Liver Cancer Emergence Associated with Antiviral Treatment: An Immune Surveillance Failure?
The availability of new direct antiviral agents to safely and effectively treat the hepatitis C virus represents a major advancement in the field of liver disease. Most patients achieve complete viral eradication sustained over time. In addition, the administration of these new agents is safe and does not require limitations when liver function is impaired. Some now expect the hepatitis C virus to be completely eradicated in a few years. However, not all data are positive. In April 2016, we published a cohort study suggesting that viral eradication with the new agents could be associated in time with the emergence of recurrent cancer sites in patients previously treated for hepatocellular carcinoma. In this review, we update our report and summarize the data provided in recent publications. We also speculate about the mechanisms for cancer emergence and stress the need for further studies.


Mitochondrial genetic variations of an introduced freshwater fish, goldfish Carassius auratus at the frontier between Europe and Asia (western Anatolia, Turkey): proximity to Europe rather than East Asia?
Carassius auratus is one of the most significant ornamental and food fishes of the world that is globally distributed and well known. Although it is known to have existed at least for six decades and expanding its distribution range in Turkish waters, there is a dearth of information on genetic structure and variations of goldfish in Turkey. In this study, four mitochondrial genes (Cytochrome b, cytochrome oxidase II, 12S ribosomal RNA, and 16S ribosomal RNA) were used to infer the genetic variations of goldfish populations sampled from western part of Anatolia, Turkey. Three populations were clustered under three haplotypes for each gene and all haplotypes were special. Cytochrome b was found to have more variable sites and higher genetic diversity than other genes. According to the haplotype networks, goldfish populations in Turkey showed high level of genetic structuring and originated from the common haplotype known in native East Asian populations of the species. Extensive sampling scheme covering whole Anatolia should provide better understanding on the dispersal pattern of the species.


Dang-Gui Buxue Tang protects against oxidant injury by enhancing cellular glutathione in H9c2 cells: role of glutathione synthesis and regeneration.
In order to investigate the biochemical mechanism of Dang-Gui Buxue Tang (DBT) involved in its cardioprotective action, the effects of DBT and related preparations on the cellular level of reduced glutathione (GSH) and on susceptibility to menadione-induced toxicity were examined in H9c2 cardiomyocytes. Treatment with herbal extract prepared from the fresh root of Astragalus membranaceus (RAM) or Angelica sinensis (RAS) alone and their combinations (D1:1-D10:1) in varying ratios of RAM to RAS (1:1 to 10:1, respectively) increased cellular GSH in a concentration-dependent manner, with the effect produced by the D5:1 extract, an authentic formula of DBT, being the most potent. The enhancement of cellular GSH was found to correlate positively with the degree of cytoprotection against menadione toxicity. Both GSH-enhancing and cytoprotective effects of DBT were largely abolished by GSH depletion as a result of buthionine sulfoximine (BSO)/phorone treatment. The DBT-induced increase in the cellular GSH level and the associated cytoprotection were also suppressed by the treatment with BSO, an inhibitor of GSH synthesis, or 1,3-bis(2-chloroethyl)-1-nitrosourea, an inhibitor of GSH regeneration. The results indicate that DBT treatment protects against oxidant injury in H9c2 cells, and that the cytoprotective action is causally related to the increase in cellular GSH level, which is likely mediated by the enhancement of GSH synthesis and regeneration.


Factors affecting the educational diagnosis of diabetic patients.
An accurate determination of the educational needs of diabetic patients is based on a wide range of patient characteristics. In the development of an assessment instrument to determine the educational needs of patients, the relative importance of numerous patient characteristics was determined. A questionnaire was mailed to 1518 health professionals who are either members of the American Association of Diabetes Educators or community health nurses in the state of Michigan. Analyses of the responses to this questionnaire have provided information regarding the knowledge, psychosocial, and demographic characteristics of patients, which are thought to be important in an educational diagnosis. Questions to measure these identified characteristics will be incorporated into an instrument that will assess the educational needs of diabetic patients.


Maternal mobile phone exposure adversely affects the electrophysiological properties of Purkinje neurons in rat offspring.
Electromagnetic field (EMF) radiations emitted from mobile phones may cause structural damage to neurons. With the increased usage of mobile phones worldwide, concerns about their possible effects on the nervous system are rising. In the present study, we aimed to elucidate the possible effects of prenatal EMF exposure on the cerebellum of offspring Wistar rats. Rats in the EMF group were exposed to 900-MHz pulse-EMF irradiation for 6h per day during all gestation period. Ten offspring per each group were evaluated for behavioral and electrophysiological evaluations. Cerebellum-related behavioral dysfunctions were analyzed using motor learning and cerebellum-dependent functional tasks (Accelerated Rotarod, Hanging and Open field tests). Whole-cell patch clamp recordings were used for electrophysiological evaluations. The results of the present study failed to show any behavioral abnormalities in rats exposed to chronic EMF radiation. However, whole-cell patch clamp recordings revealed decreased neuronal excitability of Purkinje cells in rats exposed to EMF. The most prominent changes included afterhyperpolarization amplitude, spike frequency, half width and first spike latency. In conclusion, the results of the present study show that prenatal EMF exposure results in altered electrophysiological properties of Purkinje neurons. However, these changes may not be severe enough to alter the cerebellum-dependent functional tasks.


Proteomics and Metaproteomics Add Functional, Taxonomic and Biomass Dimensions to Modeling the Ecosystem at the Mucosal-luminal Interface.
Recent efforts in gut microbiome studies have highlighted the importance of explicitly describing the ecological processes beyond correlative analysis. However, we are still at the early stage of understanding the organizational principles of the gut ecosystem, partially because of the limited information provided by currently used analytical tools in ecological modeling practices. Proteomics and metaproteomics can provide a number of insights for ecological studies, including biomass, matter and energy flow, and functional diversity. In this Mini Review, we discuss proteomics and metaproteomics-based experimental strategies that can contribute to studying the ecology, in particular at the mucosal-luminal interface (MLI) where the direct host-microbiome interaction happens. These strategies include isolation protocols for different MLI components, enrichment methods to obtain designated array of proteins, probing for specific pathways, and isotopic labeling for tracking nutrient flow. Integration of these technologies can generate spatiotemporal and site-specific biological information that supports mathematical modeling of the ecosystem at the MLI.


Autoantibodies against the insulin receptor recognize the insulin binding subunits of an oligomeric receptor.
125I-insulin was specifically cross-linked to membranes of human cultured lymphocytes (IM-9 line) using disuccinimidyl suberate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions and autoradiography of this preparation revealed a major 125I-labeled band with an apparent mol wt of 130,000 and minor bands of about 300,000 and 95,000. Labeling of these bands was inhibited by incubation of membranes with either unlabeled insulin or autoantibodies to the insulin receptor. The bands were also observed after the 125I-insulin cross-linked preparation was solubilized and immunoprecipitated with a panel of autoantibodies to the insulin receptor. However, immunoprecipitation of the 125I-insulin-receptor complex was inhibited by preincubation with excess unlabeled insulin. Finally, 125I-Fab fragments of mol wt 50,000 prepared from anti-receptor antibodies and cross-linked to membranes were resolved into a major complex of mol wt 180,000 and a minor band of 125,000. Neither band was observed when 125I-Fab fragments were cross-linked to membranes in the presence of an excess of unlabeled insulin. These findings indicate that autoantibodies to the insulin receptor are directed against the insulin binding subunits of an oligomeric receptor.


[Parenteral nutrition associated cholestasis in the newborn].
Parenteral nutrition associated cholestasis in preterm infants and newborn children is a frequent and serious disease with an incidence of 23% depended on duration of parenteral nutrition and birthweight. The incidence of liver cirrhosis is 40% when parenteral nutrition is given 74-242 days. The pathogenesis remains unclear. Several predisposing factors are discussed like immaturity, lack of hormonal stimulation by oral feeding, bacterial infection, liver toxicity of aminoacids and their products of photooxidation, lack of taurine, lack of antioxidation substances, hypermanganesaemia and pollution of infusion solutions. Furthermore sepsis during parenteral nutrition seems to multiply the risk of cholestasis. For prevention controlled studies recommend: 1. Early enteral nutrition. 2. The reduction of parenteral amino acids to less than 3 g/kg/d. 3. Light protection for parenteral solutions. 4. Cyclic infusion of parenteral nutrition. 5. The application of antibiotics (metronidazole, gentamicin) during parenteral nutrition. The most important therapeutic intervention is the beginning of oral feeding. Most of the time this leads to a decrease of icterus within two weeks. An icterus persisting longer than 3 weeks should be treated because of the risk of liver cirrhosis. Further therapeutic interventions are: 1. Cholecystokinin, good results in case studies which still has to be verified by a controlled study. 2. Ursodeoxycholic acid, its choleretic effectiveness is verified in several liver diseases by controlled studies, but it is not proven in parenteral nutrition associated cholestasis. 3. Laparoscopic biliary irrigation, successful in several case studies.


Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity.
Intercellular adhesion molecule 1 (ICAM-1) is widely distributed in shoulder synovial membrane of active polymyalgia rheumatica (PMR) and strongly expressed in granulomatous inflammatory infiltrate of the temporal artery in giant cell arteritis (GCA). ICAM-1 genes may contribute to the inflammatory PMR/GCA processes. We examined potential associations of ICAM-1 gene polymorphisms with PMR/GCA susceptibility and severity. We enrolled 121 consecutive patients with "pure" PMR and 56 patients with biopsy positive GCA residing in Reggio Emilia, Italy. Among patients with PMR, 91 had a followup duration of at least one year. Selected as control subjects were 228 healthy blood donors, 75 patients with nonarteritic central retinal artery occlusion, and 116 cataract surgery patients from the same geographic area. All PMR/GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphism at codon 241 (exon 4) and codon 469 (exon 6). The frequency of R241 was significantly higher in PMR/GCA patients [p = 0.00001, odds ratio (OR) 5.0 (95% confidence intervals, CI 2.6-9.6) ], in pure PMR patients [p = 0.00001, OR 5.0 (95% CI 2.5-10.0)], and in GCA patients [p = 0.00005; OR 5.0 (95% CI 2.2-11.5)] compared to the healthy controls. The frequency of R241 was significantly higher in total PMR/GCA patients compared to patients with nonarteritic central retinal artery occlusion [p = 0.0007; OR 5.3 (95% CI 1.8-15.5)] and cataract surgery patients [p = 0.0003; OR 4.1 (95% CI 1.8-9.0)]. The distribution of E/K 469 genotype was similar in PMR/GCA patients and in the 3 control groups. Cox proportional hazards modeling identified 2 variables that independently increased the risk of PMR relapse/recurrence: erythrocyte sedimentation rate at diagnosis > 72 mm/h [relative risk 1.6 (95% CI 1.1-2.3)] and the presence of R241 allele [relative risk 1.6 (95% CI 1.1-2.4)]. Our findings show that G/R 241 polymorphism of ICAM-1 is associated with PMR/GCA susceptibility and confers an increased risk of relapse/recurrence in PMR.


Test-retest reliability of robotic assessment measures for the evaluation of upper limb recovery.
Rehabilitation robots have built-in technology and sensors that allow accurate measurement of movement kinematics and kinetics, which can be used to derive measures related to upper limb performance and highlight changes in motor behavior due to rehabilitation. This study aimed to assess the test-retest reliability of some robot-measured parameters by analyzing their intra-session and inter-session (day-by-day) variability. The study was carried out in two groups: 31 patients after stroke and 15 healthy subjects. Both groups practiced two different motor tasks consisting of point-to-point reaching movements in the shape of two geometrical figures that were selected for the assessment of global and directional (eight directions of the workspace) test-retest reliability. The reliability of six parameters measuring movement velocity, accuracy, efficiency and smoothness was assessed intra-session and inter-session by the ICC, SEM, and CV. Healthy subjects exhibited very high ICC values (> 0.85) and low SEM for all parameters. Patients had high ICC values and low SEM but their global reliability was generally lower compared to healthy subjects. In addition, their inter-session reliability showed very high ICC values (> 0.91) and low SEM for all parameters. Direction analysis showed that in some parameters the reliability was generally high but not homogeneous in all directions. In addition, some directions showed systematic error. This study demonstrates that robot-measured parameters are reliable and can be considered ideal candidates for use in combination with impairment and functional clinical scales to evaluate motor improvement during robot-assisted neurorehabilitation.


The influence of 17-beta-estradiol 17-beta-acetate on adenylyl cyclase activity and aminoacyl-tRNA synthetase phosphatase activity in ovariectomized NMRI mice.
Adenylyl cyclase activity in the uterus of ovariectomized NMRI mice showed an increase of 87% four minutes after intraperitoneal administration of 17-beta-estradiol 17-beta-acetate in water solution, while in the liver of the same animals activity had decreased by 57%. At the same time, the activity of the 51 kDa form of the aminoacyl-tRNA synthetase phosphatase in the uterus showed an increase of 400%, while in the liver a decrease of 60% was observed. Sixty minutes after hormone injection the adenylyl cyclase activities showed no difference from controls.


Tissue-specific expression and promoter analysis of the tobacco Itp1 gene.
The Nicotiana tabacum Itp1 gene (Ntltp1) encodes a small basic protein that belongs to a class of putative lipid transfer proteins. These proteins transfer lipids between membranes in vitro, but their in vivo function remains hotly debated. This gene also serves as an important early marker for epidermis differentiation. We report here the analysis of the spatial and developmental activity of the Ntltp1 promoter, and we define a sequence element required for epidermis-specific expression. Transgenic plants were created containing 1346 bp of the Ntltp1 promoter fused upstream of the beta-glucuronidase (GUS) gene. In the mature aerial tissues, GUS activity was detected predominantly in the epidermis, whereas in younger aerial tissues, such as the shoot apical meristem and floral meristem, GUS expression was not restricted to the tunica layer. Unexpectedly, GUS activity was also detected in young roots particularly in the root epidermis. Furthermore, the Ntltp1 promoter displayed a tissue and developmental specific pattern of activity during germination. These results suggest that the Ntltp1 gene is highly expressed in regions of the plant that are vulnerable to pathogen attack and are thus consistent with the proposed function of lipid transfer proteins in plant defense. Deletions of the promoter from its 5' end revealed that the 148 bp preceding the translational start site are sufficient for epidermis-specific expression. Sequence comparison identified an eight-nucleotide palindromic sequence CTAGCTAG in the leader of Ntltp1, which is conserved in a number of other Itp genes. By gel retardation analysis, the presence of specific DNA-protein complexes in this region was demonstrated. The characterization of these factors may lead to the identification of factors that control early events in epidermis differentiation.


Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50.
Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.


Functional and molecular evidence of myelin- and neuroprotection by thyroid hormone administration in experimental allergic encephalomyelitis.
Recent data in mouse and rat demyelination models indicate that administration of thyroid hormone (TH) has a positive effect on the demyelination/remyelination balance. As axonal pathology has been recognized as an early neuropathological event in multiple sclerosis, and remyelination is considered a pre-eminent neuroprotective strategy, in this study we investigated whether TH administration improves nerve impulse propagation and protects axons. We followed up the somatosensory evoked potentials (SEPs) in triiodothyronine (T3)-treated and untreated experimental allergic encephalomyelitis (EAE) Dark-Agouti female rats during the electrical stimulation of the tail nerve. T3 treatment started on the 10th day post immunization (DPI) and a pulse administration was continued until the end of the study (33 DPI). SEPs were recorded at baseline (8 DPI) and the day after each hormone/ vehicle administration. T3 treatment was associated with better outcome of clinical and neurophysiological parameters. SEPs latencies of the two groups behaved differently, being briefer and closer to control values (=faster impulse propagation) in T3-treated animals. The effect was evident on 24 DPI. In the same groups of animals, we also investigated axonal proteins, showing that T3 administration normalizes neurofilament immunoreactivity in the fasciculus gracilis and tau hyperphosphorylation in the lumbar spinal cord of EAE animals. No sign of plasma hyperthyroidism was found; moreover, the dysregulation of TH nuclear receptor expression observed in the spinal cord of EAE animals was corrected by T3 treatment. T3 supplementation results in myelin sheath protection, nerve conduction preservation and axon protection in this animal model of multiple sclerosis.


Renal measurements on CT angiograms: correlation with graft function at living donor renal transplantation.
To determine which measurement of donor renal size on computed tomographic (CT) angiograms has the greatest correlation with renal function preoperatively in the donor and postoperatively in the transplant recipient. Informed consent was waived for this retrospective HIPAA-compliant study approved by the institutional review board. Renal length, total volume, and cortical volume were measured on renal donor CT angiograms in 111 patients. Preoperative serum creatinine values for donors and postoperative creatinine values for recipients at hospital discharge and 6, 12, 24, and 36 months after transplant were collected, and estimated glomerular filtration rate (eGFR) was calculated. Correlation coefficients with 95% confidence intervals (CIs) were obtained for renal measures and donor eGFR and for renal measures adjusted to recipient body habitus and posttransplant creatinine level in the recipient. Thresholds were set for adjusted length and volumes, and the odds ratio (OR) for creatinine level less than 1.5 mg/dL at 36 months was calculated. Renal volumes and length were correlated with donor eGFR (r=0.58 [95% CI: 0.44, 0.69] for cortical volume, 0.56 [95% CI: 0.42, 0.68] for total volume, and 0.43 [95% CI: 0.27, 0.57] for renal length). All three measures, adjusted to recipient body habitus, were correlated with recipient renal function from discharge (r=-0.41 to -0.43) up to 36 months after transplantation (r=-0.33 to -0.41). By using a threshold of 1.5 for cortical volume to recipient weight, 2.25 for total volume to recipient weight, and 0.175 for renal length to recipient weight, the odds of creatinine level greater than 1.5 mg/dL were four times as great for smaller kidney-to-recipient weight ratios, a statistically significant pattern for cortical volume (OR, 4.07; 95% CI: 1.10, 15.09) but not total volume (OR, 4.24; 95% CI: 0.90, 20.01) or renal length (OR, 4.08; 95% CI: 0.48-34.29). Renal length and volumes correlated with recipient renal function up to 36 months after transplant. A low ratio of cortical volume to recipient weight was associated with diminished renal function at 36 months after transplant.


Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus.
Physical exercise has been shown to increase adult neurogenesis in the dentate gyrus and enhances synaptic plasticity. The antiapoptotic kinase, Akt has also been shown to be phosphorylated following voluntary exercise; however, it remains unknown whether the PI3K-Akt signaling pathway is involved in exercise-induced neurogenesis and the associated facilitation of synaptic plasticity in the dentate gyrus. To gain insight into the potential role of this signaling pathway in exercise-induced neurogenesis and LTP in the dentate gyrus rats were infused with the PI3K inhibitor, LY294002 or vehicle control solution (icv) via osmotic minipumps and exercised in a running wheel for 10 days. Newborn cells in the dentate gyrus were date-labelled with BrdU on the last 3 days of exercise. Then, they were either returned to the home cage for 2 weeks to assess exercise-induced LTP and neurogenesis in the dentate gyrus, or were killed on the last day of exercise to assess proliferation and activation of the PI3K-Akt cascade using western blotting. Exercise increases cell proliferation and promotes survival of adult-born neurons in the dentate gyrus. Immediately after exercise, we found that Akt and three downstream targets, BAD, GSK3beta and FOXO1 were activated. LY294002 blocked exercise-induced phosphorylation of Akt and downstream target proteins. This had no effect on exercise-induced cell proliferation, but it abolished most of the beneficial effect of exercise on the survival of newly generated dentate gyrus neurons and prevented exercise-induced increase in dentate gyrus LTP. These results suggest that activation of the PI3 kinase-Akt signaling pathway plays a significant role via an antiapoptotic function in promoting survival of newly formed granule cells generated during exercise and the associated increase in synaptic plasticity in the dentate gyrus.


