective C-H bond difluoroalkylation of 8-aminoquinoline scaffolds with functionalized difluoromethyl bromides was developed. The reaction has broad substrate scope and provides a facile and useful access to the corresponding C5-functionalized difluoromethylated quinolines in good to excellent yields.


Neuro-endocrine correlations of hypothalamic-pituitary-thyroid axis in healthy humans.
Neuro-endocrine hormone secretion is characterized by circadian rhythmicity. Melatonin, GRH and GH are secreted during the night, CRH and ACTH secretion peak in the morning, determining the circadian rhythm of cortisol secretion, TRH and TSH show circadian variations with higher levels at night. Thyroxine levels do not change with clear circadian rhythmicity. In this paper we have considered a possible influence of cortisol and melatonin on hypothalamic-pituitary-thyroid axis function in humans. Melatonin, cortisol, TRH, TSH and FT4 serum levels were determined in blood samples obtained every four hours for 24 hours from ten healthy males, aged 36-51 years. We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. In the activity phase (06:00 h-10:00 h-14:00 h) cortisol correlated negatively with FT4, TSH correlated positively with TRH, TRH correlated positively with FT4 and melatonin correlated positively with TSH. In the resting phase (18:00 h-22:00 h-02:00 h) TRH correlated positively with FT4, melatonin correlated negatively with FT4, TSH correlated negatively with FT4, cortisol correlated positively with FT4 and TSH correlated positively with TRH. A clear circadian rhythm was validated for the time-qualified changes of melatonin and TSH secretion (with acrophase during the night), for cortisol serum levels (with acrophase in the morning), but not for TRH and FT4 serum level changes. In conclusion, the hypothalamic-pituitary-thyroid axis function may be modulated by cortisol and melatonin serum levels and by their circadian rhythmicity of variation.


[Animals go to the veterinarian, people go to the dentist].
The Dutch law and other regulations provide that only registered veterinarians can treat animals. Moreover, by law only registered individuals may use the title veterinarian or dentist. The veterinary professional should be open to advice, help, and technical assistance from other professionals working with human or animals patients. The dental treatment of animal patients must not be carried out in a dental surgery or hospital used by human patients.


New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking.
Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-analysis of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochemical characterisation confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compounds have a reduced activity against bacterial cell viability. However, the compounds prevent biofilm formation at very low concentrations, especially in the case of E. faecalis. Molecular docking studies performed estimate that this is most likely due to the inhibition of Sortase A. The new compounds could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.


An integrated genomic analysis of aryl hydrocarbon receptor-mediated inhibition of B-cell differentiation.
The aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters differentiation of B cells and suppresses antibody production. A combination of whole-genome, microarray-based chromatin immunoprecipitation (ChIP-on-chip), and time course gene expression microarray analysis was performed on the mouse B-cell line CH12.LX following exposure to lipopolysaccharide (LPS) or LPS and TCDD to identify the primary and downstream transcriptional elements of B-cell differentiation that are altered by the AHR. ChIP-on-chip analysis identified 1893 regions with a significant increase in AHR binding with TCDD treatment. Transcription factor binding site analysis on the ChIP-on-chip data showed enrichment in AHR response elements. Other transcription factors showed significant coenrichment with AHR response elements. When ChIP-on-chip regions were compared with gene expression changes at the early time points, 78 genes were identified as potential direct targets of the AHR. AHR binding and expression changes were confirmed for a subset of genes in primary mouse B cells. Network analysis examining connections between the 78 potential AHR target genes and three transcription factors known to regulate B-cell differentiation indicated multiple paths for potential regulation by the AHR. Enrichment analysis on the differentially expressed genes at each time point evaluated the downstream impact of AHR-regulated gene expression changes on B-cell-related processes. AHR-mediated impairment of B-cell differentiation occurred at multiple nodes of the B-cell differentiation network and potentially through multiple mechanisms including direct cis-acting effects on key regulators of B-cell differentiation, indirect regulation of B-cell differentiation-related pathways, and transcriptional coregulation of target genes by AHR and other transcription factors.


Characterization of folding intermediates of human carbonic anhydrase II: probing substructure by chemical labeling of SH groups introduced by site-directed mutagenesis.
By measurement of UV absorbance, CD spectra, and enzyme activity, we have shown that human carbonic anhydrase II forms a stable and compact folding intermediate at a moderate concentration of guanidine hydrochloride. The major aim of this study was to map the intermediate structure. For that reason, site-directed mutagenesis was used to introduce cysteine residues in various parts of the central beta-structure to give in each case a single cysteine residue. Thereafter, the accessibility of the introduced SH group to specific chemical labeling was used to probe the stability and compactness of the area surrounding each cysteine residue. Our results indicate that the folding intermediate has an ordered native-like secondary structure in the central part of the beta-sheet, whereas the peripheral part of the beta-sheet seems to be less ordered. A large hydrophobic cluster situated between the central beta-sheet core and secondary structure elements on the surface appears to be intact in the intermediate and is remarkably stable even at high GuHCl concentrations (> 5 M). This unusually stable substructure might function as a "seed" during the initiation of the folding process.


The health and economic burden of chickenpox and herpes zoster in Belgium.
Varicella-zoster virus causes chickenpox (CP) and after reactivation herpes zoster (HZ). Vaccines are available against both diseases warranting an assessment of the pre-vaccination burden of disease. We collected data from relevant Belgian databases and performed five surveys of CP and HZ patients. The rates at which a general practitioner is visited at least once for CP and HZ are 346 and 378/100 000 person-years, respectively. The average CP and HZ hospitalization rates are 5·3 and 14·2/100 000 person-years respectively. The direct medical cost for HZ is about twice as large as the direct medical cost for CP. The quality-adjusted life years lost for ambulatory CP patients consulting a physician is more than double that of those not consulting a physician (0·010 vs. 0·004). In conclusion, both diseases cause a substantial burden in Belgium.


Association between ambient temperature and acute myocardial infarction hospitalisations in Gothenburg, Sweden: 1985-2010.
Cardiovascular disease (CVD) is the number one cause of death globally and evidence is steadily increasing on the role of non-traditional risk factors such as meteorology and air pollution. Nevertheless, many research gaps remain, such as the association between these non-traditional risk factors and subtypes of CVD, such as acute myocardial infarction (AMI). The objective of this study was to investigate the association between daily ambient temperature and AMI hospitalisations using a case-crossover design in Gothenburg, Sweden (1985-2010). A secondary analysis was also performed for out-of-hospital ischemic heart disease (IHD) deaths. Susceptible groups by age and sex were explored. The entire year as well as the warm (April-September) and cold periods (October-March) were considered. In total 28,215 AMI hospitalisations (of 22,475 people) and 21,082 out-of-hospital IHD deaths occurred during the 26-year study period. A linear exposure-response corresponding to a 3% and 7% decrease in AMI hospitalisations was observed for an inter-quartile range (IQR) increase in the 2-day cumulative average of temperature during the entire year (11°C) and the warm period (6°C), respectively, with and without adjustment for PM₁₀, NO₂, NOx or O₃. No heat waves occurred during the warm period. No evidence of an association in the cold period nor any association between temperature and IHD deaths in the entire year, warm or cold periods--with and without adjusting for PM₁₀, NO₂, NOx or O₃ was found. No susceptible groups, based on age or sex, were identified either. The inverse association between temperature and AMI hospitalisations (entire year and warm period) in Gothenburg is in accordance with the majority of the few other studies that investigated this subtype of CVD.


The effect of muscle actions on the level of connective tissue damage.
The aim of this study was to compare the effect of concentric with eccentric muscle actions on the resulting level of damage to connective tissues by urinary concentration of hydroxyproline. Twenty-one male volunteers were divided into control group (CG), experimental concentric group (ECG), and experimental eccentric group (EEG). The measures of hydroxyproline were performed at three times: pretest, fourth week, and posttest. Biceps curl and chest press exercises also were performed with three sets of 10 repetitions two times per week for both experimental groups. Analysis of variance (ANOVA) showed a significant difference between pretest of the CG and pretest of the ECG (p = 0.002), and between pretest and posttest for the EEG (p = 0.029). Therefore, this study concluded that the level of damage to the connective tissue is greater when exercises involving eccentric muscle actions are performed. The continuity of training, however might reduce this damage.


Bradykinin-induced airway microvascular leakage is potentiated by enalaprilat but not by phosphoramidon.
The objective of the study was to determine if bradykinin-induced airway microvascular leakage in rats was altered by pretreatment of animals with enalaprilat, an inhibitor of angiotensin-converting enzyme (ACE), or phosphoramidon, an inhibitor of endopeptidase 24.11 (EP 24.11). We found that the intravascular infusion of bradykinin induced microvascular leakage of Evans blue dye in tracheal tissue (0.088 +/- 0.035 micrograms/mg tissue) that was significantly amplified by pretreatment with 3.27 mM enalaprilat (0.458 +/- 0.226 micrograms/mg tissue), but not by pretreatment with 10 mM phosphoramidon (0.082 +/- 0.0453 micrograms/mg tissue). Leakage in carinal tissue was also amplified by pretreatment with 3.27 mM enalaprilat (0.205 +/- 0.050 vs. 0.036 +/- 0.006 micrograms/mg tissue for bradykinin alone), whereas no amplification was observed in parenchymal tissue by pretreatment with either inhibitor. These findings indicate that in the rat, ACE, but not EP 24.11, modulates bradykinin-induced airway microvascular leakage following intravascular infusion of these agents.


