Control of Pathological Cardiac Hypertrophy by Transcriptional Corepressor IRF2BP2 (Interferon Regulatory Factor-2 Binding Protein 2).
The transcription factor NFAT1 (nuclear factor of activated T-cells 1), with the aid of transcriptional coactivators, has been recognized for its necessity and sufficiency to drive pathological cardiac hypertrophy. However, how the transcriptional activity of NFAT1 in terms of cardiac hypertrophy is controlled at the transcriptional level has not been well defined. Herein, we showed that a cardiac-enriched protein IRF2BP2 (interferon regulatory factor-2 binding protein 2) was further upregulated in both human and mouse hypertrophied myocardium and negatively regulated cardiomyocyte hypertrophic response in vitro. By generating cardiomyocyte-specific Irf2bp2 knockout and Irf2bp2-transgenic mouse strains, our in vivo experiments showed that, whereas IRF2BP2 loss-of-function exacerbated both aortic banding- and angiotensin II infusion-induced cardiac hypertrophic response, IRF2BP2 overexpression exerted a strong protective effect against these maladaptive processes. Particularly, IRF2BP2 directly interacted with the C-terminal transactivation domain of NFAT1 by competing with myocyte enhancer factor-2C and disturbing their transcriptional synergism, thereby impeding NFAT1-transactivated hypertrophic transcriptome. As a result, the devastating effect of Irf2bp2 deficiency on cardiac hypertrophy was largely rescued by NFAT1 blockage. Our study, thus, defined IRF2BP2 as a novel negative regulator in controlling pathological cardiac hypertrophy at the transcriptional level.


Revised Centrality Measures Tell a Robust Story of Ion Conduction in Solids.
The three most commonly used centrality measures in network theory have been adapted to consider ion conduction time rather than the number of steps. Flow-IN centrality highlights sites with the largest flow of ions from the nearest neighbor sites. Return-flow centrality highlights sites with a fast rate of first returns for the conducting ion. Flow-through centrality highlights which sites support significant flow of conducting ions and appears more robust to removal of the most central vertices. Exploring these centrality measures with the sample system of proton conduction in yttrium doped barium zirconate shows flow-through centrality to provide a robust picture with high contrast between sites involved in the most probable long-range periodic conduction paths and kinetic Monte Carlo trajectories versus sites rarely visited. The flow-through centrality, including all paths further highlights that when the most central proton site is filled, the remaining highest flow-through centrality sites are nearby, corroborating earlier studies suggesting proton pair motion. Finally, while both return-flow and flow-through centrality measure images deteriorate with noise, image restoration is possible when a detailed balance is used to calculate the smaller rate constant in a forward/backward pair.


Cancer as crisis: the critical elements of adjustment.
This study examined the course and duration of the crisis inherent in the diagnosis and treatment of cancer in women. Three groups of female patients, breast cancer, gynecological cancer, and breast biopsy patients, were compared on the variables of depression and body image. The women were assessed prior to surgery and at one- and two-month intervals in order to determine whether their crises had been resolved within the normal six-month framework. An additional follow-up was made after 20 months to evaluate any long-term effects of the diagnosis of cancer or its treatment. Results of the study revealed that only breast biopsy and mastectomy patients adapted appropriately and were able to resolve their crises. In examining the gynecological cancer patients, initial feelings of depression and body image continued to worsen even at 20 months following surgery. Implications for nursing practice are discussed, and suggestions for future research are presented.


In vitro synthesis of oxalic acid has no relevant influence on plasma oxalic acid levels in haemodialysis patients.
Plasma oxalic acid concentrations were measured in 13 chronic haemodialysis patients. The mean plasma oxalic acid concentration was 128.0 +/- 48.6 mumol/l, being approximately 8 times higher than the plasma concentration of 14 volunteers (mean = 16.8 +/- 5.2 mumol/l). Ultrafiltrates obtained in vivo from these patients showed a mean oxalic acid concentration of 138.2 +/- 56.5 mumol/l. Since in vivo ultrafiltrates are free of erythrocytes and plasma enzymes, an in vitro synthesis of oxalic acid from precursors by erythrocytes and plasma enzymes can be excluded. As the oxalic acid concentration of plasma corresponded to that of in vivo ultrafiltrates, it is concluded that any in vitro formation of oxalic acid in haemodialysis patients must be negligibly small, and is irrelevant for the measurement of plasma oxalic acid levels in patients receiving regular haemodialysis.


On the physical, spectral, and dosimetric characteristics of a new 125I brachytherapy source.
A new 125I source under the name Braquibac has been developed in Argentina for interstitial brachytherapy applications. The aim of this work is to study the new seed's design and to calculate its dosimetric parameters. Radiographic and destructive tests were carried out on inactive seeds to determine the physical characteristics of the source. Values of g(r), Lambda, F(r, Theta), and phi(an)(r), were obtained in water and air by simulation using the MCNP5 Monte Carlo code according to the methodology recommended in TG-43 and updated in TG-43U1. The dose rate constant was determined to be 0.937+/-0.004 cGy h(-1) U(-1) (overall statistical uncertainty +/-2.7%). Sk per unity activity was calculated to be 0.671+/-0.003 cGy cm2 h(-1) mCi(-1) by simulation of the seed in dry air using point detectors. Spectroscopic studies for both the new and the Amersham model 6711 seed were performed using an HPGe planar detector. The emission spectra of both seeds proved to be very similar. The anisotropy of the total photon intensity in air was measured in planes containing the seed's short and long axes using the HPGe detector. The minimum photon intensity for the new seed was 31.14+/-3.10% of the transverse intensity.


Overview of the structure-based non-genomic effects of the nuclear receptor RXRα.
The nuclear receptor RXRα (retinoid X receptor-α) is a transcription factor that regulates the expression of multiple genes. Its non-genomic function is largely related to its structure, polymeric forms and modification. Previous research revealed that some non-genomic activity of RXRα occurs via formation of heterodimers with Nur77. RXRα-Nur77 heterodimers translocate from the nucleus to the mitochondria in response to certain apoptotic stimuli and this activity correlates with cell apoptosis. More recent studies revealed a significant role for truncated RXRα (tRXRα), which interacts with the p85α subunit of the PI3K/AKT signaling pathway, leading to enhanced activation of AKT and promoting cell growth in vitro and in animals. We recently reported on a series of NSAID sulindac analogs that can bind to tRXRα through a unique binding mechanism. We also identified one analog, K-80003, which can inhibit cancer cell growth by inducing tRXRα to form a tetramer, thus disrupting p85α-tRXRα interaction. This review analyzes the non-genomic effects of RXRα in normal and tumor cells, and discusses the functional differences based on RXRα protein structure (structure source: the RCSB Protein Data Bank).


Immunoglobulin E sensitization to cross-reactive carbohydrate determinants: epidemiological study of clinical relevance and role of alcohol consumption.
The determinants and biologic significance of IgE-mediated sensitization to cross-reactive carbohydrate determinants (CCDs) are not entirely known. An association between alcohol consumption and CCD sensitization has been reported in studies from Spain and Portugal. To investigate the relationship of alcohol consumption with CCD sensitization, the role of alcohol dehydrogenase gene polymorphisms, and the clinical consequences of CCD sensitization. Serum-specific IgE sensitization (> or =0.1 kU/l) to a CCD (the N-glycan from bromelain) was assessed in 1,197 adults participating in a population-based study in Copenhagen, Denmark. Alcohol consumption and atopic symptoms (rhinitis, asthma and oral allergy syndrome) were assessed by questionnaire. Examinations included skin prick tests (SPTs), qualitative multiallergen IgE test (Phadiatop), methacholine bronchial hyperreactivity, eosinophil cationic protein and alcohol dehydrogenase (ADH) gene polymorphisms. Alcohol consumption was significantly associated with CCD sensitization and this was particularly evident in SPT-negative individuals. The fast-metabolizing allele of the ADH1b polymorphism was significantly associated with CCD sensitization in alcohol drinkers. CCD sensitization was associated with atopic symptoms, but associations attenuated markedly when adjusting for SPT reactivity. Our results suggest that the positive association between alcohol consumption and CCD sensitization is universal and not specific to certain populations. The observed association between the ADH1b polymorphism and CCD sensitization may support that alcohol is causally related to the risk of CCD sensitization. The observed association between CCD sensitization and atopic phenotypes did not appear to be independent of SPT reactivity indicating limited significance of CCD sensitization per se.


[Not Available].
In the paper a number of problems are discussed from the history of medicine--from ancient times up to the present days. The positive experience is pointed out of the centuries-long development of medicine and its enormous significance for the education and correct thinking of the doctor of today. History of medicine is considered as a living source of an exact ethics and doctrinary behaviour, as a powerful beacon enlightening the present and future of medical practice. The author supports the statement that the marxism-leninism philosophy is the only one securing correct medical thinking and action and the only one that might provide for eliminating the blind doctrinairism and various narrow-minded deviations from the research work and practice.


An investigation of DNA mismatch repair capacity under normal culture conditions and under conditions of supra-physiological challenge in human CD4+T cell clones from donors of different ages.
T cells undergo rapid clonal expansion upon antigenic stimulation to produce an effective immune response. Any defect in the DNA mismatch repair (MMR) system may have a detrimental effect on T cell proliferation. This study employed an in vitro model of human CD4+T cell ageing to investigate MMR capacity at various stages of T cell lifespan. A novel modification of the alkaline comet assay, which utilised T4 endonuclease VII to detect single base DNA mismatches, was used to assess DNA mismatch frequency. No clear pattern in DNA mismatch frequency with increasing culture age was observed. However, the ability to repair induced DNA mismatches (following treatment with acridine mutagen ICR-191) revealed an age-related decline in the efficiency of the MMR system in clones derived from a 26 and a 45-year-old donor, but not from an 80-year-old very healthy SENIEUR donor. This study suggests that unchallenged, dividing human T cell clones have variable levels of DNA mismatches throughout their lifespan, not affecting proliferation. However, when challenged with supra-physiological levels of DNA mismatches, deficiencies were found in ageing T cell clones in MMR capacity, with the exception of T cell clones from a SENIEUR donor previously shown to maintain effective DNA excision repair.


Dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the COVID-19 pandemic: A network analysis.
The 2019 coronavirus disease (COVID-19) pandemic has had a profound impact on the mental health of people worldwide. This study examined dysfunctional coronavirus anxiety in nonpsychotic psychiatric outpatients during the pandemic using the coronavirus anxiety scale (CAS) and examined the relationship between coronavirus anxiety and clinical symptoms using network analysis. In this cross-sectional study, 192 patients who first visited the psychiatric outpatient clinic of Severance Hospital during the COVID-19 pandemic with chief complaints of depressed mood, anxiety, somatic symptoms, or insomnia were included. We compared the clinical characteristics of patients with and without dysfunctional coronavirus anxiety. Network analysis was conducted to estimate the network of coronavirus anxiety and depressive, anxious, and hypochondriacal psychopathology. The results showed that 7.8% of patients exhibited dysfunctional coronavirus anxiety (CAS ≥ 5). Patients with dysfunctional coronavirus anxiety showed higher levels of health worry, somatic preoccupation, and subjective anxiety compared to patients without dysfunctional coronavirus anxiety. In the network analysis, the health worry node (Item 6 of the WI) showed the greatest number of connections with coronavirus anxiety nodes. These findings suggest that health worry may be an important bridge symptom that connects coronavirus anxiety and other clinical psychopathology. Patients with elevated health worries should be carefully monitored during the COVID-19 pandemic for exacerbation of previous symptoms and COVID-19-related psychopathology. Understanding the psychological factors in the face of the pandemic and their relationships with clinical psychiatric symptoms would help people prevent and overcome mental health problems during the pandemic.


Group 6 complexes with iron and zinc heterometals: understanding the structural, spectroscopic, and electrochemical properties of a complete series of M≡M···M' compounds.
Binuclear quadruply bonded complexes Cr(2)(dpa)(4) (1, dpa = 2,2'-dipyridylamide), Mo(2)(dpa)(4) (2), and W(2)(dpa)(4) (3) react with anhydrous FeCl(2), yielding heterometallic compounds CrCrFe(dpa)(4)Cl(2) (4), MoMoFe(dpa)(4)Cl(2) (5), and WWFe(dpa)(4)Cl(2) (6). These molecules are structurally similar, having a linear M≡M···Fe chain that is axially capped by chloride ions and is equatorially supported by the helically twisted dpa ligands. A structurally related zinc analog, CrCrZn(dpa)(4)Cl(2) (7), can be prepared upon metalation of 1 with ZnCl(2). This reaction also persistently produces a 2:1 adduct of ZnCl(2) with 1, [Cr(2)(dpa)(4)](ZnCl(2))(2) (8), which is in equilibrium with 7 and has the two zinc ions bound externally to the Cr(2) core and axial bridging chloro ligands attached to each Cr ion. The sole isolable product of the addition of ZnCl(2) to 3 is a 1:1 adduct, [W(2)(dpa)(4)]ZnCl(2) (9). The structurally related chain complexes 4, 5, 6, and 7 are characterized by X-ray crystallography, UV-vis spectroscopy, cyclic voltammetry, and (57)Fe Mössbauer spectroscopy for the iron complexes in order to gain insights into the nature of heterometallic interactions, electronic excited states, and redox properties of these compounds, which have implications for all other M≡M···M' molecules. Additionally, NMR spectroscopy has been used to gain insight into the mechanism of the metalation of 1 by Zn(II).


Strategies for transitioning therapy to aripiprazole from other antipsychotics in schizophrenia.
To determine the optimal approach for transitioning therapy to aripiprazole from other antipsychotics in schizophrenia and to describe these strategies. MEDLINE (January 2000-March 2012) and PubMed (January 2000-March 2012) searches were conducted using the search terms aripiprazole, switch, and switching. Citations from references were reviewed to identify additional primary literature. Articles identified as primary literature were considered for inclusion. Case series, opinion papers, and review articles were also examined. Literature was required to be in English. For evaluation purposes, included articles were randomized trials specifically comparing different switching strategies from an alternative antipsychotic to aripiprazole. Randomized trials and single-arm studies that evaluated the effect of a change to aripiprazole and reported switching methods were also reviewed but not evaluated. Aripiprazole, an atypical antipsychotic agent with a unique mechanism of action, causes fewer adverse effects when compared with other atypical antipsychotics. Patients unable to tolerate or unresponsive to their current regimens might benefit from a change to aripiprazole, but the best method for switching is unknown. Four randomized trials were identified that compared the efficacy, safety, and tolerability of at least 2 different switching strategies. The 5 strategies used a combination of immediate or titrated initiation of aripiprazole with immediate or tapered discontinuation of the current antipsychotic. A significant worsening of symptoms in the abrupt discontinuation group when compared with the combined tapered discontinuation groups was seen in 1 trial at week 2; however, all other comparisons yielded no significant differences among switching strategies. Strategies for transitioning therapy to aripiprazole from alternative antipsychotics in schizophrenia have been investigated in randomized trials, but studies have failed to establish a preferred method. Despite the lack of evidence, experts recommend an overlap strategy that includes maintaining the current antipsychotic dosage while titrating to a therapeutic dose of aripiprazole.


Hemodynamic and oxygen transport monitoring to titrate therapy in septic shock.
Traditionally, shock has been recognized or diagnosed by subjective signs and symptoms, particularly in septic shock, where transition from localized to systemic infection and then to septic shock may be gradual and subtle. Management has been directed toward normalizing these subjective symptoms as well as BP, heart rate, urine output, hematocrit, central venous pressure, and blood gases. The major problem is that restoration to normal values of these secondary aspects of shock do not correct the underlying tissue perfusion defect. The aim of this review is to describe a physiologic mechanistic model based on the concept that uneven vasoconstriction and maldistribution of flow are directly related to tissue hypoxia, oxygen debt, shock, shock-related organ failure, and death; second, to show that titration of therapy to optimal physiologic end-points using hemodynamic and oxygen transport monitoring is a potentially cost-effective therapeutic approach. This physiologic approach is based on the hypotheses that: a) the physiologic patterns of high-risk postoperative and septic survivors are significantly different from septic nonsurvivors; b) tissue perfusion can be evaluated by the sequential patterns of cardiac index, oxygen delivery (DO2), and oxygen consumption (VO2) measurements; c) the observed increased cardiac index and DO2 in the survivors are compensations that improve tissue oxygenation, which is reflected by the VO2 pattern; and d) the supranormal values that were documented in survivors provide objective physiologic criteria for therapeutic goals. The data suggest that a mechanistic analysis of the pathogenesis of shock may be elucidated by temporal patterns of the nonsurvivors' physiologic variables. That is, the predictive indices calculated for each variable quantitatively reflect the relationship of the early changes leading to death or survival. In essence, early changes in those variables statistically related to death may reflect pathogenic mechanisms, while early changes related to survival may be used as a first approximation to therapeutic goals. The application of this approach in prospective, randomized trials has demonstrated that prompt attainment of optimal goals (empirically defined from survivors' patterns) improved outcome in postoperative shock with and without sepsis, as well as in medical sepsis and accidental trauma. Specifically, when the optimal values of cardiac index, DO2, and VO2 used as therapeutic goals were attained in 8 to 12 hrs, there was marked and significant reduction in mortality and morbidity rates. This finding was also confirmed in 12 prospective, controlled trials, four of which were randomized. We conclude that driving septic shock patients into the survivors' patterns improves outcome, as has been shown in other shock syndromes.(ABSTRACT TRUNCATED AT 400 WORDS)


Older Adults at Increased Risk as Pedestrians in Victoria, Australia: An Examination of Crash Characteristics and Injury Outcomes.
Engaging in active transport modes (especially walking) is a healthy and environmentally friendly alternative to driving and may be particularly beneficial for older adults. However, older adults are a vulnerable group: they are at higher risk of injury compared with younger adults, mainly due to frailty and may be at increased risk of collision due to the effects of age on sensory, cognitive, and motor abilities. Moreover, our population is aging, and there is a trend for the current cohort of older adults to maintain mobility later in life compared with previous cohorts. Though these trends have serious implications for transport policy and safety, little is known about the contributing factors and injury outcomes of pedestrian collision. Further, previous research generally considers the older population as a homogeneous group and rarely considers the increased risks associated with continued ageing. Collision characteristics and injury outcomes for 2 subgroups of older pedestrians (65-74 years and 75+ years) were examined by extracting data from the state police-reported crash dataset and hospital admission/emergency department presentation data over the 10-year period between 2003 and 2012. Variables identified for analysis included pedestrian characteristics (age, gender, activity, etc.), crash location and type, injury characteristics and severity, and duration of hospital stay. A spatial analysis of crash locations was also undertaken to identify collision clusters and the contribution of environmental features on collision and injury risk. Adults over 65 years were involved in 21% of all pedestrian collisions. A high fatality rate was found among older adults, particularly for those aged 75 years and older: this group had 3.2 deaths per 100,000 population, compared to a rate of 1.3 for 65- to 74-year-olds and 0.7 for adults below 65 years of age. Older pedestrian injuries were most likely to occur while crossing the carriageway; they were also more likely to be injured in parking lots, at driveway intersections, and on sidewalks compared to younger cohorts. Spatial analyses revealed older pedestrian crash clusters on arterial roads in urban shopping precincts. Significantly higher rates of hospital admissions were found for pedestrians over the age of 75 years and for abdominal, head, and neck injuries; conversely, older adults were underrepresented in emergency department presentations (mainly lower and upper extremity injuries), suggesting an increased severity associated with older pedestrian injuries. Average length of hospital stay also increased with increasing age. This analysis revealed age differences in collision risk and injury outcomes among older adults and that aggregate analysis of older pedestrians can distort the significance of risk factors associated with older pedestrian injuries. These findings have implications that extend to the development of engineering, behavioral, and enforcement countermeasures to address the problems faced by the oldest pedestrians and reduce collision risk and improve injury outcomes.


