Combined Ankle/Knee Stretching and Pivoting Stepping Training for Children With Cerebral Palsy.
Although various treatment methods have been investigated to reduce spasticity and intoeing gait in children with cerebral palsy (CP), methods to concurrently reduce an intoeing gait and associated ankle/knee stiffness and spasticity according to a child's specific needs are lacking. This study aimed to develop a training program to improve walking function and transverse-plane (pivoting) neuromuscular control and reduce spasticity and intoeing gait deviations. Eight children with diplegic CP and intoeing gait participated in this 6-week combined robotic ankle and/or knee intelligent stretching and pivoting neuromuscular control training program (Subject-specific Stretching and Pivoting Off-axis Neuromuscular control Training, [SS-POINT]). The effects of SS-POINT were evaluated using neuromechanical, functional, and clinical outcome measures and compared to those for eight children with CP and intoeing gait who participated in pivoting neuromuscular control training (POINT) alone in a previous study. After the SS-POINT program, subjects with CP showed reduced knee stiffness and intoeing angle, and improvements in both joint and leg functions in terms of ankle and knee active range of motion, ankle dorsiflexor strength, proprioception, walking speed, balance, and minimum pivoting angle. Furthermore, improvements in proprioceptive acuity and minimum pivoting angle after the SS-POINT were greater than those after the POINT. The SS-POINT approach can be used as a subject-specific training program for improving leg and walking functions and reducing intoeing during gait. This approach can serve as an individualized intervention at the joint and walking levels to maximize intervention effects by adjusting training targets, sequences, and intensities to meet the individual needs of children with CP.


Association between use of antiemetics, antipsychotics, or antidepressants and the risk of Parkinson's disease .
Antipsychotics, antidepressants, and antiemetics are well-known causative agents of parkinsonism. However, it is not certain that the use of these medications increases the risk of Parkinson's disease (PD). We aim to define the risk of PD associated with use of antipsychotic, antidepressant, or antiemetic therapy. We conducted a population-based nested case-control study using data from the South Korean health insurance database. For each PD case, we randomly selected sex, age group, cohort entry date, duration of follow-up, and Charlson comorbidity score-matched controls (up to 3). Exposure was categorized into six groups based on treatments received 1 - 90 days before the index date (separate use of either: antiemetics; antipsychotics; or antidepressants; combined use of antiemetics with either: antipsychotics; or antidepressants; and combined use of all three). We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for PD. Final subjects included 31,428 cases and 94,284 matched controls. We observed an increased risk of PD with the separate use of antiemetics (adjusted OR, 1.08; 95% CI, 1.05 - 1.11) and that of antipsychotics (1.31; 1.12 - 1.52), and the combined use of antiemetics and antipsychotics (1.42; 1.15 - 1.75). Both antidepressants alone and with antipsychotics were not associated with higher risk of PD. Separate or concurrent use of antiemetics and antipsychotics showed increased risks of PD. Although statistical significance was observed, when taking into account that there still lie unmeasured, unconsidered confounders, there may be no clinical association present. Caution will be needed in prescribing these drugs in patients who have prognostic factors for PD. .


Analysis of corneal astigmatism with NIDEK axial length scan in caucasian cataract surgery candidates.
The aim of the study was to analyze and quantify the pattern of corneal astigmatism in Caucasian cataract surgery patients using a new optical biometer (axial length [AL] Scan, NIDEK Co., Gamagori, Japan). The datasets of cataract surgery patients acquired between March 1, 2014, and April 15, 2016, were collected and analyzed. The corneal power (flat keratometry, steep keratometry, and mean keratometry), negative cylinder power, and axis of astigmatism were recorded. Keratometry values were optically measured by optical low coherence interferometry (AL-Scan, NIDEK Co., Ltd.,) before cataract extraction. The study comprised 1233 eyes of 838 consecutive cataract candidates with a mean age of 66.8 ± 10.7 years (range 40-97 years). The mean keratometry value and corneal astigmatism were 43.69 ± 1.61 D and 0.84 ± 0.70 D, respectively. Corneal astigmatism of 1.00 D or greater was found in 344 eyes (27.9%), and 548 eyes (44.4%) had against-the-rule astigmatism. A trend toward decreasing J0 and J45 with age was found by linear regression models. The per-year increase in age was associated with a J0 and J45 decrease of 0.002 D and 0.001D, respectively. This study provides the distribution of astigmatism axis and power for cataract patients in age subsets from Turkey.