Integrated system links cost data, patient satisfaction scores for the first time.
Linking cost data, patient satisfaction scores. HBS International and The Picker Institute have joined forces to make integrated data available that directly links operational efficiency and patient satisfaction. Find out how the systems lets providers know when reducing expenses compromises care.


Myeloid blood CD11c(+) dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes.
Dendritic cells (DCs) initiate and direct immune responses. Recent studies have defined different DC populations, therefore we undertook this study comparing 2 types of myeloid DCs: blood CD11c(+) DCs and in vitro monocyte-derived DCs (Mo-DCs), which are both candidates as cellular adjuvants for cancer immunotherapy. Blood CD11c(+) DCs were prepared by cell sorting from peripheral blood mononuclear cells cultured overnight in RPMI 1640 medium supplemented with autologous or pooled AB serum. Mo-DCs were prepared in the same medium using granulocyte macrophage-colony-stimulating factor (GM-CSF)/interleukin 4 (IL-4) and differentiated/activated with lipopolysaccharide or monocyte-conditioned medium (ActMo-DCs). Morphologically, differences between the DC preparations were noted both at a light and and electron microscopic level. Blood CD11c(+) DCs expressed similar levels of HLA-DR, CD40, CD86, and CD83 as Mo-DCs. CD209 was present on Mo-DCs but not on blood CD11c(+) DCs. Blood CD11c(+) DCs generated a lower proliferative mixed leukocyte response (MLR) than Mo-DCs. Blood CD11c(+) DCs loaded with 0.1 microg/mL tetanus toxoid (TT)-generated greater T lymphocyte proliferative responses than did Mo-DCs or ActMo-DCs, but when loaded with higher TT concentrations no difference in T lymphocyte proliferative response was observed. Keyhole limpet hemocyanin (KLH)-loaded blood CD11c(+) DCs generated greater T lymphocyte proliferative responses than Mo-DCs or ActMo-DCs. Allogeneic MLR- or KLH-specific responses induced by blood CD11c(+) DCs generated more Th1 effectors than the responses induced by Mo-DCs or ActMo-DCs. These data establish several differences in the properties of blood CD11c(+) DCs, Mo-DCs, and ActMo-DCs, which suggest that blood DCs merit further consideration as DC preparations for clinical programs are evolved.


Interleukin Receptor Antagonists and Janus Kinase Inhibitors Repurposed for Treatment of COVID-19.
SARS-CoV-2 infection is the most contagious among the three coronavirus infections the world has witnessed to date, which has affected almost all parts of the world in millions of population since its outbreak in China in December 2019. Moreover, it has severely hit the world economy and therefore there is a dire need to develop the treatment of this deadly disease. A number of potential vaccines are in the early or advanced stage of clinical trials. But the development of a vaccine is a very tedious and time-consuming task. Therefore, various groups are working on repurposing of drugs with already known safety and efficacy profiles to shorten the time of development of the potential treatment. The main aim of this review article is to summarize the clinical outcomes of Interleukin receptor antagonists and Janus kinase inhibitors based drugs which have been repurposed for the treatment of COVID-19 associated with SARS-CoV-2.


HIV-1 prevalence still low in Slovakia.
Slovakia, an Eastern European country with a population of 5.3 million, "... may still be considered as one of the countries with a low incidence of HIV infection," according to a team led by Dr. V. Zachar of the Slovak Academy of Sciences in Bratislava. The results of their study appeared in the July 20, 1996, issue of AIDS Research and Human Retroviruses. Zachar performed genetic analysis of the V3 env region of HIV isolates collected in 1993 from 11 HIV-positive homosexual men. Slovakia's comprehensive testing program "... provides assurance that the prevalence of infection is not underestimated due to a massive underreporting." Along with a low incidence, Zachar found that HIV-1 infections in Slovakia also appear to be restricted to subtype B, which is also the predominant HIV subtype in North America and Western Europe. Recent reports of five or more subtypes of HIV in Great Britain suggested that it is likely that the spectrum of HIV variants will also broaden in Slovakia along with an increasing number of infections. Recently reported new cases of HIV infection transmitted by heterosexual contact, reflected a "... marked shift in the pattern of HIV epidemic", which was previously almost exclusively restricted to the homosexual population in the western region of Slovakia. Zachar also stressed the importance of continued surveillance of the various HIV subtypes in this country.


Liver histology, blood biochemistry and RNA, DNA and subcellular protein composition of various skeletal muscles of rats with experimental cirrhosis: implications for alcoholic muscle disease.
(1) Liver cirrhosis was induced in male rats by treatment with carbon tetrachloride and phenobarbitone for 130-142 days. Detailed histological examination showed all livers from rats treated with carbon tetrachloride had annular fibrosis, necrosis, loss of normal hepatic architecture and other features that were consistent with an established micronodular cirrhosis. (2) Plasma biochemical analysis showed a significant reduction in total protein concentration (13%), which was due entirely to a reduction in plasma albumin (29%). There were also large increases in the plasma activities of alkaline phosphatase (110%) and aspartate aminotransferase (159%), when compared to phenobarbitone-treated controls. Plasma cholesterol was also increased (67%), but other plasma analytes were not significantly altered. (3) The soleus (Type I), plantaris (Type II) and gastrocnemius (Types I and II) muscles were dissected and examined for possible differential effects. There were minor reductions in all three muscle weights, but these changes did not reach statistical significance. The protein, RNA and DNA concentrations, total muscle content and content relative to body weight in cirrhotic rats were also not significantly altered in any of the muscles. Cirrhosis did not cause any perturbations in derived parameters, i.e. amount of synthetic apparatus per cell, RNA/DNA ratio, apparent cell size, protein/DNA ratio and the capacity for protein synthesis or RNA/protein ratio. (4) The gastrocnemius was fractionated into soluble, stromal and myofibrillar proteins. The concentrations and contents of all three proteins were unaltered in cirrhotic animals, compared to controls. (5) It is concluded that in this experimental model of cirrhosis there were no effects on those skeletal muscle variables which are strikingly altered by chronic alcohol feeding.(ABSTRACT TRUNCATED AT 250 WORDS)


[Bone metabolic abnormality in diabetes: especially about osteoblast dysfunction].
As for the factor in the diabetes in which it takes part in a bone abnormal metabolism, this is given the insulin lack state, a high blood glucose state, and the complications accompanying diabetes, such as arteriosclerosis, neuropathy, and a renal dysfunction. The absolute, and/or relative insulin lack state deteriorate the function and reduce the number of osteoblast, in addition, the osteoblast dysfunction is also caused by the sorbitol accumulation brought in the osteoblast as the result of the continuation of high blood glucose state. It also prompts the osteoclastic bone absorption, and suppresses the expression of transcription factor gene that regulates the osteoblast differentiation, and resultantly, the apoptosis of the osteoblast is promoted. By these mechanisms intertwining, the differentiation and the maturity of the osteoblast is thought to be decrease and the bone formation process is obstructed.


NAPP: the Nucleic Acid Phylogenetic Profile Database.
Nucleic acid phylogenetic profiling (NAPP) classifies coding and non-coding sequences in a genome according to their pattern of conservation across other genomes. This procedure efficiently distinguishes clusters of functional non-coding elements in bacteria, particularly small RNAs and cis-regulatory RNAs, from other conserved sequences. In contrast to other non-coding RNA detection pipelines, NAPP does not require the presence of conserved RNA secondary structure and therefore is likely to identify previously undetected RNA genes or elements. Furthermore, as NAPP clusters contain both coding and non-coding sequences with similar occurrence profiles, they can be analyzed under a functional perspective. We recently improved the NAPP pipeline and applied it to a collection of 949 bacterial and 68 archaeal species. The database and web interface available at http://napp.u-psud.fr/ enable detailed analysis of NAPP clusters enriched in non-coding RNAs, graphical display of phylogenetic profiles, visualization of predicted RNAs in their genome context and extraction of predicted RNAs for use with genome browsers or other software.


Severe acute respiratory syndrome coronavirus accessory protein 9b is a virion-associated protein.
Eight accessory proteins have been identified in severe acute respiratory syndrome-associated coronavirus (SARS-CoV). They are believed to play roles in the viral life cycle and may contribute to the pathogenesis and virulence. ORF9b as one of these accessory proteins is located in subgenomic mRNA9 and encodes a 98 amino acid protein. However, whether 9b protein is a structural component of SARS-CoV particles remains unknown. In this study, we demonstrate that 9b protein is translated from bicistronic mRNA9 via leaky ribosome scanning and it is incorporated into both virus-like particles (VLPs) and purified SARS-CoV virions. Further analysis shows that sufficient incorporation of 9b protein into VLPs is dependent upon the co-expression of E and M proteins, but not upon the presence of either S or N protein. Our data indicate that 9b protein of SARS-CoV is another virion-associated accessory protein. This finding will lead to a better understanding of the properties of the SARS-CoV 9b protein.