Plate Fixation of Proximal Fifth Metatarsal Fracture.
Intramedullary screw fixation of fractures of the proximal fifth metatarsal bone may not be satisfactory in comminuted fractures or when the lateral metatarsal bowing has to be restored. We report our experience with plate fixation in these circumstances. Between June 1, 2009, and January 31, 2013, 13 patients who had comminuted fracture or nonunion of fracture of the proximal fifth metatarsal bone underwent plate fixation. Study patients were followed up for a mean of 500 days (range, 51-1238 days). Their medical records and radiographs were retrospectively reviewed for demographic and operative data and radiologic evidence of fracture healing. At their most recent follow-up, patients were evaluated for pain levels with a visual analog scale, for foot function with the Foot and Ankle Disability Index, and for quality of life with the 12-Item Short-Form Health Survey. Fracture union was evident in 12 patients after a mean of 56.8 days (range, 30-92 days). There was only one major complication of sural nerve neuroma and reflex sympathetic dystrophy. Four patients required reoperation for plate removal. Plate fixation of proximal fifth metatarsal comminuted fractures is associated with high union rates, relief of pain, and patient satisfaction. However, plate removal for various reasons was required in approximately one-third of the study patients. This high revision rate might be avoided by better selection of patients and meticulous intraoperative identification and preservation of the sural nerve. We recommend reserving plate fixation for proximal fifth metatarsal fractures for cases of laterally bowed fifth metatarsal or comminuted fractures.


Insecticide resistance in potential vector mosquitoes for West Nile virus in Japan.
Culex pipiens complex is the significant vector mosquito of West Nile virus. To take stock of the current situation of insecticide susceptibilities and design an ideal mosquito control strategy, we collected Culex pipiens pallens Coquillet, Culex pipiens form molestus Forskal, and Culex quinquefasciatus Say from fields in Japan and conducted bioassays for five larvicides (fenitrothion, temephos, etofenprox, diflubenzuron, and pyriproxyfen) by using a larval dipping method. Among five insecticides tested, obvious reduced susceptibilities were observed for etofenprox, which is the only pyrethroid compound registered as a larvicide in Japan. Twenty-two of 56 colonies exhibited a >10% survival rate at the etofenprox concentration of 5.7 microg/ml, which is a 10 times higher concentration of the working solution. The LC50 of a colony collected from Fukuoka prefecture for etofenprox exceeded 60 microg/ml (resistance ratio >2,307), and this colony also exhibited cross-resistance to other pyrethroids, permethrin (299-fold) and phenothrin (1,200-fold). The insect growth regulators diflubenzuron and pyriproxyfen were found to be sufficiently effective enough to control Culex larvae present, but decreased sensitivities to these insecticides were slightly detected in some colonies of Cx. p. form molestus collected from urban areas. Several etofenprox-resistant colonies of Cx. p. form molestus exhibited simultaneously decreased susceptibilities to other insecticides, including temephos, diflubenzuron, and pyriproxyfen.


POSTGLACIAL RANGE FLUCTUATION, GENETIC SUBDIVISION AND SPECIATION IN THE WESTERN NORTH AMERICAN SPOTTED FROG COMPLEX, RANA PRETIOSA.
The western North American complex of spotted frogs (Rana pretiosa) exhibits isolation-by-distance, genetic subdivision, and speciation in association with its extensive northward range shift in postglacial times. The southern relict populations of R. pretiosa species B existing at high altitudes or in desert springs have been subjected to restricted gene flow, high inbreeding, and bottlenecks to produce significant between-population genetic diversity. The more recently established northern populations, however, show genetic uniformity and isolation-by-distance, as estimated using Slatkin's (1993) statistic M̂. Middle latitude populations have higher heterozygosities than populations at either extreme. Fixed differences in allozyme variation separate 21 populations of species B from five populations of R. pretiosa species A found in southwest Washington State and the Cascades Mountains of Oregon. Morphological variation of 20 metric characters among 38 samples, examined using multiple discriminant function analysis, could partially resolve partitioning among populations but specimens from the vicinity of the type series of R. p. pretiosa could not be assigned to either species A or species B. Speciation in these frogs may not be correlated with morphological evolution since comparatively neutral allozyme changes may be established more rapidly than changes in morphology.


Hepatocyte culture utilizing porous polyvinyl formal resin maintains long-term stable albumin secretion activity.
To investigate the effects of culture conditions on the maintenance of metabolic functions of cultured hepatocytes, long-term hepatocyte culture lasting 20 days was performed under two different culture conditions, i.e. stationary cultures utilizing porous polymer (polyvinyl formal (PVF) resin) as a substratum and conventional monolayer dish cultures without PVF. Metabolic activities specific to hepatocytes were evaluated in terms of ammonia metabolism, urea synthesis, and albumin secretion. Concerning ammonia metabolic and urea synthetic activities, no significant differences in maintenance of these activities were found between the two culture conditions, and these activities rapidly decreased with the elapse of the culture period, especially during the early stage of the experiments. However, after day 10, these activities in the stationary cultures were maintained at a slightly more favorable level than in the monolayer cultures. On the other hand, compared with ammonia metabolism and urea synthesis, stable and well-maintained albumin secretion of hepatocytes (60% of the activity in day 1) was exhibited in the stationary culture experiments, despite that this particular activity under the monolayer culture condition gradually reduced to a very low level (5.7% of that on day 1) at the end of the culture. From the morphological observations, hepatocytes immobilized in the PVF resin revealed individual spherical shapes without forming multicellular aggregation, and it was suggested that this characteristic structure contributed to good albumin secretion of hepatocytes. In conclusion, the advantages of the hepatocyte culture technique utilizing PVF resin over the conventional dish culture in maintaining some representative metabolic function specific to hepatocytes were clarified.


A pharmacological analysis of an associative learning task: 5-HT(1) to 5-HT(7) receptor subtypes function on a pavlovian/instrumental autoshaped memory.
Recent studies using both invertebrates and mammals have revealed that endogenous serotonin (5-hydroxytryptamine [5-HT]) modulates plasticity processes, including learning and memory. However, little is currently known about the mechanisms, loci, or time window of the actions of 5-HT. The aim of this review is to discuss some recent results on the effects of systemic administration of selective agonists and antagonists of 5-HT on associative learning in a Pavlovian/instrumental autoshaping (P/I-A) task in rats. The results indicate that pharmacological manipulation of 5-HT1-7 receptors or 5-HT reuptake sites might modulate memory consolidation, which is consistent with the emerging notion that 5-HT plays a key role in memory formation.


Can preoperative anterior chamber angle width predict magnitude of intraocular pressure change after cataract surgery?
To determine whether preoperative anterior chamber angle width, captured by anterior segment optical coherence tomography (AS-OCT), can be a predictor of intraocular pressure (IOP) change following cataract surgery. Prospective comparative observational study. Fifty-three eyes of 53 patients awaiting cataract surgery were included. Measurement of anterior chamber angle width and IOP using AS-OCT and Goldmann's applanation tonometry, respectively, were performed before and 6 months after phacoemulsification and intraocular lens implantation. Preoperative and postoperative measurements were compared using paired t test. The prediction rule defined success as > or =20% IOP reduction from the baseline preoperative IOP measurement. Multivariate regression analysis was performed to assess the association of postoperative IOP with independent variables, including age, sex, systemic hypertension, diabetes mellitus, glaucoma, and preoperative anterior chamber angle width. Data were collected from 32 females and 21 males with visually significant cataract. Mean age was 73.3 (SD 8.2) years. Mean IOP dropped from 15.1 (SD 3.1) mm Hg to 12.8 (SD 2.5) mm Hg (p < 0.0001) after cataract extraction. Mean anterior chamber angle width increased from 24.7 degrees (SD 7.1 degrees ) to 38.1 degrees (SD 6.0 degrees ) after surgery (p < 0.001). Multivariate regression analysis did not identify preoperative variables to be significantly associated with > or =20% postoperative IOP reduction. Cataract surgery results in significant and sustained mean reductions in IOP and concurrent increases in anterior chamber angle width for a period of at least 6 months after surgery. However, measurements of the preoperative anterior chamber angle width did not predict the IOP-lowering effect of cataract surgery.


Potential ototoxicity from triamcinolone, neomycin, gramicidin and nystatin (Tri-Adcortyl) cream.
Although rare, ototoxicity from the use of aminoglycoside drops is well recognized. Ototoxicity has not been described with the use of combination aminoglycoside-steroid-antifungal creams or ointments. We present the case of a 60-year-old man with a perforated tympanic membrane who suffered a total hearing loss after the instillation of cream containing triamcinolone, neomycin, gramicidin and nystatin (Tri-Adcortyl cream) into his ear canal. On balance, we believe that a number of potentially ototoxic constituents in this cream were responsible. Other possible causes of sensorineural hearing loss and the possible mechanisms of ototoxicity of this cream are discussed. The reasons why such creams may be particularly ototoxic, compared with drops, are also considered. The authors caution against the use of such creams or ointments in the ear if there is any suspicion of a tympanic membrane perforation.


An Inclusive Re-Engagement with our Nonhuman Animal Kin: Considering Human Interrelationships with Nonhuman Animals.
As humans increasingly acknowledge the effects that they are having on the planet, there is a realisation implicit in these effects that human interrelationships with nature are actually arbitrated and expedited exploitatively. Understanding how the different discourses and histories through which the interrelationships with nature are mediated and actually told and then retold is fundamental to appreciating how humans may relate with nature less exploitatively and in ways that are more inclusionary, particularly with nonhuman animals. Humans perceive nature and individual nonhuman animals in various ways. This paper provides an investigation of how humans have socially constructed nature and their place as either within or outside of it. Such constructions are elaborated conceptually and through narrative. More pertinently, this paper examines how nature and nonhuman animals are perceived and placed within those narratives that humans construct from reality. It is stressed here that such constructions have, and may continue, to lead to a worsening of the effects that humans have on the planet if there is no acceptance or recognition that certain realities exist beyond the exploitative bounds of any human-inspired concept or narrative. This paper therefore provides the groundwork for the foundations of an ethic that is both socially and ecologically inclusive and is based on a soft realist approach.