Transforming carbon dioxide into jet fuel using an organic combustion-synthesized Fe-Mn-K catalyst.
With mounting concerns over climate change, the utilisation or conversion of carbon dioxide into sustainable, synthetic hydrocarbons fuels, most notably for transportation purposes, continues to attract worldwide interest. This is particularly true in the search for sustainable or renewable aviation fuels. These offer considerable potential since, instead of consuming fossil crude oil, the fuels are produced from carbon dioxide using sustainable renewable hydrogen and energy. We report here a synthetic protocol to the fixation of carbon dioxide by converting it directly into aviation jet fuel using novel, inexpensive iron-based catalysts. We prepare the Fe-Mn-K catalyst by the so-called Organic Combustion Method, and the catalyst shows a carbon dioxide conversion through hydrogenation to hydrocarbons in the aviation jet fuel range of 38.2%, with a yield of 17.2%, and a selectivity of 47.8%, and with an attendant low carbon monoxide (5.6%) and methane selectivity (10.4%). The conversion reaction also produces light olefins ethylene, propylene, and butenes, totalling a yield of 8.7%, which are important raw materials for the petrochemical industry and are presently also only obtained from fossil crude oil. As this carbon dioxide is extracted from air, and re-emitted from jet fuels when combusted in flight, the overall effect is a carbon-neutral fuel. This contrasts with jet fuels produced from hydrocarbon fossil sources where the combustion process unlocks the fossil carbon and places it into the atmosphere, in longevity, as aerial carbon - carbon dioxide.


Staphylococcus aureus sepsis and mitochondrial accrual of the 8-oxoguanine DNA glycosylase DNA repair enzyme in mice.
Damage to mitochondrial DNA (mtDNA) by the production of reactive oxygen species during inflammatory states, such as sepsis, is repaired by poorly understood mechanisms. To test the hypothesis that the DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), contributes to mtDNA repair in sepsis. Using a well-characterized mouse model of Staphylococcus aureus sepsis, we analyzed molecular markers for mitochondrial biogenesis and OGG1 translocation into liver mitochondria as well as OGG1 mRNA expression at 0, 24, 48, and 72 hours after infection. The effects of OGG1 RNA silencing on mtDNA content were determined in control, tumor necrosis factor-α, and peptidoglycan-exposed rat hepatoma cells. Based on in situ analysis of the OGG1 promoter region, chromatin immunoprecipitation assays were performed for nuclear respiratory factor (NRF)-1 and NRF-2α GA-binding protein (GABP) binding to the promoter of OGG1. Mice infected with 10(7) cfu S. aureus intraperitoneally demonstrated hepatic oxidative mtDNA damage and significantly lower hepatic mtDNA content as well as increased mitochondrial OGG1 protein and enzyme activity compared with control mice. The infection also caused increases in hepatic OGG1 transcript levels and NRF-1 and NRF-2α transcript and protein levels. A bioinformatics analysis of the Ogg1 gene locus identified several promoter sites containing NRF-1 and NRF-2α DNA binding motifs, and chromatin immunoprecipitation assays confirmed in situ binding of both transcription factors to the Ogg1 promoter within 24 hours of infection. These studies identify OGG1 as an early mitochondrial response protein during sepsis under regulation by the NRF-1 and NRF-2α transcription factors that regulate mitochondrial biogenesis.


A microRNA-based gene dysregulation pathway in Huntington's disease.
Huntington's disease (HD) is a dominantly-inherited neurodegenerative disorder which is incurable and ultimately fatal. HD is characterised by widespread mRNA dysregulation, particularly in neurons of the forebrain, by mechanisms which are not fully understood. Such dysregulation has been demonstrated to result, in part, from aberrant nuclear localisation of the transcriptional repressor, REST. Here, we show that expression of a number of neuronal-specific microRNAs is also dysregulated in HD tissues, probably as a result of increased repression by REST. This phenomenon is observed in both murine models of HD and in the brains of human HD sufferers. MicroRNA loss is reflected in increased levels of a number of target messenger RNAs. These data are the first to demonstrate a role for microRNAs in HD, and indicate that the molecular aetiology of HD is reflected in a loss of neuronal identity, caused in part by dysregulation of both transcriptional and post-transcriptional mechanisms.