Behavioural and hematological responses of Cyprinus carpio exposed to mercurial chloride.
The static bioassay experiments were conducted to study the hematological and behavioural responses of Cyprinus carpio after exposure to mercuric chloride. Three different concentrations i.e. 0.5, 1.0 and 1.5 ppm of mercuric chloride (HgCl2) were used for 8, 16, 24, 48, 72, 96 and 124 hrs for evaluating behavioural responses. Hematological responses were assessed after 60 days exposure to 0.1 ppm of HgCl2. The changes in body colour, movement, sluggishness or activeness, disbalance etc. constituted the observations on behavioural responses. Hematological parameters included total erythrocyte (TEC) and leukocyte (TLC) counts and hemoglobin (Hb) levels. Body colour had changed in all groups after 48 hours. The fish exposed to 0.5 ppm HgCl2 did not show any abnormal activity except colour change throughout the experiment. Though no sign of distress was observed initially in groups exposed to 1.0 and 1.5 ppm HgCl2 but abnormal posturing, disbalance and sluggishness became apparent after 72 hrs and all specimens of 1.5 ppm group had died within 124 hours. TEC and Hb levels decreased whereas TLC increased in both male and female specimens of C. carpio after exposure to 0.1 ppm HgCl2 for 60 days. These observations indicated that mercurial toxicity even at low levels, caused adverse effects on body colour, behavioural responses and hematological parameters like TEC, TLC and hemoglobin levels in C. carpio.


Reduction of procedure times in routine clinical practice with Compressed SENSE magnetic resonance imaging technique.
Acceleration of MR sequences beyond current parallel imaging techniques is possible with the Compressed SENSE technique that has recently become available for 1.5 and 3 Tesla scanners, for nearly all image contrasts and for 2D and 3D sequences. The impact of this technique on examination timing parameters and MR protocols in a clinical setting was investigated in this retrospective study. A numerical analysis of the examination timing parameters (scan time, exam time, procedure time, interscan delay time, changeover time, nonscan time) based on the MR protocols of 6 different body regions (brain, knee, lumbar spine, breast, shoulder) using MR log files was performed and the total number of examinations acquired from January to April both in 2017 and 2018 on a 1.5 T MR scanner was registered. Percentages, box plots and unpaired two-sided t tests were obtained for statistical evaluation. All examination timing parameters of the six anatomical regions analysed were significantly shortened after implementation of Compressed SENSE. On average, scan times were accelerated by 20.2% (p<0.0001) while procedure times were shortened by 16% (p<0.0001). Considering all anatomical regions and all MR protocols, 27% more examinations were performed over the same 4 month period in 2018 compared to 2017. Compressed SENSE allows for a significant acceleration of MR examinations and a considerable increase in the total number of MR examinations is possible.


Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas.
The distinction of sporadic from inherited medullary thyroid carcinomas (MTCs) is of clinical importance because of the differences in prognosis, and the need for family screening for genetic counseling required in the latter. Germline mutations in the RET protooncogene are associated with multiple endocrine neoplasia (MEN) type 2A, familial medullary thyroid carcinoma (FMTC), and MEN type 2B. Somatic point mutations in the same gene have been identified in a subset of sporadically occurring medullary thyroid carcinomas. A nonisotopic polymerase chain reaction-(PCR) based single strand conformation polymorphism (SSCP) analysis and heteroduplex gel electrophoresis method was used to screen DNA extracted from 32 formaldehyde fixed and paraffin embedded MTC specimens and normal tissue or blood of the same patient for point mutations in RET exons 10, 11, and 16. Point mutations were identified by nonisotopic cycle sequencing of PCR-products using an automated DNA-sequencer. Results were compared with the disease phenotype, clinical findings, and follow-up. Six different missense germline mutations were identified at cysteine residues 618, 630, and 634 of the cysteine-rich extracellular RET domain encoded by exons 10 and 11 in all patients with FMTC and MEN 2A. The frequency of mutations at codon 634 was higher in patients with MEN 2A than with FMTC and a 634 Cys-->Arg mutation was associated with parathyroid disease in three patients. A germline Met-->Thr point mutation at codon 918 of the RET tyrosine kinase domain was identified in all three patients with MEN 2B. Two patients with clinically sporadic MTCs and negative family history exhibited a RET germline mutation at codon 634, indicating the presence of an nonpredicted inherited MTC. Furthermore, one patient had a 618 Cys-->Ser mutation in the tumor and nontumorous thyroid DNA but not in blood DNA, indicating a mosaic mutation affecting thyroid tissue but not blood cells. Tumor specific (somatic) Met-->Thr point mutations at codon 918 were identified in 5 of 13 sporadic MTCs. The remaining eight sporadic MTCs lacked mutations in all three RET exons tested. This study demonstrates that (1) the molecular methods are not only suitable to identify asymptomatic individuals at risk for MEN 2A, FMTC, and MEN 2B but also to distinguish heritable from nonheritable MTCs using archival tissue specimens, and (2) that more MTCs than clinically expected are heritable, indicating the need for genetic analysis of all patients with MTC.


3D Printing for Cartilage Replacement: A Preliminary Study to Explore New Polymers.
The use of additive manufacturing technologies for biomedical applications must begin with the knowledge of the material to be used, by envisaging a very specific application rather than a more general aim. In this work, the preliminary study was focused on considering the cartilaginous tissue. This biological tissue exhibits different characteristics, such as thickness and mechanical properties, depending on its specific function in the body. Due to the lack of vascularization, cartilage is a supporting connective tissue with limited capacity for recovery and regeneration. For this reason, any approach, whether to repair/regenerate or as a total replacement, needs to fulfill the adequate mechanical and chemical properties of the surrounding native cartilage to be successful. This work aims to explore the possibility of using new polymers for cartilage total replacement approaches with polymeric materials processed with the specific 3D printing technique of fused filament fabrication (FFF). The materials studied were Nylon® 12 (PA12), already described for this purpose, and LAY-FOMM® 60 (FOMM). FOMM has not been described in the literature for biomedical purposes. Therefore, the chemical, thermal, swelling capacity, and mechanical properties of the filaments were thoroughly characterized to better understand the structure-properties-application relationships of this new polymer. In addition, as the FFF technology is temperature based, the properties were also evaluated in the printed specimens. Due to the envisaged application, the specimens were also characterized in the wet state. When comparing the obtained results with the properties of native cartilage, it was possible to conclude that: (i) PA12 exhibits low swelling capacity, while FOMM, in its dry and wet forms, has a higher swelling capacity, closer to that of native cartilage; (ii) the mechanical properties of the polymeric materials, especially PA12, are higher than those of native cartilage; and (iii) from the mechanical properties evaluated by ultra-micro hardness tests, the values for FOMM indicate that this material could be a good alternative for cartilage replacement in older patients. This preliminary study, essentially devoted to expanding the frontiers of the current state of the art of new polymeric materials, provides valuable indications for future work targeting the envisaged applications.


Fungal microflora and ochratoxin a risk in French vineyards.
To evaluate the ochratoxin A risk in French vineyards, five winemaking regions were investigated. An exhaustive survey of the fungal microflora of 60 grape samples was carried out at two development stages of the berries: end of veraison and harvest time. Potentially toxinogenic fungi isolated from grapes were assessed in vitro for ochratoxin A production. Ochratoxin A was also quantified in musts by high-performance liquid chromatography after cleanup on immunoaffinity columns. Among the 90 species identified, almost half are listed as mycotoxin producers, but only 2 are potentially ochratoxinogenic: Aspergillus carbonarius and Aspergillus niger. Among these strains, only A. carbonarius, isolated from the Languedoc region at harvest time, was found to produce ochratoxin A. These results were in accordance with the presence of ochratoxin A in French southern region musts (0.01-0.43 microg/L) and confirmed the major implication of A. carbonarius in ochratoxin A contamination.


Radiation-induced DNA damage in canine hemopoietic cells and stromal cells as measured by the comet assay.
Stromal cell progenitors (fibroblastoid colony-forming unit; CFU-Fs) are representative of the progenitor cell population of the hemopoietic microenvironment in bone marrow (BM). Previous studies of the radiation dose-effect relationships for colony formation have shown that canine CFU-Fs are relatively radioresistant as characterized by a D0 value of about 2.4 Gy. In contrast, hemopoietic progenitors are particularly radiosensitive (D0 values= 0.12-0.60 Gy. In the present study, the alkaline single-cell gel electrophoresis technique for the in situ quantitation of DNA strand breaks and alkali-labile sites was employed. Canine buffy coat cells from BM aspirates and cells harvested from CFU-F colonies or from mixed populations of adherent BM stomal cell (SC) layers were exposed to increasing doses of X-rays, embedded in agarose gel on slides, lysed with detergents, and placed in an electric field. DNA migrating from single cells in the gel was made visible as "comets" by ethidium bromide staining. Immediate DNA damage was much less in cultured stromal cells than in hemopoietic cells in BM aspirates. These results suggest that the observed differences in clonogenic survival could be partly due to differences in the type of the initial DNA damage between stromal cells and hemopoietic cells.