Dual Infection with Hepatitis B Virus and Hepatitis C Virus Correlated with Type 2 Diabetes Mellitus.
Conflicting data exist regarding the relationship between dual infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) with type 2 diabetes mellitus (T2DM). We assessed dual infection of HBV and HCV with the levels of blood glucose and development of DM. A total of 9621 participants in a community-based study were enrolled from 18 towns in Maoli county of Taiwan. Blood samples were collected and tested for hepatitis B surface antigen (HBsAg) and antibodies (HBsAb), antibodies against hepatitis C virus (anti-HCV) and fasting plasma glucose. DM was defined as fasting plasma glucose≥126 mg per 100 ml. Only 0.7% of total participants had HBV/HCV coinfection. The prevalence of HBV and HCV monoinfection were 9.9 and 5.7%, respectively. Adjusted blood glucose levels and development risk of T2DM (odds ratio [OR], 2.55; p<0.001) were significantly high among HBV/HCV coinfection group using multivariate linear regression adjusted for age, gender, education, race and BMI. Furthermore, using multivariate logistic regression models adjusted for covariates, HCV mono-and HBV/ HCV coinfection significantly increased on blood glucose levels. Our study shows HBV/HCV coinfection was significantly correlated with blood glucose levels. A significant proportion (28%) of participants with HBV/HCV coinfection developed T2DM. Although the precise mechanisms of dual positive infection of HBV and HCV are unclear, there is increasing evidence that dual infection of HCV and HBV is strongly associated with the development of T2DM.


Households with a stunted child and obese mother: trends and child feeding practices in a middle-income country, 1992-2008.
Middle-income countries in the intermediate stages of the nutrition transition are facing a complex picture of nutrition-related diseases with child stunting and maternal obesity coexisting within single households (SCOB). A debate exists as to whether SCOB is a true phenomenon or a statistical artefact. In this study, we examine time trends and determinants of SCOB in Egypt and test the hypothesis that increased child sugary snack consumption, and reduced fruit/vegetable consumption (markers of poor dietary diversity) are associated with SCOB. Data on 25,065 mothers and their children from the Egyptian Demographic and Health Surveys from 1992, 1995, 2005 and 2008 are used to examine trends in child stunting, maternal obesity and child-mother household type [normal/non-obese, stunted/non-obese, normal/obese, stunted/obese (SCOB)]. The association of child sugary snack and fruit/vegetable consumption with household type is also examined using multinomial logistic regression adjusting for maternal age, maternal education, child age, breastfeeding, household wealth and urban/rural residence. The prevalence of SCOB increased between the periods 1992/95 and 2005/08 despite reductions in stunting levels. This increase paralleled a rise in maternal obesity. Child sugary snack consumption was associated with higher odds (51 %) of belonging to a SCOB household compared with normal/non-obese households, while fruit/vegetable consumption was associated with lower odds (24 %). The results suggest the existence of a link between the rise in maternal obesity and an increase in SCOB, and an association between child sugary snack consumption and SCOB. Addressing SCOB may require a household-rather than individual-based approach to nutrition.


Adolescent vulnerability and the distress of rejection: Associations of adjustment problems and gender with control, emotions, and coping.
We examined adjustment problems as risks for patterns of emotions, appraisals, and coping with rejection, and explored whether these processes could account for sex (boy/girl) differences in coping. Young adolescents (N = 669, grades 6-8) completed questionnaires, which assessed responses to peer rejection threat with two short scenarios. Using structural equation modeling to test a multivariate process model, adolescents with heightened social anxiety had the most maladaptive responses to rejection threat, including elevated emotional reactions, more self-blame, and coping using more social isolation, rumination and opposition. Adolescents reporting more depressive symptoms felt less control and anticipated using less adaptive coping (less support seeking, distraction, and negotiation), whereas aggressive adolescents responded with more anger and coped via opposition. Moreover, as anticipated, sex differences in coping, symptoms, emotions, and appraisals were found. However, coping differences between boys and girls were mostly nonsignificant after accounting for symptoms, aggression, emotional reactions, and appraisals.


EFFICIENT ALGORITHMS FOR THE OPTIMAL-RATIO REGION DETECTION PROBLEMS IN DISCRETE GEOMETRY WITH APPLICATIONS.
In this paper, we study several interesting optimal-ratio region detection (ORD) problems in d-D (d ≥ 3) discrete geometric spaces, which arise in high dimensional medical image segmentation. Given a d-D voxel grid of n cells, two classes of geometric regions that are enclosed by a single or two coupled smooth heighfield surfaces defined on the entire grid domain are considered. The objective functions are normalized by a function of the desired regions, which avoids a bias to produce an overly large or small region resulting from data noise. The normalization functions that we employ are used in real medical image segmentation. To our best knowledge, no previous results on these problems in high dimensions are known. We develop a unified algorithmic framework based on a careful characterization of the intrinsic geometric structures and a nontrivial graph transformation scheme, yielding efficient polynomial time algorithms for solving these ORD problems. Our main ideas include the following. We observe that the optimal solution to the ORD problems can be obtained via the construction of a convex hull for a set of O(n) unknown 2-D points using the hand probing technique. The probing oracles are implemented by computing a minimum s-t cut in a weighted directed graph. The ORD problems are then solved by O(n) calls to the minimum s-t cut algorithm. For the class of regions bounded by a single heighfield surface, our further investigation shows that the O(n) calls to the minimum s-t cut algorithm are on a monotone parametric flow network, which enables to detect the optimal-ratio region in the complexity of computing a single maximum flow.


Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice.
Cell-matrix interactions regulate chondrocyte differentiation and survival. The alpha1beta1 integrin is a major collagen receptor that is expressed on chondrocytes. Mice with targeted inactivation of the integrin alpha1 gene (alpha1-KO mice) provide a model that can be used to address the role of cell-matrix interactions in cartilage homeostasis and osteoarthritis (OA) pathogenesis. Knee joints from alpha1-KO and wild-type (WT) BALB/c mice were harvested at ages 4-15 months. Knee joint sections were examined for inflammation, cartilage degradation, and loss of glycosaminoglycans (by Safranin O staining). Immunohistochemistry was performed to detect the distribution of alpha1 integrin, matrix metalloproteinases (MMPs), and chondrocyte apoptosis. In WT mice, the alpha1 integrin subunit was detected in hypertrophic chondrocytes in the growth plate and in a subpopulation of cells in the deep zone of articular cartilage. There was a marked increase in alpha1-positive chondrocytes in the superficial and upper mid-zones in OA-affected areas in joints from old WT mice. The alpha1-KO mice showed more severe cartilage degradation, glycosaminoglycan depletion, and synovial hyperplasia as compared with the WT mice. MMP-2 and MMP-3 expression was increased in the OA-affected areas. In cartilage from alpha1-KO mice, the cellularity was reduced and the frequency of apoptotic cells was increased. These results suggest that the alpha1 integrin subunit is involved in the early remodeling process in OA cartilage. Deficiency in the alpha1 integrin subunit is associated with an earlier deregulation of cartilage homeostasis and an accelerated, aging-dependent development of OA.


Genetic diversity and evolutionary features of type VI secretion systems in Salmonella.
Type VI secretion systems (T6SS) play key roles in bacterial pathogenesis, but their evolutionary features remain largely unclear. In this study, we conducted systematic comparisons among the documented T6SSs in Salmonella and determined their structural diversity, phylogenetic distribution and lineage-specific properties. We screened 295 Salmonella genomes for 13 T6SS core components by hidden Markov models and identified 363 T6SS clusters covering types i1, i2, i3 and i4a. Type i3 and i4a T6SSs were restricted to Salmonella enterica subspecies enterica and Salmonella bongori, respectively. whereas type i2 T6SSs were conserved between S. enterica subspecies, arizonae and diarizonae. S. enterica subspecies salamae, indica and houtenae harbored only type i1 T6SSs, which had wide distribution and high sequence diversity. The diverse Salmonella T6SSs have undergone purifying selection pressures during the bacterial evolution and may be involved in host adaptation.


Physiologic and perceptual responses to hypercarbia during warm- and cold-water immersion.
Thermoregulatory, respiratory, and perceptual responses to acute CO2 exposure during light exercise (75 W) were assessed in 12 U.S. Navy divers clad only in swim trunks while immersed to the neck in water at 18 degrees and 34 degrees C. The CO2 exposures consisted of a linear 10-min ramp increase in the inspired fraction of CO2 (FICO2) from 0 to 6% followed by 5 min of breathing 6% CO2. The ability to detect and rate the severity of hypercarbia, as well as subjective changes in thermal comfort, were assessed by comparing subjective ratings given during the CO2 exposures with those given during immersion trials where the FICO2 was maintained at 0%. Hypercarbia was recognized earlier and, at a given PETCO2, was perceived to be greater during cold- than during warm-water immersions (P < 0.01). The CO2 exposures did not affect the thermal balance of divers as assessed by changes in heat flux and rectal temperature. However, increased feelings of warmth were reported during both the cold and warm immersions when breathing raised concentrations of CO2 (P < 0.01). During the cold immersions, acute exposure to 6% CO2 significantly decreased forearm blood flow (P < 0.05), but did not affect finger blood flow. It is concluded that PETCO2 levels can reach unacceptably high concentrations (> 60 mmHg) before hypercarbia can be reliably detected by working divers. Furthermore, the ability to detect hypercarbia is poorer when immersed in warm water than when in cold water.


[Cytologic diagnosis of background and precancerous conditions based on specimens from the uterine cervix].
The authors emphasize the value of cytologic diagnosis in the detection and treatment of various conditions that may be regarded as direct or indirect precursors of carcinoma of the cervix uteri. Conditions for obtaining and treatment of the material for high-quality cytologic analysis are described. Potentialities and clinical value of the cytologic diagnosis are discussed, as are specific features of the cytograms in squamous-cell metaplasia, endocervicitis, leukoplakia, virus-induced changes in the epithelium, and dysplasia of various severity. The authors point to the important role of cytologic diagnosis in examinations of women with apparent gynecologic diseases and without manifest clinical or visual changes in the cervix uteri.


Hepatic involvement of visceral larva migrans due to Toxocara canis: a case report--CT and MR findings.
Imaging findings of hepatic lesions of visceral larva migrans are reported. A 44-year-old man presented with chills, eruptions, marked leukocytosis (31,400/microlitter), and eosinophilia (eosinophil, 72%). Multiple liver nodules were detected as low-density lesions on computed tomography (CT). They were visualized as high signal intensity lesions on T2-weighted, and as low signal intensity lesions on T1-weighted magnetic resonance imaging (MRI). The patient was diagnosed as having visceral larva migrans due to Toxocara canis, by Toxocara immnoserological test. After antihelmintic therapy, multiple liver nodules disappeared on CT. We consider that the differential diagnosis of multiple liver nodules should include visceral larva migrans.