Disorders of coagulation.
The routine preoperative performance of a platelet count, bleeding time, prothrombin time, and partial thromboplastin time will reveal most of the major inherited or acquired bleeding diatheses that are likely to be troublesome during or after an operation. Unfortunately, these screening test may fail to warn the physician of impending trouble because they fail to detect the milder bleeding tendencies. In such cases asking the patient a few specific questions may reveal a bleeding tendency not otherwise suspected. If a patient with an identified bleeding problem undergoes a surgical procedure, operative and postoperative bleeding can be minimized by continuous monitoring of the patient by the coagulation laboratory and by close collaboration among the surgeon, the hematologist, and the laboratory in the management of replacement therapy. However, if bleeding commences during or after an operation without warning, the nature of the problem must be recognized as quickly as possible in order to effect prompt treatment. By a series of simple tests, the coagulation laboratory can promptly identify the general nature of the bleeding problem and then more leisurely pinpoint it precisely.


Sedation in dentistry. Part 1: assessment of patients.
This is the first in a series of articles on the uses of sedation in general dental practice. This paper reviews current recommendations for the practice of sedation, and the importance of patient assessment as a part of treatment. The dental and psychosocial indications, as well as medical contraindications, for sedation are discussed. Future articles will expand on other areas where sedation may be a useful tool in the general dental practitioner's armamentarium. It is hoped that these articles will encourage all practitioners to consider a wider use of sedative techniques in dentistry.


Altered lipid homeostasis in Drosophila InsP3 receptor mutants leads to obesity and hyperphagia.
Obesity is a complex metabolic disorder that often manifests with a strong genetic component in humans. However, the genetic basis for obesity and the accompanying metabolic syndrome is poorly defined. At a metabolic level, obesity arises from an imbalance between the nutritional intake and energy utilization of an organism. Mechanisms that sense the metabolic state of the individual and convey this information to satiety centers help achieve this balance. Mutations in genes that alter or modify such signaling mechanisms are likely to lead to either obese individuals, who in mammals are at high risk for diabetes and cardiovascular disease, or excessively thin individuals with accompanying health problems. Here we show that Drosophila mutants for an intracellular calcium signaling channel, the inositol 1,4,5-trisphosphate receptor (InsP3R) store excess triglycerides in their fat bodies and become unnaturally obese on a normal diet. Although excess insulin signaling can rescue obesity in InsP3R mutants to some extent, we show that it is not the only cause of the defect. Through mass spectrometric analysis of lipids we find that homeostasis of storage and membrane lipids are altered in InsP3R mutants. Possibly as a compensatory mechanism, InsP3R mutant adults also feed excessively. Thus, reduced InsP3R function alters lipid metabolism and causes hyperphagia in adults. Together, the metabolic and behavioral changes lead to obesity. Our results implicate altered InsP3 signaling as a previously unknown causative factor for metabolic syndrome in humans. Importantly, our studies also suggest preventive dietary interventions.


A whole-genome microarray study of Arabidopsis thaliana semisolid callus cultures exposed to microgravity and nonmicrogravity related spaceflight conditions for 5 days on board of Shenzhou 8.
The Simbox mission was the first joint space project between Germany and China in November 2011. Eleven-day-old Arabidopsis thaliana wild type semisolid callus cultures were integrated into fully automated plant cultivation containers and exposed to spaceflight conditions within the Simbox hardware on board of the spacecraft Shenzhou 8. The related ground experiment was conducted under similar conditions. The use of an in-flight centrifuge provided a 1 g gravitational field in space. The cells were metabolically quenched after 5 days via RNAlater injection. The impact on the Arabidopsis transcriptome was investigated by means of whole-genome gene expression analysis. The results show a major impact of nonmicrogravity related spaceflight conditions. Genes that were significantly altered in transcript abundance are mainly involved in protein phosphorylation and MAPK cascade-related signaling processes, as well as in the cellular defense and stress responses. In contrast to short-term effects of microgravity (seconds, minutes), this mission identified only minor changes after 5 days of microgravity. These concerned genes coding for proteins involved in the plastid-associated translation machinery, mitochondrial electron transport, and energy production.


Modified work: prevalence and characteristics in a sample of workers with soft-tissue injuries.
Modified-work programs are designed to facilitate the return to work for employees with a work-related injury. Although extensive published literature exists that describes and evaluates "ideal" programs, to date there is a paucity of data describing practice. To address this pertinent issue, we administered a survey to a large sample of 1833 workers with soft-tissue injuries in Ontario, Canada, and asked them detailed questions about modified work and employer contact. Our results reveal that most workers (66%) were contacted by someone from their workplace to check on how they were doing. However, only a minority (36%) were offered arrangements by their employer to help them return to work after developing a work-related soft-tissue injury. Most arrangements that were offered to injured workers consisted of such temporary modifications as reduced hours (24%), flexible work hours (25%), or a lighter job (57%) rather than more permanent changes to the way that work is conducted, such as changes to the work layout or equipment (8%). Merely being contacted by the workplace to check on how the worker was doing was not associated with reduced compensation benefit duration. Workplace offers of arrangements to help the worker return to work were associated with reduced compensation benefit duration but were not statistically associated with workers' pain grade.


Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor.
The omega-3 fatty acids (FAs) found in fish and fish oils (eicosapentaenoic and docosahexaenoic acids, EPA and DHA) have been reported to have a variety of beneficial effects in cardiovascular diseases. Ecological and prospective cohort studies as well as randomized, controlled trials have supported the view that the effects of these FAs are clinically relevant. They operate via several mechanisms, all beginning with the incorporation of EPA and DHA into cell membranes. From here, these omega-3 FA alter membrane physical characteristics and the activity of membrane-bound proteins, and once released by intracellular phospholipases, can interact with ion channels, be converted into a wide variety of bioactive eicosanoids, and serve as ligands for several nuclear transcription factors thereby altering gene expression. In as much as blood levels are a strong reflection of dietary intake, it is proposed that an omega-3 FA biomarker, the omega-3 index (erythrocyte EPA+DHA) be considered at least a marker, if not a risk factor, for coronary heart disease, especially sudden cardiac death. The omega-3 index fulfils many of the requirements for a risk factor including consistent epidemiological evidence, a plausible mechanism of action, a reproducible assay, independence from classical risk factors, modifiability, and most importantly, the demonstration that raising tissue levels will reduce risk for cardiac events. For these and a number of other reasons, the omega-3 index compares very favourably with other risk factors for sudden cardiac death.


Electrophysiological measures of resting state functional connectivity and their relationship with working memory capacity in childhood.
Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher-order control regions to lower-order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter-subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto-parietal network and lower-level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability.


Survey of 34 pregnant women with hepatitis A and their neonates.
Thirty-four pregnant women with hepatitis A and their neonates were investigated on serum anti-HAV IgM, ALT (GPT) and clinical manifestations (with 34 randomized controls) during the outbreak of viral hepatitis A in Shanghai. The result showed no evidence of maternal-infant transmission of hepatitis A, and no birth defect was found. Sufficient rest and proper diet for and close surveillance of the pregnant woman were suggested to ensure the well-being of mother and child. In addition, we found immune gamma-globulin given to the neonates born of mothers with hepatitis A may be beneficial to avoid horizontal transmission of hepatitis A.


Progesterone: An enigmatic ligand for the mineralocorticoid receptor.
The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as brain, bone, lung and vasculature, in both women and men. An unusual property of progesterone is its high affinity for the mineralocorticoid receptor (MR), which regulates electrolyte transport in the kidney in humans and other terrestrial vertebrates. In humans, rats, alligators and frogs, progesterone antagonizes activation of the MR by aldosterone, the physiological mineralocorticoid in terrestrial vertebrates. In contrast, in elephant shark, ray-finned fishes and chickens, progesterone activates the MR. Interestingly, cartilaginous fishes and ray-finned fishes do not synthesize aldosterone, raising the question of which steroid(s) activate the MR in cartilaginous fishes and ray-finned fishes. The simpler synthesis of progesterone, compared to cortisol and other corticosteroids, makes progesterone a candidate physiological activator of the MR in elephant sharks and ray-finned fishes. Elephant shark and ray-finned fish MRs are expressed in diverse tissues, including heart, brain and lung, as well as, ovary and testis, two reproductive tissues that are targets for progesterone, which together suggests a multi-faceted physiological role for progesterone activation of the MR in elephant shark and ray-finned fish. The functional consequences of progesterone as an antagonist of some terrestrial vertebrate MRs and as an agonist of fish and chicken MRs are not fully understood. The physiological activities of progesterone through binding to vertebrate MRs merits further investigation.