Temperature-induced leakage from chilling-sensitive and chilling-resistant plants.
Leakage rates were determined from leaf cells loaded with rubidium and [(3)H]leucine. There was a differential response between leucine and rubidium leakage depending upon the species used. The rate of leucine leakage shows a small decline below 5 C for two altitudinal variants of Lycopersicon hirsutum Humb. and Bonpl., whereas Lycopersicon esculentum L. showed a marked increase below 5 C. Rubidium showed a marked increase in leakage rate below 10 C with the altitudinal variants, with only a slight increase for the L. esculentum species. A rough relationship existed between rubidium leakage rate at 1 C and the altitude of origin of the L. hirsutum race, the low altitudinal forms having higher leakage rates than the higher altitudinal variants. The L. esculentum lines show a rubidium leakage response similar to that of the high altitude L. hirsutum variants. Higher leakage rates were obtained if the calcium concentration in the medium was less than 1 millimolar and upon addition of metabolic poisons and detergents.The results are consistent with the view that chilling injury causes changes in the membrane and that cell leakage is an early symptom of this change in some species. Some chilling-sensitive species have increased leakage within 1 hour of exposure to chilling temperature.


Sn-protoporphyrin plus photoirradiation induces lipid peroxidation in vivo and in vitro in nonjaundiced Gunn rats.
Lipid peroxidation induced by Sn-protoporphyrin (SnPP) plus photoirradiation was investigated in vivo and in vitro using nonjaundiced Gunn rats. Membrane lipids from young adult rat brain were peroxidized by SnPP plus photoirradiation depending on the SnPP concentration and photoirradiance. Similarly, coadministration of SnPP and photoirradiation to suckling rats increased lipid peroxides in the whole blood and was found lethal. The influence of the wavelength distribution of light sources was also examined by using blue-white and green fluorescent lights. The photodynamic effect by green light irradiation whose energy distribution had no overlap with the Soret band of SnPP was about half of that produced by blue-white light with regard to the membrane peroxidation and the lethal effect on neonatal rats. We therefore conclude that the combination of SnPP and photoirradiation is a potentially hazardous treatment of neonatal jaundice.


Construction and Validation of a Potent Epigenetic Modification-Related Prognostic Signature for Osteosarcoma Patients.
Increasing evidence has shown that tumorigenesis correlates with aberrant epigenetic factors, such as DNA methylation, histone modification, RNA m6A modification, RNA binding proteins, and transcription factors. However, it is unclear that how epigenetic genes linked with alteration contribute to osteosarcoma's incidence and clinical prognosis. We developed an epigenetic modification-related prognostic model that may improve the diagnosis and prognosis of osteosarcoma. We investigated the epigenetic modification-associated genes and their clinical significance in osteosarcoma in this research. Our gene transcriptome data were obtained from the TARGET database and the GEO database. Bioinformatics techniques were used to investigate their functionalities. The diagnostic and prognostic models were constructed using univariate and multivariate Cox regression. In addition, we developed a nomogram indicating the practicability of the prognostic model described above. A risk score model constructed based on four epigenetic modification-related genes (MYC, TERT, EIF4E3, and RBM34) can effectively predict the prognosis of patients with osteosarcoma. Based on the risk score and clinical features, we constructed a nomogram. Epigenetic modification-related genes have been identified as important prognostic markers that may assist in osteosarcoma therapy therapeutic decision-making.


[Loss of heterozygosity at microsatellite marker localised near the metalloproteinase gene in patients with PEX syndrome].
The aim of the study was to evaluate the possible occurrence of loss of heterozygosity (LOH) at microsatellite marker localised near the area for metalloproteinase gene in the anterior capsule, lens nucleus, iris and trabeculum samples taken from patients with pseudoexfoliation syndrome (PEX). In our study we examined 19 patients (12 women and 7 men) with PEX syndrome who underwent surgical treatment for glaucoma, cataract or both at the same time. The mean age was 75.5 +/- 4.7, range 64-86. Specimens of the iris, anterior capsule, trabeculum and lens nucleus were taken to evaluate the possible occurrence of LOH at microsatellite marker D7S820 with fluorescent multiplex PCR method. LOH was displayed in 44% specimens of anterior capsule, 33% of iris specimen. In lens nucleus and trabeculum specimen LOH did not occur. The high frequency of LOH in PEX patients at locus D7S820 suggests that genetic factors may be involved in the etiology and pathogenesis of PEX.


The Acute Infarction Ramipril Efficacy (AIRE) Study: rationale, design, organization, and outcome definitions.
The rationale, design, organization, and outcome definitions of the Acute Infarction Ramipril Efficacy (AIRE) Study are described prospectively. A total of 2,000 patients (1,000 per treatment group) will be recruited to this multicenter, multinational, double-blind, randomized, placebo-controlled study investigating the effect of oral treatment with ramipril (2.5 or 5 mg twice daily) on the total mortality of survivors of an acute myocardial infarction (AMI) with early clinical evidence of heart failure. Secondary outcomes of the study include progression to severe/resistant heart failure (at which time the patient will be withdrawn from the study treatment), reinfarction, and stroke. Treatment will be initiated in hospital between day 3 and day 10 following AMI, and follow-up continued for an average of 15 months and a minimum of 6 months. The study data will be analyzed on an intention-to-treat basis: a single formal interim analysis will be conducted after 175 deaths. An Independent Adjudicating Panel will act as the overall ethical supervisory body for the study and will retain the randomization code. An International Steering Committee will be responsible for the clinical definitions of the secondary study outcomes, and will regularly review progress of the study. We believe that early treatment with ramipril may reduce the total mortality of patients surviving an AMI with clinical evidence of heart failure.


Cardiovascular manifestations of severe scorpion sting in India (review of 34 children).
Scorpion sting in children is a hazardous and potentially fatal condition. Of 34 children admitted to hospital in Mahad, Maharashtra State, India following scorpion sting, 14 had hypertension (130/90-170/130 mmHg), five had myocardial failure, acute pulmonary oedema developed in nine, two had tachycardia (110-200/min) and four died. Analysis of data suggests that cardiovascular morbidity and mortality depend upon the time lapse between sting and administration of vasodilators. Current management of human scorpionism consists of early admission to hospital and immediate reduction of raised blood pressure with sublingual nifedipine while peripheral action of venom is antagonized by the post-synaptic alpha blocker prazosin; in addition, digoxin, frusemide, aminophylline and oxygen are administered. The patient is kept under close surveillance in an intensive care unit. Massive life-threatening pulmonary oedema is treated with a sodium nitroprusside drip. We suggest that aggressive medical management directed at the organ system specifically affected by scorpion venom can be effective.


Influence of sex on the meiotic segregation of a t(13;17) Robertsonian translocation: a case study in the pig.
Comparison of male versus female meiotic segregation patterns for Robertsonian translocation (RT) carriers with similar genetic background has rarely been reported in mammalian species. The aim of this study was to compare the segregation patterns determined for related males and females carrying a 13;17 RT in an animal model (Sus scrofa domestica L.), using dual colour fluorescence in situ hybridization on decondensed sperm nuclei and metaphases II of in vitro-matured oocytes. In males, no association between the trivalent and the XY body was observed in any of the 90 pachytene nuclei studied, and the rate of unbalanced spermatozoa ranged between 2.96% and 3.83%. Female meiotic segregation analyses were carried out on 83 metaphase II oocytes. The rate of unbalanced gametes was higher in females than in males (28.91% versus 3.21%, P < 0.001). This difference was due to higher rates of diploid gametes (12.04% versus 0.05%) and unbalanced gametes produced by the adjacent segregation (16.86% versus 3.16%). This study is a new scientific contribution to the comparison of segregation patterns in related males and females carrying an identical chromosomal rearrangement. It allows a better understanding of the meiotic behaviour of RTs. It also clearly illustrates the relevance of swine as an animal model for such meiotic studies.


Fast and facile dissolution of cellulose with tetrabutylphosphonium hydroxide containing 40 wt% water.
Tetrabutylphosphonium hydroxide containing 40 wt% water dissolved 20 wt% cellulose at the final concentration within 5 minutes under mild stirring at 25 °C.


Chromosomal locus tracking with proper accounting of static and dynamic errors.
The mean-squared displacement (MSD) and velocity autocorrelation (VAC) of tracked single particles or molecules are ubiquitous metrics for extracting parameters that describe the object's motion, but they are both corrupted by experimental errors that hinder the quantitative extraction of underlying parameters. For the simple case of pure Brownian motion, the effects of localization error due to photon statistics ("static error") and motion blur due to finite exposure time ("dynamic error") on the MSD and VAC are already routinely treated. However, particles moving through complex environments such as cells, nuclei, or polymers often exhibit anomalous diffusion, for which the effects of these errors are less often sufficiently treated. We present data from tracked chromosomal loci in yeast that demonstrate the necessity of properly accounting for both static and dynamic error in the context of an anomalous diffusion that is consistent with a fractional Brownian motion (FBM). We compare these data to analytical forms of the expected values of the MSD and VAC for a general FBM in the presence of these errors.