Monthly access flow monitoring with increased prophylactic angioplasty did not improve fistula patency.
Regular access monitoring is recommended to detect and treat access stenosis in order to prevent access thrombosis and failure. In 1999, we instituted monthly access blood flow monitoring using the ultrasound dilution technique (UDT). In a sequential observational trial, 222 patients were studied for the impact of UDT monitoring on patency of their first arteriovenous autogenous fistula. Group 1, the historic group (before 1999), had 146 arteriovenous fistulas (50.7% upper arm), followed for 259 access-years. Group 2, the UDT-monitored group, had 76 arteriovenous fistulas (60.5% upper arm), followed for 123 access-years. Decision to refer for angiography was based on clinical criteria for group 1, and clinical criteria plus results of UDT flow monitoring in group 2. Cumulative patency was longer (P < 0.01) and the thrombosis rate was lower (P < 0.05) in group 2. However, the improvement occurred prior to initiation of UDT flow monitoring. Comparing outcomes in group 2 patients whose fistula survived to start flow monitoring with group 1 patients whose fistula survived at least 160 days (the median time to starting UDT monitoring in group 2), there was a sevenfold increase in angioplasty procedures (0.67 vs. 0.09 per access-year) but no improvement in the thrombosis rate or cumulative fistula patency. UDT monitoring increased the rate of angioplasty procedures and thereby shortened primary unassisted patency, but did not decrease the thrombosis rate or improve cumulative fistula patency.


Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study.
To evaluate the efficacy and tolerability of oral methotrexate (MTX) in rheumatoid arthritis (RA) in a long-term prospective trial. One hundred twenty-three patients with RA who completed a 9-month multicenter randomized trial comparing MTX and auranofin enrolled in this 5-year prospective study of MTX. Significant (P = 0.0001) improvement compared with baseline was noted in all clinical disease variables, functional status, and the Westergren erythrocyte sedimentation rate (ESR). "Marked improvement" occurred in 87 (71%) and 85 (69%) of the patients, respectively, in the joint pain/tenderness index and the joint swelling index at the last evaluable visit. Forty-four patients (36%) withdrew during the study. Eight (7%) withdrew due to lack of efficacy, and 8 (7%) due to adverse experiences, including 1 patient with cirrhosis. At 5 years, 64% of patients were still taking MTX and completed the study. This large prospective study of long-term MTX treatment demonstrates sustained clinical response and improvement in the Westergren ESR and functional assessment scores, with an acceptable toxicity profile.


Clinical value of fluorine-18α-methyltyrosine PET in patients with gliomas: comparison with fluorine-18 fluorodeoxyglucose PET.
We investigated the relationship between metabolic activity and histological features of gliomas using fluorine-18α-methyltyrosine (18F-FAMT) positron emission tomography (PET) compared with fluorine-18 fluorodeoxyglucose (18F-FDG) PET in 38 consecutive glioma patients. The tumor to normal brain ratios (T/N ratios) were calculated, and the relationships between T/N ratio and World Health Organization tumor grade or MIB-1 labeling index were evaluated. The diagnostic values of T/N ratios were assessed using receiver operating characteristic (ROC) curve analyses to differentiate between high-grade gliomas (HGGs) and low-grade gliomas (LGGs). Median T/N ratio of 18F-FAMT PET was 2.85, 4.65, and 4.09 for grade II, III, and IV gliomas, respectively, with significant differences between HGGs and LGGs (p = 0.006). Both T/N ratio (p = 0.016) and maximum standardized uptake value (p = 0.033) of 18F-FDG PET showed significant differences between HGGs and LGGs. ROC analysis yielded an optimal cut-off of 3.37 for the T/N ratio of 18F-FAMT PET to differentiate between HGGs and LGGs (sensitivity 81%, specificity 67%, accuracy 76%, area under the ROC curve 0.776). Positive predictive value was 84%, and negative predictive value was 62%. T/N ratio of 18F-FAMT PET was not correlated with MIB-1 labeling index in all gliomas, whereas T/N ratio of 18F-FDG PET was positively correlated (r s = 0.400, p = 0.013). Significant positive correlation was observed between T/N ratios of 18F-FDG and 18F-FAMT (r s = 0.454, p = 0.004), but median T/N ratio of 18F-FAMT PET was significantly higher than that of 18F-FDG PET in all grades of glioma. The T/N ratio of 18F-FAMT uptake has high positive predictive value for detection of HGGs. 18F-FAMT PET had higher T/N ratio, with better tumor-normal brain contrast, compared to 18F-FDG PET in both LGGs and HGGs. Therefore, 18F-FAMT is a useful radiotracer for the preoperative visualization of gliomas.


[The in vitro model of inhalation anesthesia using rodent ventilator].
To set up a method of applying inhalation anesthesia in rodent using rodent ventilator and to study the dynamic procedure of the in vitro model. The output port of the anesthesia machine was connected to the input port of the rodent ventilator, which was connected to a syringe simulating the lung. After supply of anesthetic gas, the gas samples from the input port of the ventilator and the syringe in the end-expiratory phase were collected at 10, 20, 30, 40, 50, 60, 90, 120, 180, 300, 600 and 900 seconds respectively and were determined using the gas chromatography(GC). The ratios of the anesthetic concentrations of the syringe to that of the input port were calculated (CE/CI). In elimination phase, the gas samples from the syringe were collected at 0,10, 20, 30, 40, 50, 60, 90, 120, 180, 300, 600 and 900 seconds respectively and were determined by GC. The ratios of the anesthetic concentrations of the gas at 10, 20, 30, 40, 50, 60, 90, 120, 180, 300, 600 and 900 seconds to that at 0 second were calculated(C'E/C0). CE/CI increased in the inhalation phase, there was an inverse relationship between CE/CI and time, the correlation coefficients were 0.90, 0.95 and 0.93 respectively (P < 0.01). The mathematical fitting equations were y = -0.19 + 0.19x(-1), y = -7.75 + 0.99x(-1), and y = -7.21 + 0.97x(-1) respectively. C'E/C0 decreased in the elimination phase,the correlation coefficients were 0.90, 0.94 and 0.95 respectively (P < 0.01). The mathematic fitting eqations were y = 5.65-0.02x(-1), y = 7.82-0.01x(-1),and y = 8.20-0.01x(-1), respectively. The in vitro model of rodent inhalation anesthesia using the rodent ventilator was set up. The establishment of this model has provided a basis for studies on inhalation anesthesia in rodents.


Do PCL-R scores from state or defense experts best predict future misconduct among civilly committed sex offenders?
In a recent study of sex offender civil commitment proceedings, Murrie et al. (Psychol Public Policy Law 15:19-53, 2009) found that state-retained experts consistently assigned higher PCL-R total scores than defense-retained experts for the same offenders (Cohen's d > .83). This finding raises an important question about the validity of these discrepant scores: Which type of score, state or defense evaluator, provides the most useful information about risk? We examined the ability of PCL-R total scores from state and defense evaluators to predict future misconduct among civilly committed sex offenders (N = 38). For comparison, we also examined predictive validity when two state experts evaluated the same offender (N = 32). Agreement between evaluators was low for cases with opposing experts (ICCA,1 = .43 to .52) and for cases with two state experts (ICCA,1 = .40). Nevertheless, scores from state and defense experts demonstrated similar levels of predictive validity (AUC values in the .70 range), although scores from different types of state evaluators (corrections-contracted vs. prosecution-retained) did not. The finding of mean differences between opposing evaluator scores, but similar levels of predictive validity, suggests that scores from opposing experts in SVP cases may need to be interpreted differently depending on who assigned them. Findings have important implications for understanding how rater disagreement may relate to predictive validity.


The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids.
The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASH patients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy-proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2 ), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis-driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534-548).


Difficult asthma.
Children with asthma who are not well controlled in spite of optimum therapy outlined in Asthma Management Guidelines are said to have 'difficult-to manage asthma' or 'difficult asthma'. Several phenotypes of this subset of asthma have been described. However, before any child is labeled as difficult asthma a thorough search for an alternative diagnosis should be made. Thus, one should look for recurrent aspiration pneumonia, tuberculosis, foreign body aspiration, tracheomalacia, bronchomalacia, cystic fibrosis etc. Causes of treatment failure range from unidentified exacerbating factors, noncompliance, inappropriate inhalers and spacers and true steroid dependence or resistance. Economics of the treatment and social beliefs should also be taken into consideration at the time of finalizing the management plan. Management involves recognizing and correcting the above factors. However, steroids form the main pillar of treatment. Majority of the patients can be controlled by optimizing inhaled steroid therapy and possibly adding steroid sparing agents. Thus, long acting bata-2 agonists, long acting theophyllines and leukotriene inhibiters may be useful. A few children will require continuous oral steroid therapy and an occasional one may be actually steroid steroid resistant. Such children are best managed at asthma specialist centers where experimental drugs like, methotrexate cyclosporin or IVIG may be tried on an individual basis under close monitoring.


Curative effect of minimally invasive surgery on palmar and foot hyperhidrosis and its influence on serum-related cytokines and immunoglobulins.
The curative effect of minimally invasive surgery on palmar and foot hyperhidrosis and its influence on serum-related cytokines and immunoglobulins were investigated. Seventy-six patients with palmar and foot hyperhidrosis admitted to Yunnan University Hospital from August 2014 to July 2016 were selected and randomly divided into control group (n=38) and observation group (n=38) using a random number table. Patients in control group received drug therapy, while those in observation group underwent laparoscopic thoracic-4 sympathetic chain combined with thoracic-3 branch amputation. The therapeutic effects of patients in the two groups were compared. The levels of serum C-reactive protein (CRP), interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) of patients in the two groups were measured by enzyme-linked immunosorbent assay (ELISA) before treatment and at one week after treatment. The levels of immunoglobulin G (IgG), IgA and IgM were detected by immunoturbidimetry. The quality of life (QOL) in patients was evaluated by quality-of-life index (iQOL) before and after treatment. The total effective rate in the observation group was significantly higher than that in the control group (P<0.05). The serum levels of CRP, IL-6, IL-10 and TNF-α of patients in the two groups were higher at one week after treatment than those before treatment (P<0.05), and there were no significant differences between the two groups (P>0.05). At one week after treatment, IgG, IgM and IgA levels of patients in the two groups were remarkably increased (P<0.05), and there were no significant differences between the two groups (P>0.05). After treatment, the iQQL scores of patients in the two groups were significantly decreased, and iQQL score in observation group was decreased more significantly compared with that in control group (P<0.05). Compared with drug therapy, minimally invasive surgery is more effective in the treatment of palmar and foot hyperhidrosis with smaller trauma and inflammatory reaction, and it has less influence on serum immunoglobulin levels, which is conducive to the rehabilitation of patients.