Will a Short Training Session Improve Multiple-Choice Item-Writing Quality by Dental School Faculty? A Pilot Study.
Faculty members are expected to write high-quality multiple-choice questions (MCQs) in order to accurately assess dental students' achievement. However, most dental school faculty members are not trained to write MCQs. Extensive faculty development programs have been used to help educators write better test items. The aim of this pilot study was to determine if a short workshop would result in improved MCQ item-writing by dental school faculty at one U.S. dental school. A total of 24 dental school faculty members who had previously written MCQs were randomized into a no-intervention group and an intervention group in 2015. Six previously written MCQs were randomly selected from each of the faculty members and given an item quality score. The intervention group participated in a training session of one-hour duration that focused on reviewing standard item-writing guidelines to improve in-house MCQs. The no-intervention group did not receive any training but did receive encouragement and an explanation of why good MCQ writing was important. The faculty members were then asked to revise their previously written questions, and these were given an item quality score. The item quality scores for each faculty member were averaged, and the difference from pre-training to post-training scores was evaluated. The results showed a significant difference between pre-training and post-training MCQ difference scores for the intervention group (p=0.04). This pilot study provides evidence that the training session of short duration was effective in improving the quality of in-house MCQs.


A mitotic transcriptional switch in polycystic kidney disease.
Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor required for the expression of several renal cystic genes and whose prenatal deletion leads to polycystic kidney disease (PKD). We show here that inactivation of Hnf1b from postnatal day 10 onward does not elicit cystic dilations in tubules after their proliferative morphogenetic elongation is over. Cystogenic resistance is intrinsically linked to the quiescent state of cells. In fact, when Hnf1b deficient quiescent cells are forced to proliferate by an ischemia-reperfusion injury, they give rise to cysts, owing to loss of oriented cell division. Remarkably, in quiescent cells, the transcription of crucial cystogenic target genes is maintained even in the absence of HNF-1beta. However, their expression is lost as soon as cells proliferate and the chromatin of target genes acquires heterochromatin marks. These results unveil a previously undescribed aspect of gene regulation. It is well established that transcription is shut off during the mitotic condensation of chromatin. We propose that transcription factors such as HNF-1beta might be involved in reprogramming gene expression after transcriptional silencing is induced by mitotic chromatin condensation. Notably, HNF-1beta remains associated with the mitotically condensed chromosomal barrels. This association suggests that HNF-1beta is a bookmarking factor that is necessary for reopening the chromatin of target genes after mitotic silencing.


[Process of gentamycin sorption in liquid- and solid-phase countercurrent flow].
The experimental data on sorption of gentamicin from model solutions in a continuous multisectional apparatus with a counter-current flow of liquid and solid phases are presented. Carboxylic cation exchange resins were used in the study. The effect of various parameters on gentamicin sorption was investigated and the rational process conditions were determined. The use of counter-current sorption for isolation of gentamicin from solutions was shown to be efficient.


Making difficult decisions with older patients on medical wards.
Decision making with older people can be difficult because of medical complexity, uncertainty (about prognosis, treatment effectiveness and priorities), difficulties brought by cognitive and communication impairment and the multiple family and other stakeholders who may need to be involved. The usual approach, based on balancing benefits and burdens of a treatment, and then deciding on the basis of autonomy (or best interests for someone lacking mental capacity), within the constraints of resources and equity, remains valid, but is often inadequate. In addition, approaches relying on optimal communication and relationship building and professional virtues are important. Older people vary in their medical status, views and preferences more than younger people and these variations must be sought and accommodated, using a shared decision-making approach. This includes adapting to the increasing numbers of people from different cultures.


Targeting of Tumor Neovasculature with GrB/VEGF121, a Novel Cytotoxic Fusion Protein.
Angiogenesis is a critical process in numerous diseases, and intervention in neovascularization has therapeutic value in several disease settings, including ocular diseases, arthritis, and in tumor progression and metastatic spread. Various vascular targeting agents have been developed, including those that inhibit growth factor receptor tyrosine kinases, blocking antibodies that interfere with receptor signal transduction, and strategies that trap growth factor ligands. Limited anti-tumor efficacy studies have suggested that the targeted delivery of the human pro-apoptotic molecule Granzyme B to tumor cells has significant potential for cancer treatment. Here, we review biological vascular targeting agents, and describe a unique vascular targeting agent composed of Granzyme B and the VEGF receptor ligand VEGF121. The fusion protein GrB/VEGF121 demonstrates cytotoxicity at nanomolar or sub-nanomolar levels, excellent pharmacokinetic and efficacy profiles, and has significant therapeutic potential targeting tumor vasculature.


Thyroid hormone changes in chronic spinal cord injury.
Spinal cord injury (SCI) impacts metabolic function and deranges various hormonal axes. Previous studies characterizing thyroid hormones in SCI reported depressed triiodothyronine (T3) and thyroxin (T4), primarily in acute tetraplegics. These studies cited an 11-13 percent incidence of low T3 syndrome (LT3S) in SCI patients, with an increased incidence in tetraplegics (20-36 percent). The purpose of this study was to evaluate thyroid function and determine the incidence and clinical relevance of LT3S in the chronic SCI population. Thyroid function tests were performed on 30 chronic SCI patients (14 tetraplegics and 16 paraplegics) and 30 age- and gender-matched controls. Mean T3 and T4 levels were significantly depressed in SCI patients relative to controls, while T3 resin uptake (T3RU) values were significantly elevated. LT3S only occurred in the SCI population with an incidence of 23.3 percent. SCI patients with LT3S did not differ significantly from those without in the level or completeness of injury, age or the interval since injury. They did, however, have co-existent pathology: decubiti, urinary tract infections, etc. When SCI patients with normal T3 were compared with controls, they still had depressed mean T3 levels. We conclude that LT3S occurs frequently in the chronic SCI population and suggest that depressed serum T3 levels may predispose SCI patients to sick euthyroidism in the face of minor pathologic insult.


Rotational characteristics of the Warner-Lambert Softcon hydrophilic contact lenses.
The rotational characteristics of seven Warner-Lambert Softcon soft hydrophilic contact lenses were monitored on the subject's eye by direct observation and photographically for approximately 30 minutes. Lens parameters which altered the rate and direction of rotation were recorded and evaluated.


[Oral vaccination with live attenuated rotavirus].
A randomized, double-blind trial was performed to assess serological response and clinical protection for acute gastroenteritis due to rotavirus in 103 children aged 6 to 18 months, after a single dose of RIT 4237 live attenuated bovine rotavirus vaccine or placebo. Seroconversion, determined by enzyme-linked immunoabsorbent assay (ELISA), was significantly greater in initially seronegative vaccines compared with control group (p less than 0.0001); clinical protection rate was low in this study group and it is therefore concluded that seroconversion by itself is not sufficient to measure vaccine efficacy.


A common denominator: calculating hospitalization rates for ambulatory care-sensitive conditions in California.
Chronic health conditions are considered ambulatory care-sensitive conditions (ACSC) when the illness is controllable with effective and timely outpatient care that can potentially prevent the need for hospitalizations. Hospitalization rates for ACSC serve as an indicator of the access to and quality of primary care for chronic conditions. Standard methods to calculate hospitalization rates incorporate the total population in the denominator instead of the total population at risk for a hospitalization. By accounting for people with an ACSC, this study compares standard methods to a disease prevalence-adjusted method to highlight the importance of adjusting for ACSC prevalence when using ACSC hospitalizations in assessing primary care outpatient services. We combined California Health Interview Survey and hospital discharge data to calculate standard (crude and age-adjusted) and disease prevalence-adjusted hospitalization rates for hypertension and congestive heart failure. To compare rate calculations, we ranked California counties by their hospitalization rate. Counties had high prevalence and low numbers of hospitalizations for hypertension; their rankings for hospitalization rates for hypertension did not vary, even after accounting for prevalence. In contrast, counties had low prevalence and high numbers of hospitalizations for congestive heart failure; their rankings varied substantially for congestive heart failure after accounting for prevalence. Because the number of people diagnosed with an ACSC is rising and costs to treat these conditions are increasing, our findings suggest that more accurate measures of ACSC hospitalization rates are needed. Incorporating disease prevalence will contribute to ACSC research by improving the validity of hospitalization rates as a measure for quality of primary care services.


Radial imaging with multipolar magnetic encoding fields.
We present reconstruction methods for radial magnetic resonance imaging (MRI) data which were spatially encoded using a pair of orthogonal multipolar magnetic fields for in-plane encoding and parallel imaging. It is shown that a direct method exists in addition to iterative reconstruction. Standard direct projection reconstruction algorithms can be combined with a previously developed direct reconstruction for multipolar encoding fields acquired with Cartesian trajectories. The algorithm is simplified by recasting the reconstruction problem into polar coordinates. In this formulation distortion and aliasing become separate effects. Distortion occurs only along the radial direction and aliasing along the azimuthal direction. Moreover, aliased points are equidistantly distributed in this representation, and, consequently, Cartesian SENSE is directly applicable with highly effective unfolding properties for radio-frequency coils arranged with a radial symmetry. The direct and iterative methods are applied to simulated data to analyze basic properties of the algorithms and for the first time also measured in vivo data are presented. The results are compared to linear spatial encoding using a radial trajectory and quadrupolar encoding using a Cartesian trajectory. The direct reconstruction gives good results for fully sampled datasets. Undersampled datasets, however, show star-shaped artifacts, which are significantly reduced with the iterative reconstruction.


Glucokinase mutations in pediatric patients with impaired fasting glucose.
Our aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach. Overall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY). GCK gene sequencing was performed in all participants. Fifty-three Italian families with 44 different mutations affecting the GCK and co-segregating with the clinical phenotype of GCK/MODY were identified. All mutations were in heterozygous state. In Sample 1, GCK defects were found in 32/36 (88.9%) subjects selected with strict MODY diagnostic criteria, while in Sample 2 GCK defects were found in 21/64 (32.8%) subjects selected with mild MODY diagnostic criteria. Our study enlarged the wide spectrum of GCK defects by adding 9 novel variants. The application of strict recruitment criteria resulted in 88.9% incidence of GCK/MODY, which confirmed it as the commonest form of MODY in the Italian population. In order to avoid misdiagnosis of GCK/MODY, it could be useful to perform molecular screening even if one or more clinical parameters for the diagnosis of MODY are missing. Computational analysis is useful to understand the effect of GCK defect on protein functionality, especially when the novel identified variant is a missense mutation and/or parents' DNA is not available.


Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: a randomized double-blind placebo-controlled study.
Evidence suggests that flavonoid-containing diets reduce cardiovascular risk, but the mechanisms responsible are unclear. In the present study, we sought to determine the effect of flavanol-rich cocoa on vascular function in individuals with CAD (coronary artery disease). Forty subjects (61+/-8 years; 30 male) with CAD were recruited to a 6-week randomized double-blind placebo-controlled study. Subjects consumed either a flavanol-rich chocolate bar and cocoa beverage daily (total flavanols, 444 mg/day) or matching isocaloric placebos daily (total flavanols, 19.6 mg/day) for 6 weeks. Brachial artery FMD (flow-mediated dilation) and SAC (systemic arterial compliance) were assessed at baseline, 90 min following the first beverage and after 3 and 6 weeks of daily consumption. Soluble cellular adhesion molecules and FBF (forearm blood flow) responses to ACh (acetylcholine chloride; 3-30 microg/min) and SNP (sodium nitroprusside; 0.3-3 microg/min) infusions, forearm ischaemia and isotonic forearm exercise were assessed at baseline and after 6 weeks. FMD, SAC and FBF responses did not differ between groups at baseline. No acute or chronic changes in FMD or SAC were seen in either group. No difference in soluble cellular adhesion molecules, FBF responses to ischaemia, exercise, SNP or ACh was seen in the group receiving flavanol-rich cocoa between baseline and 6 weeks. These data suggest that over a 6-week period, flavanol-rich cocoa does not modify vascular function in patients with established CAD.


Validity of an illness severity measure for headache in a population sample of migraine sufferers.
The headache impact questionnaire (HImQ) is used to measure pain and activity limitations from headache over a 3-month recall period. In a prior study, the test-retest reliability of the eight-item HImQ score was found to be relatively high (0.86). In the current study, we examined the validity of the eight-item HImQ by comparing the overall score and individual items to equivalent measures from a 90-day diary. Pain and activity limitations due to headache were assessed in a population-based sample of 132 migraine headache sufferers enrolled in a 90-day daily diary study who completed the HImQ at the end of the study. The HImQ score was derived from four frequency-based questions (i.e. number of headaches, missed days of work, missed days of chores, or missed days of non-work activity) and four summary measures of average experience across headaches (i.e. average pain intensity, and average reduced effectiveness when having a headache at work, during household chores, and in non-work activity). Diary based measures were used as the gold standard in evaluating the HImQ score. Mean and median values of frequency-based HImQ items (e.g. number of headaches) were similar to equivalent diary measures, indicating no systematic bias. In contrast, HImQ measures of average experience across attacks (e.g. average pain intensity) overestimated equivalent diary measures and, in general, better approximated diary measures for migraine headaches, rather than all headaches. The highest correlations between HImQ and diary items were observed for headache frequency and average pain intensity, the two general headache measures, followed by measures of reduced effectiveness. Among frequency-based measures, the strength of the correlation was directly related to the magnitude of the mean. The higher the mean value, the higher the correlation. The correlation between the HImQ score and diary based score was 0.49. The HImQ score is moderately valid. Frequency-based items (e.g. number of missed work days) were found to be unbiased and the highest correlation coefficients were observed for frequency-based items with relatively high mean counts (number of headaches, number of missed non-work days). These findings have implications for measuring severity of chronic episodic conditions like headache, asthma, back pain, arthritis, epilepsy, and panic disorder, which can cause limitations to activities. The validity of illness severity measures may be improved by using frequency-based questions to assess both missed activity days and days with significantly reduced effectiveness or productivity (e.g. by 50% or more). By combining the count for both missed days and days where productivity is substantially reduced, the mean of the frequency-based measure will be increased, a factor which may improve the overall validity of the item. A severity measure can be derived from such items by simple addition and provides a scale with intuitively meaningful units.


Cbl-mediated ubiquitinylation and negative regulation of Vav.
The Cbl ubiquitin ligase has emerged as a negative regulator of receptor and non-receptor tyrosine kinases. Cbl is known to associate with the proto-oncogene product Vav, a hematopoietic-restricted Rac guanine nucleotide exchange factor, but the consequences of this interaction remain to be elucidated. Using immortalized T cell lines from Cbl(+/+) and Cbl(-/-) mice, and transfection analyses in 293T cells, we demonstrate that Vav undergoes Cbl-dependent ubiquitinylation under conditions that promote Cbl and Vav phosphorylation. Interaction with Cbl also induced the loss of phosphorylated Vav. In addition, we show that an activated Vav mutant (Vav-Y174F) is more sensitive to Cbl-dependent ubiquitinylation. We demonstrate that the Cbl-dependent ubiquitinylation of Vav requires Cbl/Vav association through phosphorylated Tyr-700 on Cbl, and also requires an intact Cbl RING finger domain. Finally, using transfection analyses in the Jurkat T cell line, we show that Cbl, but not its ubiquitin ligase mutant, can inhibit Vav-dependent signaling. Thus, our findings strongly support the role of Cbl, via its ubiquitin ligase activity, as a negative regulator of activated Vav.


Obesity in perimenopause - current treatment options based on pathogenetic factors.
The health of post-menopausal women has become of paramount concern due to the aging of the world's population. Concurrently, the prevalence of obesity among postmenopausal women is expected to increase, presenting a significant public health challenge. Although weight gain during menopause is a well-observed phenomenon, its underlying causes and mechanisms remain incompletely understood. This manuscript reviews the literature to explore potential hormonal factors and pathomechanisms contributing to obesity during perimenopause, aiming to identify pathogenic factors that can guide treatment selection. Menopause-induced hormonal changes, including hypoestrogenaemia, hypergonadotropinaemia, relative hyperandrogenaemia, growth hormone deficiency, leptin resistance, and chronic stress affecting the hypothalamic-pituitary-adrenal axis, have been implicated in the onset of obesity in perimenopausal women. These hormonal fluctuations, alongside lowered daily energy expenditure, lead to metabolic alterations that elevate the risk of developing metabolic disorders and cardiovascular diseases. Weight gain in perimenopausal women is associated with higher total and abdominal adipose tissue and lower lean body mass. Addressing this issue requires individualized behavioural management, supported by effective pharmacological therapy, and, when warranted, complemented by bariatric surgery. Modern obesity treatment therapies have demonstrated safety and efficacy in clinical trials, offering the potential to reduce excess body fat, improve metabolic profiles, lower cardiovascular risk, and enhance the quality and longevity of women's lives. In addition to standard obesity therapies, the article examines different treatment strategies based on obesity's pathogenic factors, which may offer promising options for treating obesity with or without complications in perimenopausal women. One such potential approach is menopausal hormone therapy (MHT), which hypothetically targets visceral obesity by reducing visceral adipose tissue accumulation, preserving metabolically active lean body mass, and improving lipid profiles. However, despite these reported benefits, gynaecological and endocrinological societies currently do not recommend the use of MHT for obesity prevention or treatment, necessitating further research for validation. Emerging evidence suggests that visceral obesity could result from hypoestrogenaemia during perimenopause, potentially justifying the use of MHT as a causal treatment. This highlights the importance of advancing research efforts to unravel the intricate hormonal and metabolic changes that occur during perimenopause and their role in obesity development.


[Association of UCP2 rs659366 polymorphisms with the outcomes of patients after surgery for colorectal cancer].
To explore the association between UCP2 rs659366 polymorphisms and the outcomes of patients after surgery for colorectal cancer. The study was conducted among a cohort of 501 patients with primary colorectal cancer who had surgery in Sichuan Cancer Hospital during March 2010 and July 2013. The outcomes of the patients were followed up. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied to detect UPC2 rs659366 genotypes. The log-rank test was performed to analyze the effects of clinical features on patients' outcomes. The correlation between UCP2 rs659366 polymorphisms and the outcomes of patients was analyzed using the Cox proportional hazard model. In this study, the median of follow-up time was 44.23(0.13-78.53)months, and 101 out of 501 (20.2%) patients failed to follow-up. The log-rank test showed the tumor site, TNM stage, vascular invasion, perineural invasion and the preoperative carcino-embryonic antigen(CEA) level were significantly associated with the outcome of colorectal cancer (P<0.05 or P<0.01). The overall survival rate of patients with AA, GA and GG genotypes were 62.7%, 69.9% and 75.5%, respectively. Multivariate analysis according to Cox proportional hazard model taking the GG genotype as the reference indicated that the AA genotype increased risks for survival of patients (HR=1.823); under the dominant genetic model taking GG genotype as reference, GA+AA genotypes increased risks for the poorer outcomes of patients (HR=1.498); the addictive genetic model showed that allele A increased the hazard for the poorer outcomes (HR=1.787). The UCP2 rs659366 polymorphisms are significantly associated with the outcome of patients with colorectal cancer.


Painful connections: densification versus fibrosis of fascia.
Deep fascia has long been considered a source of pain, secondary to nerve pain receptors becoming enmeshed within the pathological changes to which fascia are subject. Densification and fibrosis are among such changes. They can modify the mechanical properties of deep fasciae and damage the function of underlying muscles or organs. Distinguishing between these two different changes in fascia, and understanding the connective tissue matrix within fascia, together with the mechanical forces involved, will make it possible to assign more specific treatment modalities to relieve chronic pain syndromes. This review provides an overall description of deep fasciae and the mechanical properties in order to identify the various alterations that can lead to pain. Diet, exercise, and overuse syndromes are able to modify the viscosity of loose connective tissue within fascia, causing densification, an alteration that is easily reversible. Trauma, surgery, diabetes, and aging alter the fibrous layers of fasciae, leading to fascial fibrosis.