DNA damage by 5-aminolevulinic and 4,5-dioxovaleric acids in the presence of ferritin.
Cellular accumulation of 5-aminolevulinic acid (ALA), the first specific intermediate of heme biosynthesis, is correlated in liver biopsy samples of acute intermittent porphyria affected patients with an increase in the occurrence of hepatic cancers and the formation of ferritin deposits in hepatocytes. 5-Aminolevulinic acid is able to undergo enolization and to be subsequently oxidized in a reaction catalyzed by iron complexes yielding 4,5-dioxovaleric acid (DOVA). The released superoxide radical (O(*-)(2)) is involved in the formation of reactive hydroxyl radical ((*)OH) or related species arising from a Fenton-type reaction mediated by Fe(II) and Cu(I). This leads to DNA oxidation. The metal catalyzed oxidation of ALA may be exalted by the O(*-)(2) and enoyl radical-mediated release of Fe(II) ions from ferritin. We report here the potentiating effect of ferritin on the ALA-mediated cleavage of plasmid DNA and the enhancement of the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodGuo). Plasmid pBR322 was incubated with ALA and varying amounts of purified ferritin. DNA damage was assessed by gel electrophoresis analysis of the open and the linear forms of the plasmid from the native supercoiled structure. Addition of either the DNA compacting polyamine spermidine or the metal chelator ethylenediaminetetraacetic acid (EDTA) inhibited the damage. It was also shown that ALA in the presence of ferritin is able to increase the oxidation of the guanine moiety of monomeric 2'-deoxyguanosine (dGuo) and calf thymus DNA (CTDNA) to form 8-oxodGuo as inferred from high performance liquid chromatography (HPLC) measurements using electrochemical detection. The formation of the adduct dGuo-DOVA was detected in CTDNA upon incubation with ALA and ferritin. In a subsequent investigation, the aldehyde DOVA was also able to induces strand breaks in pBR322 DNA.


[MITOCHONDRIAL DYSFUNCTION: MODERN ASPECTS OF THERAPY (REVIEW)].
Mitochondrial diseases are considered as one of the major problems of modern interdisciplinary neonatology and pediatrics. Mitochondrial pathology can be revealed as refractory myoclonic or multifocal seizures, craniofacial dysostosis, dysmetabolic manifestations and respiratory disorders. Central nervous system (CNS), muscles, heart, liver and kidneys is involved in this pathological process. An important criterion for diagnosis of mitochondrial dysfunction is increases in blood lactate and pyruvate levels; the absolute criterion - molecular genetic diagnostic studies of mitochondrial DNA. Polymorphism of clinical symptoms complicates the process of early diagnostics, the lack clear recommendations complicates therapy. Modern aspects of treatment of mitochondrial dysfunction in various neurological syndromes are based primarily in improving the efficiency of the processes of oxidative phosphorylation at the system level. Dietary carbohydrate restriction, and medication (Coenzyme Q10, Idebenonum, Cofactors, drugs which reduce lactic acidosis- Dimephosphon, Dichloroacetate, Antioxidants, Anticonvulsants and Antidiabetic agents, vitamins C, E, K, hemotransfusions) is prescribed. Such complex approach allows us to achieve a reduction in lactate-acidosis, and improve the condition of patients in 70% of cases.


Description of a new genus of Euliina with unique coupling adaptations of the male and female (Lepidoptera: Tortricidae: Tortricinae: Cochylini).
Ancoruncus langeri, new genus and new species, is described and illustrated from the Neotropics (Bolivia). It is assigned to the tribe Cochylini (subtribe Euliina) in the family Tortricidae. Ancoruncus langeri is characterized by an unusual, strongly developed uncus, distally expanded into an anchor-like, bilobed apical process and a complex gnathos in male genitalia, as well as an unusual configuration of the anterior lobes of the papillae anales, and tergum 8 with the anterior area bearing a double pocket in the female genitalia. The hypothetical dorsal coupling mechanism of the male and female genitalia is discussed.


Characterization of the complete chloroplast genome sequence of Malus kansuensis (Rosaceae).
The Malus kansuensis belongs to the Malus genus of Rosaceae family and it is an important apple rootstock resource native to China. Here, its complete chloroplast genome was sequenced and assembled by high-throughput Illumina sequencing data. The DNA was circular in shape with 160,133 bp length, containing IRA and IRB inverted repeat regions (26,354 bp), large single-copy region (LSC) (88,141 bp), and small single-copy region (SSC)(19,284 bp). In the chloroplast genome, 129 functional genes were predicted, including 85 protein-coding genes, 36 tRNA genes, and 8 rRNA genes. The phylogenetic tree basically accords with the traditional taxonomy of the order Malus genus of Rosaceae family.


The one-pot synthesis of quinolines via Co(iii)-catalyzed C-H activation/carbonylation/cyclization of anilines.
We herein disclose a novel Co(iii)-catalyzed C-H activation/carbonylation/cyclization of anilines with ketones using paraformaldehyde as the carbonyl source, giving direct access to diverse quinolines with broad functional group tolerance and in good to excellent yields. Moreover, exclusive site-/region-selectivity was observed in this versatile transformation.


Long non‑coding RNA LINC01224 promotes cell proliferation and inhibits apoptosis by regulating AKT3 expression via targeting miR‑485‑5p in endometrial carcinoma.
Endometrial carcinoma (EC) is the most common cancer in women worldwide, yet little is known about the underlying molecular basis of EC development. LINC01224, a novel long non‑coding (lnc)RNA, was recently identified as an oncogene in various types of cancer. However, the function and underlying mechanism of LINC01224 in EC is still unclear. A total of 50 pairs of tumor and adjacent normal tissue from patients with EC, three EC cell lines and one human normal endometrial stromal cell (ESC) line were subjected to reverse transcription‑quantitative PCR assay to evaluate the expression levels of LINC01224. Cell Counting Kit‑8, colony formation and flow cytometry assays were used to assess cell proliferation and apoptosis. Western blotting was used to measure expression levels of apoptosis‑ and proliferation‑associated proteins and AKT3 protein. A xenograft model of HEC1A cells was established to validate the in vivo function of LINC01224 in EC tumor growth. Starbase 3.0 database prediction and luciferase reporter and RNA pull‑down assays were performed to verify the binding sites between LINC01224 and microRNA (miR)‑485‑5p and miR‑485‑5p and AKT3. LINC01224 expression was significantly upregulated in both EC tumor tissue and cell lines. The upregulation of LINC01224 was negatively associated with survival of patients with EC. Functionally, LINC01224 promoted proliferation and inhibited apoptosis of EC cells; LINC01224 directly bound to and downregulated miR‑485‑5p to elevate the expression levels of AKT3, thereby promoting EC progression. LINC01224 depletion in EC cells hindered tumor growth in a xenograft model. The tumor suppressing effect of LINC01224‑knockdown on EC progression was partly rescued by treatment with miR‑485‑5p inhibitor. The present data demonstrated the expression levels, clinical relevance and functional mechanism of LINC01224 in EC. LINC01224 promoted EC development via sponging miR‑485‑5p to elevate AKT3 expression levels; this may provide a promising therapeutic target pathway for EC treatment.


An evaluation of patient satisfaction amongst family practice patients with diverse ethnic backgrounds.
The aim of this study was to examine the impact of patients' ethnic diversity on the patient satisfaction rates. We used the methodology developed in an international EUROPE study. The patients were asked to fill in self-administered questionnaires on their evaluations of the care received in the year prior to the survey. The instrument consists of 23 questions regarding specific family physicians' tasks evaluated on a 5 point Likert scale. Primary care practices of the National Railway Primary Health Care Services in Slovenia. A questionnaire was handed out to 600 patients cared for by 10 physicians. Percentages of highly satisfied patients in groups of patients with different ethnic backgrounds. We achieved 65.7% response rate. The overall satisfaction was lower in non-Slovenian patients, however was not significant (83.6 vs. 85.8 points, p = NS). Non-Slovenian patients were less satisfied with regard to: "quick relief of their symptoms", "helping them to feel well so as to be able to perform their normal daily activities", physicians'"thoroughness" and their explanations concerning what the patients wanted to know about their symptoms and/or illness. In a multivariate analysis Slovenian nationality predicted higher patient satisfaction with the clinical "performance" of physicians. As family practice remains an important source of primary health care for all patients, the providers should address the needs of all members of society regardless their social or cultural background. Undergraduate and postgraduate curricula have to address communication skills emphasising cultural differences.


Cyclooxygenase and neuroinflammation in Parkinson's disease neurodegeneration.
Cyclooxygenase (COX) expression in the brain is associated with pro-inflammatory activities, which are instrumental in neurodegenerative processes such as Parkinson's disease (PD). It is discussed that drugs with the capacity to rescue dopaminergic neurons from microglia toxicity and neuroinflammatory processes may result in an amelioration of parkinsonian symptoms by delaying the onset or slowing progression. This article reviews the involvement of COX in neuroinflammation, specifically focussing at the role of selective COX-2 inhibition in neuroinflammation and neurodegeneration in Parkinson's disease.