Random matrix ensembles from nonextensive entropy.
The classical Gaussian ensembles of random matrices can be constructed by maximizing Boltzmann-Gibbs-Shannon's entropy, S(BGS) = -integral dH[P(H)]ln[P(H)], with suitable constraints. Here, we construct and analyze random-matrix ensembles arising from the generalized entropy S(q) = [1- integral dH [P(H)](q)] /(q-1) (thus, S1 = S(BGS) ). The resulting ensembles are characterized by a parameter q measuring the degree of nonextensivity of the entropic form. Making q-->1 recovers the Gaussian ensembles. If q not equal 1, the joint probability distributions P(H) cannot be factorized, i.e., the matrix elements of H are correlated. In the limit of large matrices two different regimes are observed. When q<1, P(H) has compact support, and the fluctuations tend asymptotically to those of the Gaussian ensembles. Anomalies appear for q>1 : Both P(H) and the marginal distributions P( H(ij) ) show power-law tails. Numerical analyses reveal that the nearest-neighbor spacing distribution is also long-tailed (not Wigner-Dyson) and, after proper scaling, very close to the result for the 2 x 2 case--a generalization of Wigner's surmise. We discuss connections of these "nonextensive" ensembles with other non-Gaussian ones, such as the so-called Lévy ensembles and those arising from soft confinement.


Pseudorange Measurement Method Based on AIS Signals.
In order to use the existing automatic identification system (AIS) to provide additional navigation and positioning services, a complete pseudorange measurements solution is presented in this paper. Through the mathematical analysis of the AIS signal, the bit-0-phases in the digital sequences were determined as the timestamps. Monte Carlo simulation was carried out to compare the accuracy of the zero-crossing and differential peak, which are two timestamp detection methods in the additive white Gaussian noise (AWGN) channel. Considering the low-speed and low-dynamic motion characteristics of ships, an optimal estimation method based on the minimum mean square error is proposed to improve detection accuracy. Furthermore, the α difference filter algorithm was used to achieve the fusion of the optimal estimation results of the two detection methods. The results show that the algorithm can greatly improve the accuracy of pseudorange estimation under low signal-to-noise ratio (SNR) conditions. In order to verify the effectiveness of the scheme, prototypes containing the measurement scheme were developed and field tests in Xinghai Bay of Dalian (China) were performed. The test results show that the pseudorange measurement accuracy was better than 28 m (σ) without any modification of the existing AIS system.


A novel role for Twist-1 in pulp homeostasis.
The molecular mechanisms that maintain the equilibrium of odontoblast progenitor cells in dental pulp are unknown. Here we tested whether homeostasis in dental pulp is modulated by Twist-1, a nuclear protein that partners with Runx2 during osteoblast differentiation. Our analysis of Twist-1(+/-) mice revealed phenotypic changes that involved an earlier onset of dentin matrix formation, increased alkaline phosphatase activity, and pulp stones within the pulp. RT-PCR analyses revealed Twist-1 expression in several adult organs, including pulp. Decreased levels of Twist-1 led to higher levels of type I collagen and Dspp gene expression in perivascular cells associated with the pulp stones. In mice heterozygous for both Twist-1 and Runx2 inactivation, the phenotype of pulp stones appeared completely rescued. These findings suggest that Twist-1 plays a key role in restraining odontoblast differentiation, thus maintaining homeostasis in dental pulp. Furthermore, Twist-1 functions in dental pulp are dependent on its interaction with Runx2.


[Use of microcapsular leptospiral antigens for detecting specific antibodies].
The sensitivity of microcapsular leptospiral antigens, produced by Japan Lyophilization Laboratory and intended for use in tests for the detection of antibodies to leptospires in the sera of experimentally immunized laboratory animals, were studied. The comparative study of the microcapsular agglutination (MCA) test and other serological tests, such as the microagglutination (MA) test and the indirect enzyme immunoassay (EIA), was made. The leptospiral antigens under study were found to actively react with serospecific and group-specific antibodies. In infected guinea pigs and rabbits specific antibodies could be detected from days 3-4 in the MCA test and only from days 5-7 in the MA test. The average antibody level determined by titration in the MCA test was 3.3 times higher and in indirect EIA, 4.3 times higher than that determined by titration in the MA test. These data make it possible to recommend the use of microcapsular leptospiral antigens for the early diagnosis of leptospirosis.


Peer review and PSRO: an update.
The author provides a summary of developments in peer review and Professional Standards Review Organizations (PSROs) within APA, the federal government, and the American Medical Association between June 1974 and June 1975. He discusses the reaction of the medical profession to the interim guidelines from the U.S. Department of Health, Education, and Welfare and the problems of financing PSROs. He concludes that the key issues for PSROs and peer review in general are the availability and effectiveness of local review components, and that lack of involvement on the part of psychiatry will only ensure that nonpsychiatrists will design the review procedures.


The VA Maryland Health Care System's telemental health program.
The VA Maryland Health Care System introduced videoconferencing technology to provide psychiatry, evidenced-based psychotherapy, case management, and patient education at rural clinics where it was difficult to recruit providers. Telemental health services enable rural clinics to offer additional services, such as case management and patient education. Services have been expanded to urban outpatient clinics where a limited number of mental health clinic hours are available. This technology expands the availability of mental health providers and services, allowing patients to receive services from providers located at distant medical centers.


[Thyroglobulin RT-PCR method for detection of lymph node metastases during the course of differentiated thyroid cancers].
In patients with a suspicion of recurrence of differentiated thyroid cancer with metastases to lymph nodes, detection of thyroglobulin (Tg) mRNA in fine needle biopsy material may support the interpretation of classic cytological examination in cases where it fails to detect lymph node involvement early enough. Prospective study of thyroglobulin mRNA detection in neck lymph nodes in patients with suspected differentiated thyroid cancer (DTC) metastases. 70 nodes from 60 patients with suspected DTC recurrence were investigated. Patients with suspicion of lymph node metastases of other types of cancer were included as a control group. Thyroglobulin RT-PCR was conducted in residual material left after preparation of cytological smears from fine needle biopsy specimens. Primers spanning exons 3-5 were used with 39 cycles of PCR. RNA isolation control and cDNA amplification were carried out using GADPH starters. Classical cytology confirmed nodal involvement in 22 of DTC patients, RT-PCR Tg was positive in 20 of them (91%). Among 48 patients with a suspicion of DTC recurrence and negative cytology, Tg mRNA was found twice. One positive RT-PCR result was confirmed by repeated cytology conducted 4-6 months later and followed by surgery. No positive result of RT-PCR was obtained with other head and neck malignancies. The overall specificity was estimated with 98%. RT-PCR Tg shows sufficient specificity to be applied in further studies estimating its usefulness in fine needle biopsy for early detection of lymph node metastases in differentiated thyroid cancer.


Mini Mass Spectrometer Integrated with a Miniature Ion Funnel.
Previously, a continuous atmospheric pressure interfaced miniature mass spectrometer was developed in our lab. The continuous atmospheric pressure interface improves system robustness, stability, and scan speed, but it also results in limited ion transfer efficiency and reduced mass resolution. To solve these problems, a miniature ion funnel was designed and integrated into the miniature mass spectrometer for the first time. Besides ion transfer efficiency, dimension and power consumption of the ion funnel also need to be considered throughout the design process. After a systematic optimization, the designed miniature ion funnel could increase ion transfer efficiency by more than 10 times, while lowering the background pressure of ion trap by ∼2 times. As a result, sensitivity and mass resolution of the second generation miniature mass spectrometer were improved by 20 times and ∼2 times, respectively, while maintaining its high scan speed and stability. A sensitive and robust mini-MS, capable of coupling with ambient ionization sources would meet the needs of many on-site chemical analysis applications, such as in food, drug, and agricultural administrations, forensic science, homeland security, and etc.


Secondary substrate utilization of methylene chloride by an isolated strain of Pseudomonas sp.
Secondary substrate utilization of methylene chloride was analyzed by using Pseudomonas sp. strain LP. Both batch and continuously fed reactors demonstrated that this strain was capable of simultaneously consuming two substrates at different concentrations: the primary substrate at the higher concentration (milligrams per liter) and the secondary substrate at the lower concentration (micrograms per liter). The rate of methylene chloride utilization at trace concentrations was greater in the presence of the primary substrate, acetate, than without it. However, when the substrate roles were changed, the acetate secondary substrate utilization rate was less when methylene chloride was present. Thus, substrate interactions are important in the kinetics of secondary substrate utilization. Pseudomonas sp. strain LP showed a preference toward degrading methylene chloride over acetate, whether it was the primary or secondary substrate, providing it was below an inhibitory concentration of ca. 10 mg/liter.


Validation of an HPLC method for quantitation of MDMA in tablets.
An isocratic reversed-phase high-performance liquid chromatography (HPLC) method is developed and validated for the quantitation of 3,4-methylenedioxymethamphetamine (MDMA) in tablets. The chromatographic separation is achieved with potassium phosphate buffer (pH 3.2)-acetonitrile (9:1, v/v) as mobile phase, a Chromspher B column, and UV detection at 210 nm. The calibration curve is linear from 1.4 to 111 microg/mL. The percent relative standard deviation for intra- and interday precision studies is 2.7% each. The measurement uncertainty is estimated to 9%. The method is specific and successfully used for routine quantitation of MDMA in tablets.


Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial.
Children with familial hypercholesterolemia have endothelial dysfunction and increased carotid intima-media thickness (IMT), which herald the premature atherosclerotic disease they develop later in life. Although intervention therapy in the causal pathway of this disorder has been available for more than a decade, the long-term efficacy and safety of cholesterol-lowering medication have not been evaluated in children. To determine the 2-year efficacy and safety of pravastatin therapy in children with familial hypercholesterolemia. Randomized, double-blind, placebo-controlled trial that recruited children between December 7, 1997, and October 4, 1999, and followed them up for 2 years. Two hundred fourteen children with familial hypercholesterolemia, aged 8 to 18 years and recruited from an academic medical referral center in the Netherlands. After initiation of a fat-restricted diet and encouragement of regular physical activity, children were randomly assigned to receive treatment with pravastatin, 20 to 40 mg/d (n = 106), or a placebo tablet (n = 108). The primary efficacy outcome was the change from baseline in mean carotid IMT compared between the 2 groups over 2 years; the principal safety outcomes were growth, maturation, and hormone level measurements over 2 years as well as changes in muscle and liver enzyme levels. Compared with baseline, carotid IMT showed a trend toward regression with pravastatin (mean [SD], -0.010 [0.048] mm; P =.049), whereas a trend toward progression was observed in the placebo group (mean [SD], +0.005 [0.044] mm; P =.28). The mean (SD) change in IMT compared between the 2 groups (0.014 [0.046] mm) was significant (P =.02). Also, pravastatin significantly reduced mean low-density lipoprotein cholesterol levels compared with placebo (-24.1% vs +0.3%, respectively; P<.001). No differences were observed for growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume between the 2 groups. Two years of pravastatin therapy induced a significant regression of carotid atherosclerosis in children with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue.


The Strength of hERG Inhibition by Erythromycin at Different Temperatures Might Be Due to Its Interacting Features with the Channels.
Erythromycin is one of the few compounds that remarkably increase ether-a-go-go-related gene (hERG) inhibition from room temperature (RT) to physiological temperature (PT). Understanding how erythromycin inhibits the hERG could help us to decide which compounds are needed for further studies. The whole-cell patch clamp technique was used to investigate the effects of erythromycin on hERG channels at different temperatures. While erythromycin caused a concentration-dependent inhibition of cardiac hERG channels, it also shifted the steady-state activation and steady-state inactivation of the channel to the left and significantly accelerated the onset of inactivation at both temperatures, although temperature itself caused a profound change in the dynamics of hERG channels. Our data also suggest that the binding pattern to S6 of the channels changes at PT. In contrast, cisapride, a well-known hERG blocker whose inhibition is not affected by temperature, does not change its critical binding sites after the temperature is raised to PT. Our data suggest that erythromycin is unique and that the shift in hERG inhibition may not apply to other compounds.


An amphipathic sequence in the cytoplasmic tail of HIV-1 Env alters cell tropism and modulates viral receptor specificity.
The human immunodeficiency virus type 1 (HIV-1) 92UG046 Env protein, obtained from a CD4-independent HIV-1 primary isolate (Zerhouni et al., 2004), has the ability to initiate an infection in HeLa cells expressing CD4 when carrying the full-length (FL) Env, but uses CD8 molecules for receptor-mediated entry when carrying a truncated Env (CT84). To determine whether a specific length or structure in the cytoplasmic tail (CT) is responsible for this alteration of tropism, we compared a series of Env constructs with different CT truncations and the presence or absence of an amphipathic alpha- helical sequence. We found that truncated constructs containing the alpha-helical LLP-2 structure in their CT domains conferred a switch from CD4 to CD8 tropism. The results support the conclusion that the structure of the CT domain can play an important role in determining receptor specificity.


Red/ox states of human protein disulfide isomerase regulate binding affinity of 17 beta-estradiol.
Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operating as both oxidoreductase and molecular chaperone in the endoplasmic reticulum of cells. hPDI thiol-disulfide interchange reactions lead to the adoption of two distinct red/ox conformations with different substrate preferences. hPDI also displays high binding capacity for some endogenous steroid hormones including 17 beta-estradiol (E2) and thus contributes to the regulation of their intracellular concentration, storage and actions. The primary focus of this study was to investigate the impact of E2 binding on functional activity of recombinant hPDI. Then, we examined the effect of E2 binding on structural alteration of hPDI red/ox conformations and its influence on affinity and position of interaction using experimental and computational analysis. Our results revealed that interaction of one E2 per each hPDI molecule led to the inhibition of hPDI reductase activity and conformational changes in both oxidation states. Mutually, E2-binding position were also redox-regulated with higher affinity in oxidized hPDI compare to the reduced form. The importance of histidine-256 protonation states in distinct binding preferences of E2 were also demonstrated in hPDI red/ox conformations. These findings might pave the way for better understanding of the mechanisms behind the redox-dependent hormone-binding activity of hPDI.


Radionuclide methods for evaluating the results of thrombolytic therapy.
In summary, a variety of nuclear techniques may be used to investigate the effects of thrombolytic therapy and myocardial reperfusion. Assessments of global and regional ventricular function, myocardial perfusion, and metabolic integrity are available and appear to add substantially to conventional assessment. Timing of studies appears to be critical. Complementary data can be obtained in both the acute and convalescent phase of myocardial infarction.


Pre-transplant cytoreductive therapy can improve overall survival of patients with MDS-AML but not MDS-EB2 receiving HLA-matched sibling donor peripheral blood stem cell transplantation.
To evaluate whether cytoreductive therapy is needed for myelodysplastic syndromes (MDS) patients with excess blasts type 2 (MDS-EB2) and acute myeloid leukemia derived from MDS (MDS-AML) before HLA-matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT), we retrospectively analyzed 80 cases of MDS-EB2 and MDS-AML patients who received MSD-PBSCT between February 2006 and December 2019 in our hospital. The 3-years overall survival (OS) rate and disease-free survival (DFS) rate were (59.1±5.8)% and (52.5±5.7)%, respectively. The 3-years non-relapse mortality (NRM) rate and relapse rate (RR) were (22.4±0.2)% and (25.4±0.2)%, respectively. Univariate analysis showed that, hematopoietic cell transplantation comorbidity index (HCT-CI) ≥ 2, poor/very poor karyotype and occurrence of grade III-IV acute graft-versus-host disease (aGVHD) are risk factors for OS. Patients received pre-transplant cytoreductive therapy (PCT) and obtained complete remission (CR) had significantly higher OS rate than those who failed to achieve CR (non-CR group) and those who did not receive PCT (non-PCT group) [(80.0±8.3)% versus (38.1±10.6)% versus (56.1±9.3)%, P=0.010]. PCT significantly increased the OS rate [(62.2±10.0)% versus (20.0±17.9)%, P=0.013] for MDS-AML patients but not for MDS-EB2 patients [(59.2±11.1)% versus (62.9±10.1)%, P=0.991]. Our findings suggest reducing tumor burden by cytoreductive therapy to obtain CR before transplant improves OS. For MDS-AML patients, PCT is beneficial, while for MDS-EB2 patients, PCT is not necessary.


On the Computing Potential of Intracellular Vesicles.
Collision-based computing (CBC) is a form of unconventional computing in which travelling localisations represent data and conditional routing of signals determines the output state; collisions between localisations represent logical operations. We investigated patterns of Ca2+-containing vesicle distribution within a live organism, slime mould Physarum polycephalum, with confocal microscopy and observed them colliding regularly. Vesicles travel down cytoskeletal 'circuitry' and their collisions may result in reflection, fusion or annihilation. We demonstrate through experimental observations that naturally-occurring vesicle dynamics may be characterised as a computationally-universal set of Boolean logical operations and present a 'vesicle modification' of the archetypal CBC 'billiard ball model' of computation. We proceed to discuss the viability of intracellular vesicles as an unconventional computing substrate in which we delineate practical considerations for reliable vesicle 'programming' in both in vivo and in vitro vesicle computing architectures and present optimised designs for both single logical gates and combinatorial logic circuits based on cytoskeletal network conformations. The results presented here demonstrate the first characterisation of intracelluar phenomena as collision-based computing and hence the viability of biological substrates for computing.


Preparation of Chondroitin Sulfate-Glycyl-Prednisolone Conjugate Nanogel and Its Efficacy in Rats with Ulcerative Colitis.
A conjugate between chondroitin sulfate (CS) and glycyl-prednisolone (GP), named CS-GP, was produced by carbodiimide coupling at a high GP/CS ratio. CS-GP was not water-soluble and gave a nanogel (NG) in aqueous solution. Two types of nanogels, NG(I) and NG(II), with prednisolone (PD) contents of 5.5 and 21.1% (w/w), respectively, were obtained. They had particle sizes of approximately 280 and 570 nm, respectively, and showed negative ζ-potentials of approximately -40 mV. The PD release rate was slower in the nanogels than in a solution of CS-GP with a PD content of 1.4% (w/w). The PD release rate was slower in NG(II) than in NG(I), and was elevated at pH 7.4 than at pH 6.8. NG(II) was applied in vivo to rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis, and its therapeutic efficacy and pharmacokinetic features were investigated. The therapeutic efficacy of NG(II) was slightly better than that of PD alone. Drug delivery to the lower intestines was enhanced with NG(II). The CS-GP nanogel has potential as a potent DDS for the treatment of ulcerative colitis.


Extradural Anesthesia in a Case of Mild Head Injury.
We experienced a case posted for bilateral lower limb surgery in a patient having mild traumatic brain injury (TBI), where administration of graded epidural anesthesia led to agitation, probably resulting from the transient elevation of intracranial pressure (ICP). Due to the wide range of benefits provided by regional anesthesia, an anesthetist should be aware of the possible options for perioperative management to best handle such polytrauma cases. In this case, agitation was managed with a bolus of benzodiazepine and maintenance infusion of dexmedetomidine while the six-hour-long surgery continued with epidural anesthesia. This patient was a smoker who had bronchospasm and underlying pneumonia precluding a high risk for postoperative ventilatory support if only general anesthesia was administered. Post-surgery the patient was conscious, oriented, and pain-free leading to early mobilization and discharge from the hospital. The patient did not report any neurological deterioration in a follow-up period of one month.


Post-Transplant Pregnancy and Contraception.
Placed in a historical context, this overview focuses on post-transpant pregnancy, fatherhood, and contraception in women and men. The critical importance of early reproductive counseling because of improved sexual function and the early return of ovulation and menses post-transplant is emphasized. We explain the decision making regarding contraception choices. The available data on the safety of immunosuppressive drugs in pregnancy, and for men desiring fatherhood, are detailed. The risk of maternal ingestion of mycophenolate products on the in utero fetus is considered and contrasted with the lack of concern for their use by men fathering children. Pregnancy risks to the allograft, baby, and mother are discussed. An infant's exposure to specific immunosuppressant medications through breastfeeding is reviewed. The ethics and realities of post-transplant parenthood are explored.