Improved gfp and inaZ broad-host-range promoter-probe vectors.
A new set of broad-host-range promoter-probe vectors has been constructed. One subset contains the pVS1 and p15a replicons and confers resistance to either gentamicin or kanamycin. The other set contains the broad-host-range replicon from pBBR1 and confers resistance to kanamycin, tetracycline, ampicillin, or spectinomycin/streptomycin. Both plasmid sets are highly stable and are maintained without selection for more than 30 generations in several bacterial taxa. Each plasmid contains a promoter-probe cassette that consists of a multicloning site, containing several unique restriction sites, and gfp or inaZ as a reporter gene. The cassette is bound by transcriptional terminators to permit the insertion of strong promoters and to insulate the cassette from external transcription enabling the detection of weak or moderate promoters. The vector suite was augmented with derivatives of the kanamycin-resistant gfp promoter-probe plasmids that encode Gfp variants with different half-life times.


Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM.
Insulin resistance for glucose metabolism in skeletal muscle is a key feature in NIDDM. The quantitative role of the cellular effectors of glucose metabolism in determining this insulin resistance is still imperfectly known. We assessed transmembrane glucose transport and intracellular glucose phosphorylation in vivo in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin clamp studies in combination with the forearm balance technique (brachial artery and deep forearm vein catheterization) in five nonobese NIDDM patients and seven age- and weight-matched control subjects (study 1). D-Mannitol (a nontransportable molecule), 3-O-[14C]methyl-D-glucose (transportable, but not metabolizable) and D[3-3H]glucose (transportable and metabolizable) were simultaneously injected into the brachial artery, and the washout curves were measured in the deep venous effluent blood. In vivo rates of transmembrane transport and intracellular phosphorylation of D-glucose in forearm muscle were determined by analyzing the washout curves with the aid of a multicompartmental model of glucose kinetics in forearm tissues. At similar steady-state concentrations of plasma insulin (approximately 500 pmol/l) and glucose (approximately 5.0 mmol/l), the rates of transmembrane influx (34.3 +/- 9.1 vs. 58.5 +/- 6.5 micromol x min(-1) x kg(-1), P < 0.05) and intracellular phosphorylation (5.4 +/- 1.6 vs. 38.8 +/- 5.1 micromol x min(-1) x kg(-1), P < 0.01) in skeletal muscle were markedly lower in the NIDDM patients than in the control subjects. In the NIDDM patients (study 2), the insulin clamp was repeated at hyperglycemia, (approximately 13 mmol/l) trying to match the rates of transmembrane glucose influx measured during the clamp in the controls. The rate of transmembrane glucose influx (62 +/- 15 micromol x min(-1) x kg(-1)) in the NIDDM patients was similar to the control subjects, but the rate of intracellular glucose phosphorylation (16.6 +/- 7.5 micromol x min(-1) x kg(-1)), although threefold higher than in the patients during study 1 (P < 0.05), was still approximately 60% lower than in the control subjects (P < 0.05). These data suggest that when assessed in vivo, both transmembrane transport and intracellular phosphorylation of glucose are refractory to insulin action and add to each other in determining insulin resistance in skeletal muscle of NIDDM patients. It will be of interest to compare the present results with the in vivo quantitation of the initial rate of muscle glucose transport when methodology to perform this measurement becomes available.


Experience with a medicolegal decision-making system for occupational hearing loss-related tinnitus.
Owing to an increasing number of requests for compensation, a medicolegal decision-making system for tinnitus related to noise-induced hearing loss (NIHL) has been elaborated at the Federal Belgian Institute of Occupational Diseases. Experience with 113 patients, all of them claiming compensation for NIHL and tinnitus, is now available. The patients underwent an exhaustive audiological investigation, and their professional career and noise exposure were carefully and objectively documented. We reviewed the group of 35 "accepted" cases (i.e., with chronic tinnitus recognized as related to NIHL and financially compensated as an occupational disease) and analyzed the medicolegal arguments for acceptance or rejection. In these patients, tinnitus was mostly bilateral, was perceived on average at a frequency of 4 KHz and with a supraliminal intensity of 7.2 dB, and lasted on average for 7.3 years. To gain better insight into the relationship between cochlear damage and chronic tinnitus, we compared our group to a control group of 35 patients with similar hearing thresholds at 3 and 4 KHz but free of tinnitus. The main difference is a significantly steeper slope of the audiometric curve between 2 and 3 KHz in the tinnitus group. Furthermore, a notch in the distortion product-gram is noticed in 60% of the ears affected by tinnitus versus 9% of the ears in the control group. This abrupt discontinuity in the activity along the tonotopic axis of the auditory system-the main characteristic of NIHL-could be a factor eliciting tinnitus, as a correspondence between the audiometric notch and tinnitus frequency appears to exist.