On Vulnerability of Selected IoT Systems to Radio Jamming-A Proposal of Deployment Practices.
Weightless and SigFox are both narrowband communication systems designed for the Internet of Things, along with some other counterparts such as LoRa (Long Range) and narrowband Internet of Things (NB-IoT). As systems dedicated specifically for long-range operations, they possess considerable processing gain for energetic link budget improvement and a remarkable immunity to interference. The paper describes outcomes of a measurement campaign during which the Weightless and SigFox performance was tested against variable interference, generated in an anechoic chamber. Results allow the quantitative appraisal of the system behavior under these harsh conditions with respect to different operational modes of the two investigated IoT systems. The outcomes are then investigated with respect to an intentional radio jammer attempting to block a base station (BS) operation by directly radiating an interfering signal towards it. An Interference Margin is proposed for a quantitative expression of a system's resilience to jamming. This margin, calculated for all available configuration settings, allows the clear assessment of which combination of a system's operational parameters does and which does not provide immunity to this type of radio attack.


Study on Neurological Consequence of Eclampsia.
The present study was carried out in the Department of Obstetrics and Gynecology at Mymensingh Medical College Hospital, Mymensingh, Bangladesh for a period of one year from 1st June 2009 to 30th June 2010 to see the Neurological Consequence of Eclampsia. A total number of 37 patients were enrolled in this study. Among 37 patients majority are in the age group of 21-30 years which is 19(51.4%) cases followed by less than or equal to 20 years and more than 30 years which are 13(35.1%) cases and 5(13.5%) cases respectively. Knee jerk is present in 28(75.7%) cases and absent in 8(21.6%) cases. The exaggerated knee jerk is present in only in 1(2.7%) case. The rate of Glasgow coma scale is less than 5 in 21(56.8%) cases, 14(37.8%) cases in 5-10 and 2(5.4%) cases is in more than 10. Focal sign is absent in 22(59.5%) cases and present in 15(40.5%) cases. Majority of the patients is presented with absence of neck stiffness which is 35(94.6%) cases and the rest 2(5.4%) cases are presented with neck stiffness. Flexor planter response is found in 20(54.1%) cases which is the highest in number followed by extensor which is 15(40.5%) cases. In only 2(5.4%) cases the planter reflex is not elicitable. Presence of infarct is found in 15(40.5%) cases which is the highest number. Cerebral edema and Presence of haemorrhage is found in 3(8.1%) cases in each. Leuko-encephalopathy is found in 2(5.4%) cases. Encephalopathy and Both infarct & haemorrhage is found in 1(2.7%) case of each. Normal CT scan findings of brain are found in 12(32.4%) cases.


The human MYOD1 transgene is suppressed by 5-bromodeoxyuridine in mouse myoblasts.
5-Bromodeoxyuridine (BrdU) immediately and clearly suppresses expression of the mouse Myod1 and human MYOD1 genes in myoblastic cells. Despite various studies, its molecular mechanism remains unknown. We failed to identify a BrdU-responsive element of the genes in experiments in which reporter constructs containing known regulatory sequences were transferred to mouse C2C12 myoblasts. Therefore, we transferred human chromosome 11 containing the MYOD1 gene to the cells by microcell-mediated chromosome transfer. In the resulting microcell hybrids, BrdU suppressed expression of the transgene, as determined by quantitative real-time RT-PCR analysis. We then transfected human PAC clones containing the MYOD1 gene to the cells. In the resulting transfectants, BrdU suppressed the transgene similarly. Deletion analysis suggested that a BrdU-responsive element or chromatin structure exists between 24 and 47 kb upstream of the gene. These results are the first demonstrating BrdU-responsiveness of a transgene for the known BrdU-responsive genes and facilitating determination of its precise responsible structure.


Salvianolic acid A promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes through regulation of the AMPK-PGC1α signalling pathway.
Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes (T2DM). Decreased mitochondrial abundance and function were found in white adipose tissue (WAT) of T2DM patients. Therefore, promoting WAT mitochondrial biogenesis and improving adipocyte metabolism may be strategies to prevent and reverse T2DM. Salvianolic acid A (SAA) has been found to exert anti-diabetic and lipid disorder-improving effects. However whether SAA benefits mitochondrial biogenesis and function in adipose tissue is unclear. Here, we evaluated SAA's effect on mitochondrial biogenesis and function in 3T3-L1 adipocytes and investigated its potential regulatory mechanism. Results showed that SAA treatment significantly promoted the transcription and expression of peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Meanwhile, SAA treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) quantity, mitochondrial mass, and expression of mitochondrial respiratory chain enzyme complexes III and complex IV. These enhancements were accompanied by enhanced phosphorylation of AMPK and ACC and were suppressed by Compound C, a specific AMPK inhibitor. Furthermore, SAA treatment improved adipocytes mitochondrial respiration and stimulated ATP generation. These findings indicate that SAA exerts a potential therapeutic capacity against adipocytes mitochondrial dysfunction in diabetes by activating the AMPK-PGC-1α pathway.


Student tobacco use, secondhand smoke exposure, and policy beliefs before and after implementation of a tobacco-free campus policy: Analysis of five U.S. college and university campuses.
The adoption of comprehensive tobacco policies by colleges and universities may help reduce student tobacco use. To this end, The American Cancer Society's Tobacco-Free Generation Campus Initiative (TFGCI) awarded grants to 106 higher learning institutions to adopt 100% tobacco-free campus policies. This study measured changes in student tobacco use, reported exposure to secondhand smoke, and support for types of tobacco policies among five TFGCI grantee institutions who implemented 100% tobacco-free policies. Students at five U.S. TFGCI grantee institutions completed two independent cross-sectional online surveys regarding tobacco use, exposure to secondhand smoke, and policy attitudes, once before (n = 2499) and once after (n = 1667) their campuses adopted a tobacco-free policy. Students were less likely to report current cigarette smoking (aOR: 0.73, 95% C.I.: 0.63, 0.85) and exposure to secondhand smoke on campus (aOR: 0.42, 95% C.I.: 0.23, 0.76) following the policy change. In contrast, students were more likely to report past 30-day use of electronic nicotine delivery systems (ENDS) (aOR: 2.16, C.I.: 1.77, 2.63) following the policy change, despite the policy's inclusion of all tobacco and nicotine products. Tobacco-free campus policies can be associated with decreases in tobacco product use and environmental smoke exposure. The extent of their effectiveness may vary by product and the inclusion of tailored messaging, cessation support, and enforcement approaches. To discourage use of these products among students, colleges and universities should adopt 100% tobacco-free policies, monitor product use trends, offer cessation support and messaging customized for specific groups and products, and utilize a comprehensive enforcement strategy.


Diabetes is associated with a higher risk of mortality among women in a middle-income country: Results form the Mexican Teacher's cohort study.
In Mexico City, the mortality rate among patients with diabetes appears to be four times that of people without diabetes. Our study aimed to refine analyses of the impact of diabetes on mortality in a large cohort of women from different areas in Mexico with healthcare insurance. Our study followed 111,299 women with comprehensive healthcare coverage from the Mexican Teachers' Cohort. After a median follow-up of 7.8years, 5514 (5%) prevalent self-reported diabetes cases and 4023 incident cases were identified, while deaths were identified through employers' databases and next-of-kin reports, with dates and causes of death for 1121 women obtained from mortality databases. Hazard ratios (HRs) for total and cause-specific mortality were estimated by Cox regression models, using follow-up time as the time scale and allowing for time-variable diabetes status after adjusting for age, socioeconomic status, use of health services, and anthropometric and lifestyle variables. In multivariable-adjusted models, the HR for all-cause mortality was 3.28 (95% CI: 2.86-3.75) in women with vs. without diabetes. The impact of diabetes on mortality was higher in rural vs. urban areas (HR: 4.72 vs. 2.98, respectively). HRs were 1.57 and 23.44 for cancer and renal disease mortality, respectively. In women with healthcare coverage in Mexico, the magnitude of the association between diabetes and all-cause mortality was higher than that observed in high-income countries, but less than what has previously been reported for Mexico. Such elevated mortality suggests a lack of adequate access to quality diabetes care in the population despite comprehensive healthcare coverage.


Assessment of the validity of the CUDIT-R in a subpopulation of cannabis users.
The Cannabis Use Disorders Identification Test-Revised (CUDIT-R) is an 8-item measure used to screen for cannabis use disorders (CUD). Despite widespread use of the tool, assessments of the CUDIT-R's validity in subpopulations are limited. The current study tested the structural validity and internal consistency of one of the most widely used screening measures for CUD (i.e., CUDIT-R) among a sample of military veterans who use cannabis for medicinal purposes. The present study used confirmatory factor analysis (CFA) to test the internal consistency and validity of the single-factor structure of the original screener among a sample of veterans who use cannabis for medicinal purposes (n = 90 [90% male]; Mage = 55.31, SD = 15.37). Measures included demographics and the CUDIT-R, obtained from the baseline assessment of an ongoing longitudinal study. The CFA revealed that the single-factor model previously validated in recreational using samples only accounted for 38.34% of total variance in responses on the CUDIT-R (χ2 = 66.09, df = 28, p < 0.05; RMSEA = 0.06) and demonstrated acceptable but modest internal consistency (Cronbach's α = 0.73). More psychometric work is needed to determine the reliability and validity of using the CUDIT-R to screen for CUD among military veterans who use medicinal cannabis and other subpopulations of cannabis users.