Phosphorylation of osteopontin peptides mediates adsorption to and incorporation into calcium oxalate crystals.
Phosphorylated peptides of osteopontin (OPN) have been shown to inhibit the growth of the {100} face of calcium oxalate monohydrate (COM). The inhibitory potency has been shown to be dependent on the phosphate content of the peptide. The purpose of this study is to better understand the means by which phosphate groups promote crystal growth inhibition by OPN peptides. Peptides of rat bone OPN 220-235 peptides have been synthesized with zero (P0), 1 (P1) or 3 (P3) phosphate modifications. COM crystals were grown in the presence of 0.1-10 microg of P0, P1 or P3. P0 incorporation into COM crystals was evident at 10 microg/ml of peptide, whereas the phosphorylated peptides P1 and P3 were incorporated at all tested concentrations. At 5 microg/ml of P3, COM crystals exhibited a 'dumbbell' morphology. To study the peptide-mineral interaction, surface frequency plots were constructed from molecular dynamics simulations of OPN peptide adsorption. Carboxylate and phosphate groups were found to adsorb in specific orientations to the COM {100} surface. In conclusion, it appears that the phosphate groups on OPN peptides are capable of interacting with the COM {100} surface. This interaction appears to increase the adsorption energy of the peptide to the surface, thus enhancing its inhibitory potency.


Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes.
The aim of this study was to investigate the effect of insulin and an insulin-sensitizing agent, rosiglitazone (RSG), on the production of plasminogen-activator inhibitor-1 (PAI-1) in isolated subcutaneous abdominal adipocytes. Human tissue-type plasminogen activator (t-PA) was also measured to assess changes in overall thrombotic risk. The mean depot-specific expression of PAI-1 and t-PA mRNA (n = 42) in subcutaneous abdominal (n = 21), omental (n = 10) and thigh (n = 11) adipose tissue depots was examined. Furthermore, subcutaneous adipocytes were treated with insulin, RSG and insulin in combination with RSG (10-8 m) for 48 h. Conditioned media were collected and enzyme-linked immunosorbent assays performed for PAI-1 and t-PA (n = 12) antigen. PAI-1 and t-PA mRNA levels were also assessed. PAI-1 mRNA levels were significantly higher in subcutaneous and omental abdominal tissue than in thigh fat (p = 0.037 and p = 0.014). No change in t-PA mRNA expression between the adipose tissue depots was observed. Insulin stimulated PAI-1 protein secretion in a concentration-dependent manner in adipocytes (control: 68.3 +/- 1.2 ng/ml (s.e.m.); 10 nm insulin: 73.7 +/- 3.8 ng/ml upward arrow; 100 nm insulin: 86.8 +/- 4.1 ng/ml upward arrow **; 1000 nm insulin: 102.0 +/- 4.8 ng/ml upward arrow ***; **p < 0.01, ***p < 0.001). In contrast, insulin + RSG (10-8 m) reduced PAI-1 production relative to insulin alone (***p < 0.001), whilst RSG alone reduced PAI-1 protein secretion in a concentration-dependent manner (RSG at 10-10 m: 50.4 +/- 2.87 ng/ml downward arrow ***; RSG at 10-5 m: 30.3 +/- 2.0 ng/ml downward arrow ***; p < 0.001). No difference was observed between control and treatments for t-PA secretion (range 7-11 ng/ml). Insulin stimulated PAI-1 secretion, whilst RSG reduced both PAI-1 secretion alone and in combination with insulin. These data suggest that adipose tissue may contribute significantly to the elevated circulating PAI-1 in obesity. Therefore, RSG's effects on PAI-1 production in adipose tissue may contribute to the fall in circulating PAI-1 levels observed in patients receiving RSG therapy.


Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus.
Background: Glioblastoma multiforme and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic approach for these malignancies. Here we evaluate the oncolytic capacity of the neurovirulent and partly IFNβ-resistant Semliki Forest virus (SFV)-4 in glioblastoma multiformes and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal central nervous system (CNS) cells through insertion of microRNA target sequences for miR124, miR125, miR134.Methods: Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and glioblastoma multiforme cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and a syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFNβ in inhibiting therapeutic efficacy was investigated.Results: The introduction of miRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured four of eight mice (50%) with NXS2 and three of 11 mice (27%) with CT-2A, but not for GL261 tumor-bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFNβ by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFNβ response and interferon-α/β receptor-1 expression.Conclusions: SFV4miRT has reduced neurovirulence, while retaining its oncolytic capacity. SFV4miRT is an excellent candidate for treatment of glioblastoma multiforme and neuroblastoma with low IFN-β secretion. Clin Cancer Res; 23(6); 1519-30. ©2016 AACR.


The anti-STAT1 polyphenol myricetin inhibits M1 microglia activation and counteracts neuronal death.
Microglia activation toward M1 pro-inflammatory phenotype represents one of the earliest events of neurological disorders. Therefore, reducing microglia activation should inhibit neuroinflammation, thereby delaying the progression of neurodegeneration. Recently, we pointed out the role of STAT1 signaling in hypoxia-induced M1 activation and proposed STAT1 as a suitable molecular target for the prevention and treatment of neurodegeneration. Myricetin (MYR) is a natural flavonoid that exhibits a specific anti-STAT1 activity correlated with its direct interaction with STAT1 protein itself. Herein, we investigated the anti-inflammatory effect of MYR and its ability to protect neurons from death in an in vitro model of neurotoxicity using the neuroblast-like SH-SY5Y cells that were exposed to conditioned media from hypoxia-activated microglia BV2 cells. We demonstrate that MYR pretreatment is able to switch off hypoxia-induced M1 microglia polarization through the inhibition of STAT1 signaling. The analysis of the molecular mechanism suggests that the direct interaction of MYR with STAT1 impairs its S-glutathionylation and phosphorylation. Moreover, treatment of SH-SY5Y cells with conditioned medium from hypoxia-activated microglia pretreated with MYR produced a significant reduction in neuronal viability. Our data indicate that MYR may represent a promising candidate for prevention and treatment of neuroinflammation in neurodegenerative disorders.


Treatment of dental and orthodontic complications in thalassaemia.
Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains cause haemolytic anaemia by causing membrane damage and cell death within organ systems and destruction of erythroid precursors in the bone marrow. The life-long management of the general health effects of thalassaemia in affected individuals is a highly challenging issue in and of itself; and failure to deal with dental and orthodontic complications in people with thalassaemia exacerbates the public health, financial and personal burden posed by the condition. There exists a lack of evidence-based guidelines for care-seekers and providers to best deal with such dental and orthodontic complications in thalassaemia, which this review seeks to address. The main objective of this review was to assess different methods to treat dental and orthodontic complications in people with thalassaemia. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews.Date of last search: 01 August 2019.We also searched nine online databases (PubMed, Google Scholar, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Literature in the Health Sciences in Latin America and the Caribbean database, African Index Medicus, Index Medicus for South East Asia Region, Index Medicus for the Eastern Mediterranean Region, Indexing of Indian Medical Journals). We searched the reference lists of relevant articles and reviews and contacted haematologists, experts in fields of dentistry, organizations, pharmaceutical companies and researchers working in this field.Date of last search: 22 July 2019. We searched for published or unpublished randomised controlled trials for treatment of dental and orthodontic complications in individuals diagnosed with thalassaemia, irrespective of phenotype, severity, age, gender and ethnic origin. Two review authors independently screened 35,202 titles from search results. We identified four unique randomised controlled trials, of which one seemed potentially relevant. Based on closer inspection, the trial was found not to be eligible for inclusion. We did not find any relevant trials for inclusion in the review. We were unable to draw any conclusions due to the lack of available data and trials. This review highlights the need for conducting and appropriate reporting, of high-quality randomised controlled trials investigating the effectiveness of various treatment modalities for dental and orthodontic complications in people with thalassaemia.


Linear-dendritic copolymer composed of polyethylene glycol and all-trans-retinoic acid as drug delivery platform for paclitaxel against breast cancer.
A new linear-dendritic copolymer composed of poly(ethylene glycol) (PEG) and all-trans-retinoic acid (ATRA) was synthesized as the anticancer drug delivery platform (PEG-G3-RA8). It can self-assemble into core-shell micelles with a low critical micelle concentration (CMC) at 3.48 mg/L. Paclitaxel (PTX) was encapsulated into PEG-G3-RA8 to form PEG-G3-RA8/PTX micelles for breast cancer treatment. The optimized formulation had high drug loading efficacy (20% w/w of drug copolymer ratio), nanosized diameter (27.6 nm), and narrow distribution (PDI = 0.103). Compared with Taxol, PEG-G3-RA8/PTX remained highly stable in the serum-containing cell medium and exhibited 4-fold higher cellular uptake. Besides, near-infrared fluorescence (NIR) optical imaging results indicated that fluorescent probe loaded micelle had a preferential accumulation in breast tumors. Pharmacokinetics and biodistribution studies (10 mg/kg) showed the area under the plasma concentration-time curve (AUC0-∞) and mean residence time (MRT0-∞) for PEG-G3-RA8/PTX and Taxol were 12.006 ± 0.605 mg/L h, 2.264 ± 0.041 h and 15.966 ± 1.614 mg/L h, 1.726 ± 0.097 h, respectively. The tumor accumulation of PEG-G3-RA8/PTX group was 1.89-fold higher than that of Taxol group 24 h postinjection. With the advantages like efficient cellular uptake and preferential tumor accumulation, PEG-G3-RA8/PTX showed superior therapeutic efficacy on MCF-7 tumor bearing mice compared to Taxol.