Expression of FOXM1 and related proteins in breast cancer molecular subtypes.
Forkhead box (FOX) proteins constitute an extended family of transcriptional regulators. FOXM1 is ubiquitously expressed in cells undergoing proliferation, and overexpression of FOXM1 is associated with poor prognosis in various malignant tumours. FOXM1 and FOXO3a are often transcriptionally antagonistic. FOXO3a plays a critical tumour-suppressive role in breast cancer. FOXO activity is modulated by its acetylation status, which is regulated by class III histone deacetylases (sirtuins; also known as SIRTs). This study evaluated the role of FOX proteins and their regulators in each molecular subtype of breast cancer. Immunohistochemical expressions of FOXM1, FOXO3a, SIRT1 and SIRT6 were evaluated in tissue microarray blocks containing 688 consecutive breast cancer samples. Mean expression levels were used to categorize tumours according to the expression of each protein (high or low). High expression of FOXM1 was significantly correlated with high SIRT1 and SIRT6 expression, higher histologic grade and triple-negative breast cancer (TNBC). High expression of nuclear FOXO3a and nuclear SIRT1 was correlated with a lower histologic grade and the hormone receptor-positive/HER2-negative subtype. In survival analysis, FOXM1 was an independent adverse prognostic factor for disease-free and overall survival in the hormone receptor-positive/HER2-negative subtype but not in the HER2-positive subtype or TNBC. In conclusion, although high FOXM1 expression was noted in the TNBC subtype, it had no prognostic impact in TNBC. However, it had prognostic significance in the hormone receptor-positive/HER2-negative subtype.


Congenital anomalies of the kidney and urinary tract: an embryogenetic review.
Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of disorders that result from abnormalities of the urinary collecting system, abnormal embryonic migration of the kidneys, or abnormal renal parenchyma development. These disorders are commonly found in humans, accounting for 20-30% of all genetic malformations diagnosed during the prenatal period. It has been estimated that CAKUT are responsible for 30-50% of all children with chronic renal disease worldwide and that some anomalies can predispose to adult-onset diseases, such as hypertension. Currently, there is much speculation regarding the pathogenesis of CAKUT. Common genetic background with variable penetrance plays a role in the development of the wide spectrum of CAKUT phenotypes. This review aims to summarize the possible mechanisms by which genes responsible for kidney and urinary tract morphogenesis might be implicated in the pathogenesis of CAKUT.


Cytokinins and the CRE1 receptor influence endogenous gibberellin levels in Medicago truncatula.
Gibberellins (GAs) and cytokinins (CKs) are hormones that play antagonistic roles in several developmental processes in plants. However, there has been little exploration of their reciprocal interactions. Recent work in Medicago truncatula has revealed that GA signalling can regulate CK levels and response in roots. Here, we examine the reciprocal interaction, by assessing how CKs and the CRE1 (Cytokinin Response 1) CK receptor may influence endogenous GA levels. Real-Time RT-PCR analyses revealed that the expression of key GA biosynthesis genes is regulated in response to a short-term CK treatment and requires the CRE1 receptor. Similarly, GA quantifications indicated that a short-term CK treatment decreases the GA1 pool in wild-type plants and that GA levels are increased in the cre1 mutant compared to the wild-type. These data suggest that the M. truncatula CRE1-dependent CK signaling pathway negatively regulates bioactive GA levels.


Italian multicentric pilot study on MBL2 genetic polymorphisms in HIV positive pregnant women and their children.
We investigated genetic polymorphisms of MBL2 gene, in a cohort of 90 Italian HIV-1 pregnant seropositive women and their children in order to understand whether the MBL2 genotype of HIV-1 positive mothers might be related to their ability to transmit the virus to their children. DNA was extracted from Iso Code Stix cards, and MBL2 genotyping was performed by Melting Temperature Assay. The frequency of the MBL2 0/0 homozygotes was higher in HIV-1 positive mothers than in healthy controls, the MBL2 0/0 genotype was more frequent in children born from HIV positive mothers than healthy subjects. We have confirmed the association of polymorphisms involving a gene of the innate immunity with an increased risk of being infected by HIV. These polymorphisms were also evidenced in children born from HIV+ mothers, but the risk of infection was strongly reduced by cesarean delivery and by antiretroviral treatment.


[Posterior hypothalamus action on gastric secretion (author's transl)].
Three groups of cats with surgically created total gastric pouches were employed in this experiment. They were divided as follows: in one group the innervation of the pouch was left intact; in another group the symphathetic innervation of the pouch was removed; and in the third group the pouch was completely denervated. It was seen that an infusion of histamine induced gastric secretion in all three groups. And when the secretion became constant it proved to be less acidic and more abundant in the sympathectomized group and also in the group that had suffered complete denervation. It was observed now that stimulating the posterior hypothalamus of the innervated group produced, in all of the cats, a decrease in the amount of acid secreted per unit of time. Consequently, it was seen that a symphathectomy did not eliminate the gastric effects produced when the posterior hypothalamus was stimulated. Specifically, stimulation of the posterior hypothalamus produced an increase in the amount of secretion rather than a decrease. The increase produced in these animals can be shown not to be due to irradiation of the anterior hypothalamus as the same response is obtained when a symphathectomy is combined with a vagotomy. It is, therefore, believed that it may be concluded that the Posterior hypothalamus does not produce its effect exclusively through its nervous pathways. It is believed its effect may possibly be mediated by an unknown substance liberated upon stimulation which then reaches the stomach by way of its blood supply.


Electrospun Anion-Conducting Ionomer Fibers-Effect of Humidity on Final Properties.
Anion-conducting ionomer-based nanofibers mats are prepared by electrospinning (ES) technique. Depending on the relative humidity (RH) during the ES process (RHES), ionomer nanofibers with different morphologies are obtained. The effect of relative humidity on the ionomer nanofibers morphology, ionic conductivity, and water uptake (WU) is studied. A branching effect in the ES fibers found to occur mostly at RHES < 30% is discussed. The anion conductivity and WU of the ionomer electrospun mats prepared at the lowest RHES are found to be higher than in those prepared at higher RHES. This effect can be ascribed to the large diameter of the ionomer fibers, which have a higher WU. Understanding the effect of RH during the ES process on ionomer-based fibers' properties is critical for the preparation of electrospun fiber mats for specific applications, such as electrochemical devices.


Interpreting NMR data for beta-peptides using molecular dynamics simulations.
NMR is one of the most used techniques to resolve structure of proteins and peptides in solution. However, inconsistencies may occur due to the fact that a polypeptide may adopt more than one conformation. Since the NOE distance bounds and (3)J-values used in such structure determination represent a nonlinear average over the total ensemble of conformers, imposition of NOE or (3)J-value restraints to obtain one unique conformation is not an appropriate procedure in such cases. Here, we show that unrestrained MD simulation of a solute in solution using a high-quality force field yields a conformational ensemble that is largely compatible with the experimental NMR data on the solute. Four 100 ns MD simulations of two forms of a nine-residue beta-peptide in methanol at two temperatures produced conformational ensembles that were used to interpret the NMR data on this molecule and resolve inconsistencies between the experimental NOEs. The protected and unprotected forms of the beta-peptide adopt predominantly a 12/10-helix in agreement with the qualitative interpretation of the NMR data. However, a particular NOE was not compatible with this helix indicating the presence of other conformations. The simulations showed that 3(14)()-helical structures were present in the ensemble of the unprotected form and that their presence correlates with the fulfillment of the particular NOE. Additionally, all inter-hydrogen distances were calculated to compare NOEs predicted by the simulations to the ones observed experimentally. The MD conformational ensembles allowed for a detailed and consistent interpretation of the experimental data and showed the small but specific conformational differences between the protected and unprotected forms of the peptide.


Computed tomography of intracranial extramedullary hematopoiesis.
Patients with extramedullary hematopoiesis may be divided into two main groups. The first group shows paraosseous foci that may result from "herniation" of medullary tissue from the underlying bone. This is seen in hemolytic disorders where the marrow has tremendous activity. The second group shows extraosseous soft tissue foci, which may arise from multipotential stem cells. This occurs when the marrow activity is ineffectual, as in the myeloproliferative disorders or, rarely, with toxic or tumoral marrow destruction. We present a patient with myelosclerosis and four intracranial masses of hematopoietic tissue in the subdural space. We believe this is the first description of the cranial CT findings in this condition.


Detecting gene-gene interactions using affected sib pair analysis with covariates.
Interest has recently focussed on allowing for interactions between loci as a way to increase power to detect linkage. In this paper, a simplified logistic regression method was used to perform affected sib pair analyses allowing for the inclusion of data from other loci. A systematic search of two-locus disease models was carried out to determine the situations in which this was advantageous. If IBD information is available (e.g. from a genome scan), it is unlikely that allowing for interactions will give a large lod score in the absence of linkage evidence from sinlge-locus analysis. Furthermore, allowing for interactions rarely gave a significant increase in power to detect linkage over a single-locus analysis, except for heterogeneity models with low K(P). Conversely, the availability of disease-associated genotypes may greatly increase the power both to detect linkage to a second locus and interaction between the loci. These results indicate that when only IBD information is available, two-locus analysis of genome scan data should be restricted to regions giving peaks under single-locus analysis. If disease-associated genotypes are available, it may be worth re-analysing the whole genome.


Structure and Conformational Dynamics of the Human Spliceosomal Bact Complex.
The spliceosome is a highly dynamic macromolecular complex that precisely excises introns from pre-mRNA. Here we report the cryo-EM 3D structure of the human Bact spliceosome at 3.4 Å resolution. In the Bact state, the spliceosome is activated but not catalytically primed, so that it is functionally blocked prior to the first catalytic step of splicing. The spliceosomal core is similar to the yeast Bact spliceosome; important differences include the presence of the RNA helicase aquarius and peptidyl prolyl isomerases. To examine the overall dynamic behavior of the purified spliceosome, we developed a principal component analysis-based approach. Calculating the energy landscape revealed eight major conformational states, which we refined to higher resolution. Conformational differences of the highly flexible structural components between these eight states reveal how spliceosomal components contribute to the assembly of the spliceosome, allowing it to generate a dynamic interaction network required for its subsequent catalytic activation.