Isoflurane preconditioning increases survival of rat skin random-pattern flaps by induction of HIF-1α expression.
Survival of random-pattern skin flaps is important for the success of plastic and reconstructive surgeries. This study investigates isoflurane-induced protection against ischemia of skin flap and the underlying molecular mechanism in this process. Human umbilical vein endothelial cells (HUVECs) and human skin fibroblast cells were exposed to isoflurane for 4 h. Expression of hypoxia inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were analyzed up to 24 h post isoflurane exposure using qRT-PCR and western blot, or ELISA analyses. PI3K inhibitors--LY 294002 and wortmannin, mTOR inhibitor--rapamycin, and GSK3β inhibitor--SB 216763 were used respectively to assess the effects of isoflurane treatment and HIF-1α expression. Furthermore, 40 rats were randomly divided into 5 groups (control, isoflurane, scrambled siRNA plus isoflurane, HIF-1α siRNA plus isoflurane, and DMOG) and subjected to random-pattern skin flaps operation. Rats were prepared for evaluation of flap survival and full-feld laser perfusion imager (FLPI) (at 7 day) and microvessel density evaluation (at 10 day). Isoflurane exposure induced expression of HIF-1α protein, HO-1 and VEGF mRNA and proteins in a time-dependent manner. Both LY 294002 and wortmannin inhibited phospho-Akt, phospho-mTOR, phospho-GSK 3β and HIF-1α expression after isoflurane exposure. Both wortmannin and rapamycin inhibited isoflurane-induced phospho-4E-BP1 (Ser 65) and phospho-P70(s6k) (Thr 389) and HIF-1α expression. SB 216763 pre-treatment could further enhance isoflurane-induced expression of phospho-GSK 3β (Ser 9) and HIF-1α protein compared to the isoflurane-alone cells. In animal experiments, isoflurane alone, scrambled siRNA plus isoflurane, or DMOG groups had significantly upregulated vascularity and increased survival of the skin flaps compared to the controls. However, HIF-1α knockdown abrogated the protective effect of isoflurane preconditioning in rats. Isoflurane preconditioning improves survival of skin flaps by up the regulation of HIF-1α expression via Akt-mTOR and Akt-GSK 3β signaling pathways.


Morphological and clinical risk factors for posterior communicating artery aneurysm rupture.
Recent studies have shown that posterior circulation aneurysms, specifically posterior communicating artery (PCoA) aneurysms, are more likely to rupture than other aneurysms. To date, few studies have investigated the factors contributing to PCoA aneurysm rupture. The authors aimed to identify morphological and clinical characteristics predisposing to PCoA aneurysm rupture. The authors retrospectively reviewed 134 consecutive patients with PCoA aneurysms managed at their facility between July 2003 and December 2012. The authors divided patients into groups of those with aneurysmal rupture (n = 39) and without aneurysmal rupture (n = 95) and compared morphological and clinical characteristics. Morphological characteristics were mainly evaluated by 3D CT angiography and included diameter of arteries (anterior cerebral artery, middle cerebral artery, and internal carotid artery), size of the aneurysm, dome-to-neck ratio, neck direction of the aneurysmal dome around the PCoA (medial, lateral, superior, inferior, and posterior), aneurysm bleb formation, whether the PCoA was fetal type, and the existence of other intracranial unruptured aneurysm(s). Patients with ruptured PCoA aneurysms were significantly younger (a higher proportion were < 60 years of age) and a significantly higher proportion of patients with ruptured PCoA aneurysms showed a lateral direction of the aneurysmal dome around the PCoA, had bleb formation, and the aneurysm was > 7 mm in diameter and/or the dome-to-neck ratio was > 2.0. Multivariate logistic regression analysis showed age < 60 years (OR 4.3, p = 0.011), history of hypertension (OR 5.1, p = 0.008), lateral direction of the aneurysmal dome around the PCoA (OR 6.7, p = 0.0001), and bleb formation (OR 11, p < 0.0001) to be significantly associated with PCoA aneurysm rupture. The present results demonstrated that lateral projection of a PCoA aneurysm may be related to rupture.


Long-Term Hearing Loss after Acute Acoustic Trauma in the French Military: A Retrospective Study.
Acute acoustic trauma (AAT) is characterized by cochlea-vestibular signs following intense noise exposure, often caused by impulse noise. French military faces a high risk of AAT because of the use of weapons with peak sound levels exceeding 150 dB. Hearing loss (HL) resulting from AAT can have a significant impact on quality of life and operational capacity. The aim of this study was to assess the prevalence of long-term hearing impairment after AAT. The study involved a retrospective review of computer-based patient records from four military medical centers in Northeast France between January 2016 and December 2021. The inclusion criteria required the presence of cochlea-vestibular signs following impulse acoustic exposure and the absence of other causes. Sociodemographic and clinical data were collected, including audiometric data before and after exposure. The primary end point was the presence of a threshold elevation greater than 10 dB between reference and late audiograms. A total of 419 patients were included in the analysis, with a majority of males (n = 419; 84.7%) and a mean age of 23.6 yrs. The most common causative agent was the 5.56-mm assault rifle (n = 327; 78.0%). Tinnitus was the most frequent symptom (n = 366; 87.4%), followed by hypoacusis (n = 147; 35.1%) and earache (n = 89; 21.2%). The initial audiograms showed no HL in 31.0% of cases, while the mean deficit across all frequencies was 15.4 dB. All patients received corticosteroid therapy, with a mean duration of 6.0 d. Late audiograms conducted at an average interval of 448.0 d after AAT revealed a prevalence of long-term HL exceeding 20%. Higher doses of corticosteroid therapy (>1 mg/kg) were associated with a reduced frequency of long-term HL. This study highlights the prevalence of long-term hearing impairment after AAT in the French military. The findings emphasize the importance of preventive measures, including proper use of hearing protection devices, and the need for timely diagnosis and treatment. Further research is warranted to explore gender susceptibility to AAT and evaluate the impact of different weapons on AAT characteristics. The study also underscores the potential benefits of higher doses of corticosteroid therapy in reducing the risk of long-term hearing impairment. Overall, the findings contribute to a better understanding of AAT and can inform strategies for its prevention and management in military settings.


Water-Soluble Pristine C60 Fullerene Inhibits Liver Alterations Associated with Hepatocellular Carcinoma in Rat.
Excessive production of reactive oxygen species is the main cause of hepatocellular carcinoma (HCC) initiation and progression. Water-soluble pristine C60 fullerene is a powerful and non-toxic antioxidant, therefore, its effect under rat HCC model and its possible mechanisms were aimed to be discovered. Studies on HepG2 cells (human HCC) demonstrated C60 fullerene ability to inhibit cell growth (IC50 = 108.2 μmol), to induce apoptosis, to downregulate glucose-6-phosphate dehydrogenase, to upregulate vimentin and p53 expression and to alter HepG2 redox state. If applied to animals experienced HCC in dose of 0.25 mg/kg per day starting at liver cirrhosis stage, C60 fullerene improved post-treatment survival similar to reference 5-fluorouracil (31 and 30 compared to 17 weeks) and inhibited metastasis unlike the latter. Furthermore, C60 fullerene substantially attenuated liver injury and fibrosis, decreased liver enzymes, and normalized bilirubin and redox markers (elevated by 1.7-7.7 times under HCC). Thus, C60 fullerene ability to inhibit HepG2 cell growth and HCC development and metastasis and to improve animal survival was concluded. C60 fullerene cytostatic action might be realized through apoptosis induction and glucose-6-phosphate dehydrogenase downregulation in addition to its antioxidant activity.


Factoring 51 and 85 with 8 qubits.
We construct simplified quantum circuits for Shor's order-finding algorithm for composites N given by products of the Fermat primes 3, 5, 17, 257, and 65537. Such composites, including the previously studied case of 15, as well as 51, 85, 771, 1285, 4369, … have the simplifying property that the order of a modulo N for every base a coprime to N is a power of 2, significantly reducing the usual phase estimation precision requirement. Prime factorization of 51 and 85 can be demonstrated with only 8 qubits and a modular exponentiation circuit consisting of no more than four CNOT gates.


Reject option to reduce false prediction rates for EEG-motor imagery based BCI.
The Filter Bank Common Spatial Pattern (FBCSP) algorithm had been shown to be effective in performing multi-class Electroencephalogram (EEG) decoding of motor imagery using the one-versus-the-rest approach on the BCI Competition IV Dataset IIa. In this paper, we propose a method to reduce false detection rates of decoding through a rejection option based on the difference in the posterior probability computed by the Naïve Bayesian classifier. We applied the proposed approach on the BCI Competition IV Dataset IIa, and the results showed a decrease in the false detection rates from 34.6 % to 6.9%, while average decoded trials decreased from 93.2% to 34.2% using a rejection threshold between 0.1 and 0.9. We subsequently formulated a method to optimize the rejection threshold based on the maximum F0.5 score. The optimal rejection threshold yielded an average decrease in false detection rate to 19.1% with an average of 67.5% of trials decoded. The results showed the feasibility of decreasing false detection rates at a cost of rejection. Nevertheless, the results suggest that the use of reject option (RO) may be used as a training feedback system to train subjects' overt and covert EEG control strategies for better (dexterity and safety) continuous control of external device.