Analysis of the expression of human tumor antigens in ovarian cancer tissues.
Biomarkers for early detection of cancer have great clinical diagnostic potential. Numerous reports have documented the generation of humoral immune responses that are triggered in response to changes in protein expression patterns in tumor tissues and these biomarkers are referred to as tumor associated antigens (TAAs). Using a high-throughput technology, we previously identified 65 proteins as diagnostically useful TAAs by profiling the humoral immune responses in ovarian cancer (OVCA) patients. Here we determined the expression status of some of those TAAs in tissues from OVCA patients. The protein expression patterns of 4 of those 65 antigens, namely NASP, RCAS1, Nijmegen breakage syndrome1 (NBS1) and eIF5A, along with p53 and Her2 (known molecular prognosticators) and two proteins that interact with NBS1, MRE11 and RAD50, were assessed by immunohistochemistry (IHC). NASP and RCAS1 proteins were more frequently expressed in ovarian cancer tissues than with normal ovarian tissue and serous cystadenomas and MRE11 was less frequently expressed. When evaluated simultaneously, only NASP and MRE11 remained statistically significant with sensitivity of 66% and specificity of 89%. None of these proteins' expression levels were prognostic for survival. Together, our results indicate that occurrence of humoral immune responses against some of these TAAs in OVCA patients is triggered by antigen protein overexpression.


Acute-phase responses in transgenic mice with CNS overexpression of IL-1 receptor antagonist.
The interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous antagonist that blocks the effects of the proinflammatory cytokines IL-1alpha and IL-1beta by occupying the type I IL-1 receptor. Here we describe transgenic mice with astrocyte-directed overexpression of the human secreted IL-1ra (hsIL-1ra) under the control of the murine glial fibrillary acidic protein (GFAP) promoter. Two GFAP-hsIL-1ra strains have been generated and characterized further: GILRA2 and GILRA4. These strains show a brain-specific expression of the hsIL-1ra at the mRNA and protein levels. The hsIL-1ra protein was approximated to approximately 50 ng/brain in cytosolic fractions of whole brain homogenates, with no differences between male and female mice or between the two strains. Furthermore, the protein is secreted, inasmuch as the concentration of hsIL-1ra in the cerebrospinal fluid was 13 (GILRA2) to 28 (GILRA4) times higher in the transgenic mice than in the control animals. To characterize the transgenic phenotype, GILRA mice and nontransgenic controls were injected with recombinant human IL-1beta (central injection) or lipopolysaccharide (LPS, peripheral injection). The febrile response elicited by IL-1beta (50 ng/mouse icv) was abolished in hsIL-1ra-overexpressing animals, suggesting that the central IL-1 receptors were occupied by antagonist. The peripheral LPS injection (25 micrograms/kg ip) triggered a fever in overexpressing and control animals. Moreover, no differences were found in LPS-induced (100 and 1,000 micrograms/kg ip; 1 and 6 h after injection) IL-1beta and IL-6 serum levels between GILRA and wild-type mice. On the basis of these results, we suggest that binding of central IL-1 to central IL-1 receptors is not important in LPS-induced fever or LPS-induced IL-1beta and IL-6 plasma levels.


[Medical and biological safety assessment of genetically modified soybean event MON 89788. Report 2. Genotoxicologic, immunologic and allergologic examinations].
There are presented the results of genotoxicologic, immunologic and allergologic examinations which were conducted within the framework of integrated medical and biological assessment of genetically modified second generation soybean event MON 89788. Analysis of damages of DNA and structural chromosome aberrations, assessment of the allergenic potential and immunoreactive properties has not confirmed any genotoxic, allergenic and immunotoxic effect of soybean event MON 89788.


Violent paroxysmal activity drives self-feeding magma replenishment at Mt. Etna.
A new sequence of eruptions occurred at Mt. Etna volcano during the first half of 2017, after almost 8 months of quiescence. These episodes had low-to-mild intensity and markedly differ from the violent paroxysms occurred at the Voragine Crater (VOR) during December 2015 and May 2016. Despite the general weak explosive nature of the eruptions, the activity during 2017 revealed unusually complex dynamics of magma ascent and interaction. Detection and investigation of such dynamics required a multidisciplinary approach in which bulk rock compositions, crystal chemical zoning, diffusion chronometry and ground deformation data have been combined. Bulk rock major and trace elements suggest that the 2017 magmas followed a differentiation path similar to that experienced by magmas erupted at Mt. Etna during the 2015-16 eruptions at VOR. Olivine core compositions and zoning patterns indicate the presence of multiple magmatic environments at depth that strictly interacted each other through some episodes of intrusion and mixing before and during the 2017 eruptive events. Timescales retrieved from diffusion chronometry on olivine normal and reverse zoning correlate well with the ground deformation stages detected through geodetic data and associated models, thus allowing to track the evolution through time of the 2017 volcanic activity. Combination of all petrological and geodetic observations supports the idea that dynamics of magma transfer driving the eruptive episodes of 2017 have been a direct consequence of the violent eruptions occurred at VOR on May 2016, which boosted the ascent of new magma from depth and improved the efficiency of the plumbing system to transfer it upward to the surface. We propose a mechanism of self-feeding replenishment of the volcano plumbing system during 2017, where magma recharge from depth is triggered by sudden unloading of the magma column consequential to the violent paroxysmal activity occurred on May 2016 at VOR.


Current status of soil and groundwater remediation technologies in Taiwan.
The purpose of this review is the analysis of the soil and groundwater remediation technologies referred as in situ chemical oxidation and phytoremediation, and to discuss the successes that have been made. The technology of phytoremediation has yet to be commercially accepted but shows emerging capabilities. In situ chemical oxidation (ISCO) is a frequently used technology in Taiwan for the remediation of organic compounds. Several studies have been conducted in Taiwan so show their feasibility and potential. This article reviews studies concerning these two remediation technologies. Other processes such as monitored natural attenuation, flushing, thermal treatment, or soil washing are not covered within this article.


Limits of principal components analysis for producing a common trait space: implications for inferring selection, contingency, and chance in evolution.
Comparing patterns of divergence among separate lineages or groups has posed an especially difficult challenge for biologists. Recently a new, conceptually simple methodology called the "ordered-axis plot" approach was introduced for the purpose of comparing patterns of diversity in a common morphospace. This technique involves a combination of principal components analysis (PCA) and linear regression. Given the common use of these statistics the potential for the widespread use of the ordered axis approach is high. However, there are a number of drawbacks to this approach, most notably that lineages with the greatest amount of variance will largely bias interpretations from analyses involving a common morphospace. Therefore, without meeting a set of a priori requirements regarding data structure the ordered-axis plot approach will likely produce misleading results. Morphological data sets from cichlid fishes endemic to Lakes Tanganyika, Malawi, and Victoria were used to statistically demonstrate how separate groups can have differing contributions to a common morphospace produced by a PCA. Through a matrix superimposition of eigenvectors (scale-free trajectories of variation identified by PCA) we show that some groups contribute more to the trajectories of variation identified in a common morphospace. Furthermore, through a set of randomization tests we show that a common morphospace model partitions variation differently than group-specific models. Finally, we demonstrate how these limitations may influence an ordered-axis plot approach by performing a comparison on data sets with known alterations in covariance structure. Using these results we provide a set of criteria that must be met before a common morphospace can be reliably used. Our results suggest that a common morphospace produced by PCA would not be useful for producing biologically meaningful results unless a restrictive set of criteria are met. We therefore suggest biologists be aware of the limitations of the ordered-axis plot approach before employing it on their own data, and possibly consider other, less restrictive methods for addressing the same question.


Vitamin C suppresses proliferation of the human melanoma cell SK-MEL-2 through the inhibition of cyclooxygenase-2 (COX-2) expression and the modulation of insulin-like growth factor II (IGF-II) production.
Vitamin C plays a crucial role in the suppression of proliferation of several types of cancer. Over-expression of cyclooxygenase (COX)-2 and type I insulin-like growth factor (IGF) receptor are important for proliferation and protection from apoptosis in malignancies. However, its specific mechanisms, especially the interaction between COX-2 expression and IGF-I axis mediated by vitamin C, remain yet to be clarified. Therefore, we investigated the effects of vitamin C on the proliferation of melanoma cells via the modulation of COX-2 expression and IGF-I axis. As a result, we found that 1.0 mM vitamin C inhibits the proliferation of SK-MEL-2 without induction of apoptosis. At that moment, IGF-II production was decreased, followed by the inhibition of COX-2 activity. IGF-IR expression was also down-regulated by vitamin C treatment. It coincided with the result from the inhibition of COX-2 by NS-398 and COX-2 siRNA. In addition, the decreased IGF-IR expression by vitamin C was restored by the treatment of recombinant prostaglandin E2. Finally, we determined whether the signal pathway would be involved in vitamin C-induced IGF-II and IGF-IR down-regulation. When the cells were exposed to SB203580, a specific inhibitor of p38 MAPK, COX-2 expression was dramatically recovered. In addition, phosphorylated p38 MAPK was increased after vitamin C treatment. Taken together, vitamin C suppresses proliferation of the human melanoma cell line SK-MEL2 via the down-regulation of IGF-II production and IGF-IR expression, which is followed by the activation of p38 MAPK and the inhibition of COX-2 expression.


Selective removal of impulse noise based on homogeneity level information.
In this paper, we propose a decision-based, signal-adaptive median filtering algorithm for removal of impulse noise. Our algorithm achieves accurate noise detection and high SNR measures without smearing the fine details and edges in the image. The notion of homogeneity level is defined for pixel values based on their global and local statistical properties. The cooccurrence matrix technique is used to represent the correlations between a pixel and its neighbors, and to derive the upper and lower bound of the homogeneity level. Noise detection is performed at two stages: noise candidates are first selected using the homogeneity level, and then a refining process follows to eliminate false detections. The noise detection scheme does not use a quantitative decision measure, but uses qualitative structural information, and it is not subject to burdensome computations for optimization of the threshold values. Empirical results indicate that our scheme performs significantly better than other median filters, in terms of noise suppression and detail preservation.


Cellular cardiomyoplasty for myocardial infarction: a 2014 evidence-based update.
Myocardial infarction is one of the main cause of mortality in many countries. Therefore, an effective therapy for myocardial infarction is required. Reperfusion and other conventional therapy have been the mainstay therapy for myocardial infarction. However, many patients remain refractory to this therapy. Cellular cardiomyoplasty is considered a novel therapy, in which stem cells are used for cardiac repair. Stem cells are potential therapeutic approach that could be the ultimate solution for salvaging damaged cardiomyocyte. Based on current studies, stem cells are a promising therapeutic approach for myocardial infarction. However, some challenges need to be answered by future studies before this novel therapy can be widely applied. As we advance our understanding, all questions behind stem cell therapy would finally be revealed, and eventually provide the ultimate solution for ischaemic cardiac repair. This paper provide an overview of the latest progress in stem cell therapy for myocardial infarction.


The role of intramyocardial pressure during coronary sinus interventions: a computer model study.
A model consisting of an arterial, a capillary, and a venous compartment was developed to reproduce experimentally determined hemodynamic results of the arterial and venous sides of the coronary circulation. From the model, intramyocardial flow between capillaries and veins, which is inaccessable to measurement, was then estimated. Results are given for normal perfusion and coronary sinus occlusion conditions. For both conditions, intramyocardial pressure was varied within the model in order to study its impact on intramyocardial flow. For low and moderate intramyocardial pressures under coronary sinus occlusion, retrograde flow from veins to capillaries was seen to increase with increasing intramyocardial pressure. However, for very high values of intramyocardial pressure, which are close to left ventricular pressure, retrograde flow declined.


Early childhood development and parental training interventions in rural China: a systematic review and meta-analysis.
Inadequate care during early childhood can lead to long-term deficits in skills. Parenting programmes that encourage investment in young children are a promising tool for improving early development outcomes and long-term opportunities in low-income and middle-income regions, such as rural China. We conducted a systematic review and a meta-analysis to investigate the prevalence of early developmental delays and stimulating parenting practices as well as the effect of parental training programmes on child development outcomes in rural China. We obtained data in English from EconPapers, PubMed, PsycARTICLES, Cochrane Library, Web of Science and Scopus (Elsevier) and in Chinese from China National Knowledge Infrastructure, Wanfang Data and VIP Information. We conducted frequentist meta-analyses of aggregate data and estimated random-effects meta-regressions. Certainty of evidence was rated according to the Grading of Recommendations Assessment, Development and Evaluation approach. We identified 19 observational studies on the prevalence of developmental delays and stimulating parenting practices for children under 5 years of age (n=19 762) and ten studies on the impact of parental training programmes on early child development (n=13 766). Children's risk of cognitive, language and social-emotional delays in the rural study sites (covering 14 provinces mostly in Central and Western China) was 45%, 46%, and 36%, respectively. Parental training programmes had a positive impact on child cognition, language and social-emotional development. There is evidence to suggest that early developmental delay and the absence of stimulating parenting practices (ie, reading, storytelling and singing with children) may be prevalent across rural, low-income and middle-income regions in Central and Western China. Results support the effectiveness of parental training programmes to improve early development by encouraging parental engagement. This study was registered with PROSPERO (CRD42020218852).


Intravenous hydration with a 2.5% glucose solution in Type II diabetes.
Physicians are often unclear about how fast intravenous glucose solutions should be administered to adequately hydrate patients with Type II diabetes while avoiding hyperglycaemia and excessive plasma volume expansion. The aim of the present study was to analyse the disposition of a 2.5% glucose solution and create a nomogram which could serve as a guide to fluid therapy in these patients. Twelve males (mean body mass index, 29 kg/m(2)) with Type II diabetes due to insulin resistance, as quantified by an euglycaemic hyperinsulinaemic glucose clamp, received an infusion of iso-osmotic 2.5% glucose solution with electrolytes (70 mmol/l sodium, 45 mmol/l chloride and 25 mmol/l acetate) at individual rates over 30 and 60 min respectively. Blood glucose and haemoglobin levels were measured repeatedly over 3.5 h to estimate the kinetics of glucose and fluid volume. Mean insulin sensitivity was 4.2x10(-4) dlxkg(-1)xmin(-1)x(micro-units/ml)(-1). The individualized infusion rates reached the predetermined blood glucose level of 12 mmol/l with a mean difference of 0.2 mmol/l. The disposition of glucose was an important factor governing fluid distribution. The volume of distribution of exogenous glucose averaged 19.8 litres, but for the fluid volume it was only 3.7 litres. The clearance was 0.37 litre/min for glucose and 0.10 litre/min for the fluid volume, and the results of the 30-min and 60-min infusions agreed reasonably well. It is concluded that kinetic analysis can be used to guide the infusion time and infusion rate of 2.5% glucose to reach any predetermined glucose level and volume expansion.


[Personality traits of persons with borderline arterial hypertension and patients with essential hypertension].
A study of 402 individuals with marginal arterial hypertension (MAH) and patients with essential hypertension (EH), stages 1, 2 and 3, demonstrated a variety of psychopathologic syndromes (hypochondria, anxiety, hysteria, depression, cardiophobia) in 52.8, 77.3, 82.5 and 80%, respectively. Specific personality features have been identified as pertaining to MAH (hyperthymism, sthenism, demonstrativeness, psychasthenia) and EH (psychasthenia, intraversion, cycloidy).


Expectations for future relationship satisfaction: Unique sources and critical implications for commitment.
Contemporary perspectives on relationship commitment posit that intimates decide whether or not to maintain a relationship based on their commitment to that relationship, and that they base such commitment partially on their current satisfaction with that relationship. Nevertheless, given that ending a relationship requires knowing about both the current state of the relationship and the likely future state of the relationship, we propose that people base their commitment to a relationship more on their expected future satisfaction with the relationship than on their current satisfaction with that relationship. Six studies provided evidence for these ideas. Study 1 demonstrated that expected satisfaction is shaped by not only current satisfaction but also several unique indicators of the likelihood of future satisfaction, including anticipated life events, plans to improve the relationship, and individual differences. Then, using a combination of cross-sectional, experimental, and longitudinal methods, Studies 2 through 6 demonstrated that (a) expected satisfaction was a stronger predictor of relationship commitment, maintenance behaviors, and/or divorce than was current satisfaction and (b) expected satisfaction mediated the association between current satisfaction and these outcomes. These findings highlight not only the need to incorporate expected satisfaction into extent perspectives on commitment, but also the importance of expectations for decision-making processes more broadly. (PsycINFO Database Record


Molecular mechanism of the rifampicin -RNA polymerase interaction.
Equilibrium and kinetic studies of the interaction of rifampicin with RNA polymerase of Escherichia coli were performed by exploiting the quenching of intrinsic fluorescence of the protein by the drug. Fluorimetric titrations show that rifampicin binds stoichiometrically to the core and holoenzyme with an apparent Kd of less than or equal to 3 x 10(-9) M. Neither the addition of template nor the formation of the initiation complex in the presence of dinucleotide and nucleoside triphosphate prevents the rifampicin-enzyme interaction. Although the equilibrium binding constant for the rifampicin-RNA polymerase complex is about the same for the core and holoenzyme and the holoenzyme-T7 DNA complex, stopped-flow studies indicate that the rates at which rifampicin interacts with these enzyme forms are different. In all three cases, the kinetic data can be interpreted in terms of a mechanism in which the rapid bimolecular binding of rifampicin to RNA polymerase is followed by a relatively slow isomerization of the drug enzyme complex: (See article). While the values of dissociation constant K1 = (k-1/k1), for the first binary complex (ER) are similar, the rate constant for the forward isomerization, k2, decrease in the order of core enzyme greater than holoenzyme greater than the holoenzyme-T7 DNA complex. The fact that this order is parallel to the relative rates of inactivation of the enzymes and the enzyme-DNA complex suggests that the inactivation may be due to the rifampicin-induced isomerization (conformational change) of the enzyme. This is supported by our observations that an enzyme complex which is in the process of elongating RNA chains can still bind rifampicin, although the enzyme activity is not inhibited by such binding. The values of overall binding constants calculated from the kinetic parameters, 1-2 x 10(-9) M, are in good agreement with the values of the apparent Kd obtained from fluorimetric titrations and Ki determined by enzymatic assays. In addition, the observations that the formation of an initiation complex leads to a significant but not complete rifampicin-resistant RNA synthesis and the recent finding that rifampicin only partly inhibits the formation of the first phosphodiester bond in an abortive initiation of RNA chains are consistent with our kinetic mechansim, i.e., the existence of two forms of the rifampicin-RNA polymerase complex, only one of which is able to initiate the RNA chains.


[The chronological structure of the population count of the taiga tick in the Maritime Territory].
A time series analysis of 23-years observations of the Ixodes persulcatus imago dynamics was carried out. The tick were counted in forests of the western Sikhote-Alin' foothills near Ussuriysk. The fluctuations of the ticks number are quasiperiodical. They are formed by near 3-years oscillations, long-term non linear trend and accidental component. The observed process was described by means of a statistic model. This model combines the harmonic regression analysis with linear regression analysis. The determination coefficients are 90.8% and 92.7% for the descriptive and prognostic models respectively. The difference between two groups of environmental factors, which influence on the tick number, is discussed. These factors are: 1) the directly influencing factors (functional factors), 2) the factors influencing by dint of natural rhythms being general for a biocoenosis (synchronizing factors).