Advances in the treatment of heart failure.
The intensive care clinician has available techniques for assessing the six major determinants of left ventricular function in patients with heart failure and therapeutic approaches for optimizing these determinants and restoring ventricular performance. With the objective data provided via the thermodilution pulmonary arterial catheter, the schema in Figure 12 can be used as a framework for the hemodynamic management of unstable patients. When the filling pressure is less than 20 mm Hg and the cardiac index is greater than 2.5 L/min/m2, no active hemodynamic intervention is indicated. If the patient has recurrent angina or significant hypertension, the use of sublingual nitrates or other agents is indicated to reduce the afterload. Patients who have a low stroke volume are candidates for volume expansion. Filling pressures above 24 mm Hg need to be reduced. Patients with acute pulmonary venous hypertension will frequently respond to sublingual nitrates and bedrest. Patients with persistent congestive heart failure will require supplemental diuretics and more powerful vasodilators. The management of severe low cardiac output and cardiogenic shock may required the addition of supplemental catecholamines and, in selected patients, the intra-aortic balloon pump. In addition to optimizing the ventricular preload and afterload, the treatment of rate, rhythm and conduction disturbances, and the correction of hypoxia and metabolic disturbances are essential. Finally, the ideal treatment for the management of heart failure is to prevent or at least limit the injury to the ventricular myocardium and to correct reversible causes contributing to the patient's symptoms.


[The role of cell adhesion, multidrug resistance and cell proliferation in short-term recurrent cases with T1G3 superficial bladder cancer].
To evaluate the roles of cell adhesion, multidrug resistance and cell proliferation in short-term recurrent cases with superficial bladder cancer, and the prognostic value of the three indexes. Immunohistochemical staining for E-cad, P-gp and Ki-67 was performed on the tumors of 100 patients with stage T0-T1 transitional cell carcinoma of the bladder who had been included in a retrospective research by follow-up. E-cad and P-gp expression was positive in 51 (43.2%)and 17 (14.4%) of the tumors, respectively and mean proliferation index (PI) was 22.1%. The decrease in E-cad expression was accompanied with the increasing recurrent episodes (P < 0.05), while increase of P-gp expression and PI were accompanied with the increasing recurrence episodes (P < 0.05). There was significant difference according to E-cad, P-gp positivity and between T(1)G(3) patients and no-T(1)G(3) patients (P < 0.05). There was negative correlation of E-cad expression with P-gp expression and PI. Minimum adhesion, strong drug resistance and maximum proliferation are the main factors that promote short-term recurrence of superficial bladder cancer and also the inherent reasons for easy recurrence and high malignancy of T(1)G(3) tumors. During this course, the three aspects may interact.


Prognostic significance of miR-181b and miR-21 in gastric cancer patients treated with S-1/Oxaliplatin or Doxifluridine/Oxaliplatin.
The goal of this study is to evaluate the effectiveness of S-1/Oxaliplatin vs. Doxifluridine/Oxaliplatin regimen and to identify miRNAs as potential prognostic biomarkers in gastric cancer patients. The expression of candidate miRNAs was quantified from fifty-five late stage gastric cancer FFPE specimens. Gastric cancer patients with KPS>70 were recruited for the trial. The control group was treated with 400 mg/twice/day Doxifluridine plus i.v. with Oxaliplatin at 130 mg/m(2)/first day/4 week cycle. The testing group was treated with S-1 at 40 mg/twice/day/4 week cycle plus i.v. with Oxaliplatin at 130 mg/m(2)/first day/4 week cycle. Total RNAs were extracted from normal and gastric tumor specimens. The levels of miRNAs were quantified using real time qRT-PCR expression analysis. The overall objective response rate (CR+PR) of patients treated with S-1/Oxaliplatin was 33.3% (CR+PR) vs. 17.6% (CR+PR) with Doxifluridine/Oxaliplatin for advanced stage gastric cancer patients. The average overall survival for patients treated with S-1/Oxaliplatin was 7.80 month vs. 7.30 month with patients treated with Doxifluridine/Oxaliplatin. The expression of miR-181b (P = 0.022) and miR-21 (P = 0.0029) was significantly overexpressed in gastric tumors compared to normal gastric tissues. Kaplan-Meier survival analysis revealed that low levels of miR-21 expression (Log rank test, hazard ratio: 0.17, CI = 0.06-0.45; P = 0.0004) and miR-181b (Log rank test, hazard ratio: 0.37, CI = 0.16-0.87; P = 0.018) are closely associated with better patient's overall survival for both S-1 and Doxifluridine based regimens. Patients treated with S-1/Oxaliplatin had a better response than those treated with Doxifluridine/Oxaliplatin. miR-21 and miR-181b hold great potential as prognostic biomarkers in late stage gastric cancer.


Inhibition of cytokinin action and of heat/aging induced potential for cytokinin action by inhibitors of membrane synthesis and function.
Data to support the hypothesis that cytokinin action, in inducing the biosynthetic pathway involved in betacyanin synthesis in Amaranthus tri-color seedlings, is dependent on both membrane synthesis and function is presented. The experimental system included a pretreatment of heat shock (40 degrees C) and aging of cotyledon explants. This produced the conditions necessary for the full expression of cytokinin potential during the subsequent betacyanin induction. Cerulenin, an inhibitor of fatty acid and sterol synthesis, inhibited both the heat-induced potential for cytokinin action and the benzyladenine-dependent induction itself. This was also true of metyrapone, an inhibitor of hydroxylation reactions involving cytochrome P450. Gammexane, an inhibitor of phospholipid turnover, impaired the heat-induced process but not the benzyladenine-dependent betacyanin accumulation. This was also the case with 2-isopropyl-4-dimethylamino-5-methyl phenyl-1-piperidine carboxylate methyl chloride, an inhibitor of the cyclization steps in sterol and gibberellin synthesis. Filipin at 100 micrograms per milliliter inhibited both processes, particularly the heat-induced potential. The effect of various steroids and fatty acids on induction is recorded together with experiments aimed at using them to reverse some of the inhibitions. The effect of cerulenin on heat-induced potential was partially reversed by preparations of Amaranthus lipids. Some reversal of the filipin effects was obtained with beta-sitosterol and stigmasterol. It is concluded that menbrane synthesis is stimulated during the heat/aging pretreatment and during the induction and that some membrane function(s) is necessary for subsequent cytokinin action.


Docking of chromaffin granules--a necessary step in exocytosis?
Putative docking of secretory vesicles comprising recognition of and attachment to future fusion sites in the plasma membrane has been investigated in chromaffin cells of the bovine adrenal medulla and in rat phaeochromocytoma (PC 12) cells. Upon permeabilization with digitonin, secretion can be stimulated in both cell types by increasing the free Ca2+-concentration to microM levels. Secretory activity can be elicited up to 1 hr after starting permeabilization and despite the loss of soluble cytoplasmic components indicating a stable attachment of granules to the plasma membrane awaiting the trigger for fusion. Docked granules can be observed in the electron microscope in permeabilized PC 12 cells which contain a large proportion of their granules aligned underneath the plasma membrane. The population of putatively docked granules in chromaffin cells cannot be as readily discerned due to the dispersal of granules throughout the cytoplasm. Further experiments comparing PC 12 and chromaffin cells suggest that active docking but not transport of granules can still be performed by permeabilized cells in the presence of Ca2+: a short (2 min) pulse of Ca2+ in PC 12 cells leads to the secretion of almost all releasable hormone over a 15 min observation period whereas, in chromaffin cells, with only a small proportion of granules docked, withdrawal of Ca2+ leads to an immediate halt in secretion. Transport of chromaffin granules from the Golgi to the plasma membrane docking sites seems to depend on a mechanism sensitive to permeabilization. This is shown by the difference in the amount of hormone released from the two permeabilized cell types, reflecting the contrast in the proportion of granules docked to the plasma membrane in PC 12 or chromaffin cells. Neither docking nor the docked state are influenced by cytochalasin B or colchicine. The permeabilized cell system is a valuable technique for the in vitro study of interaction between secretory vesicles and their target membrane.


Papillary thyroid carcinoma behavior: clues in the tumor microenvironment.
The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4-4.5, P = 5.4 × 10-4). Increased dendritic cells (OR = 3.4, CI = 1.9-6.3, P = 5.5 × 10-5) and neutrophils (OR = 10.5, CI = 2.7-44, P = 8.7 × 10-4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6-13, P = 4.9 × 10-3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10-3, CI = 5.3 × 10-5-0.031, P = 4.1 × 10-5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.


Cutaneous malignant melanoma associated with papillary thyroid cancer.
As the survival from cutaneous malignant melanoma and its clinical concerns have been steadily increasing, the possibility has been raised of an increased risk of second primary cancers in the patients with malignant melanoma. Especially, recent studies have identified an association between cutaneous malignant melanoma and thyroid carcinoma. We here report on a case of cutaneous malignant melanoma that developed in a 61-year-old female patient who had hypothyroidism caused by papillary thyroid carcinoma. We suggest that the individuals who have cutaneous malignant melanoma may be predisposed to other primary cancers and especially thyroid carcinoma. Continuous monitoring of the thyroid function in melanoma patients is required because hypothyroidism can worsen due to malignant melanoma and this is probably associated with thyroid carcinoma.