Effect of bee venom on IL-6, COX-2 and VEGF levels in polycystic ovarian syndrome induced in Wistar rats by estradiol valerate.
Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenemia, hirsutism, chronic anovulation and vascular disorder. Interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are triggered by inflammatory stimuli and lead to angiogenesis and pathogenesis of the ovary. Honeybee venom (HBV) contains an array of biologically active components possessing various pharmaceutical properties. This study was designed to assess the possibility of HBV application as an anti-inflammatory therapeutic agent to suppress levels of the main inflammatory mediators IL-6, COX-2 and VEGF.To induce PCOS, 1 mg of estradiol valerate (EV) per 100 g of body weight was subcutaneously (SC) injected into eight-week-old rats. After 60 days, 0.5 mg/kg of HBV was administered Intraperitoneal (IP) for 14 consecutive days, and the results of PCOS treatment were investigated. Rats were then anesthetized with CO2, and the ovaries were surgically removed. Serum IL-6 was detected by the ELISA kit. Immunoexpression of COX-2 and VEGF were examined in three groups: EV-induced PCOS, HBV-treated PCOS and control animals. Thickness of theca layer, number and diameter of cysts and levels of IL-6 significantly decreased in HBV group relative to PCOS group. The immunohistochemical analysis showed an increase in COX-2 and VEGF expression in PCOS group whereas HBV-treated rats presented weak and irregular immunostaining. Our results suggest that the beneficial effect of HBV may be mediated through its inhibitory effect on serum IL-6 level and ovarian COX-2 and VEGF expression.


Terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome: a randomized, placebo controlled trial.
We evaluate terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome. The study included 100, 20 to-50-year-old subjects who met the consensus criteria for chronic prostatitis/chronic pelvic pain syndrome and had not received previous alpha-blockers. Subjects were randomized to receive terazosin with dose escalation from 1 to 5 mg. daily or placebo for 14 weeks. The primary criterion for response was scoring 2 or less ("delighted-to-mostly satisfied") on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) quality of life item. The secondary criterion for response was greater than 50% reduction in NIH-CPSI pain score at 14 weeks. Other outcomes included total and NIH-CPSI domain scores, International Prostate Symptom Score, peak urinary flow rate, post-void residual urine and adverse effects. Using the primary criterion 24 of 43 evaluable subjects (56%) responded in the terazosin group compared to 14 of 43 (36%) in the placebo group (p = 0.03). Using the secondary criterion 26 of 43 subjects (60%) responded in the terazosin group compared to 16 of 43 (37%) in the placebo group (p = 0.03). The terazosin group had greater reductions (p <0.05) in NIH-CPSI total score, individual domain scores and International Prostate Symptom Score than the placebo group. There was no difference in peak urinary flow rate or post-void residual. In the terazosin group 18 patients (42%) had side effects compared to 9 (21%) in the placebo group (p = 0.04). Terazosin proved superior to placebo for patients with chronic prostatitis/chronic pelvic pain syndrome who had not received alpha-blockers previously.


TRAP is necessary for gliding motility and infectivity of plasmodium sporozoites.
Many protozoans of the phylum Apicomplexa are invasive parasites that exhibit a substrate-dependent gliding motility. Plasmodium (malaria) sporozoites, the stage of the parasite that invades the salivary glands of the mosquito vector and the liver of the vertebrate host, express a surface protein called thrombospondin-related anonymous protein (TRAP) that has homologs in other Apicomplexa. By gene targeting in a rodent Plasmodium, we demonstrate that TRAP is critical for sporozoite infection of the mosquito salivary glands and the rat liver, and is essential for sporozoite gliding motility in vitro. This suggests that in Plasmodium sporozoites, and likely in other Apicomplexa, gliding locomotion and cell invasion have a common molecular basis.


A functional polymorphism of TIR-domain-containing adaptor protein is not associated with axial spondyloarthritis.
A genetic variant of the toll-like receptor (TLR)2/4 adaptor protein TIRAP (single nucleotide polymorphism (SNP) C539T) was identified in a UK and in several African populations. The heterozygous genotype of this SNP has been associated with protection from severe infections. This allele results in an attenuated response to bacterial pathogens. As an exaggerated innate immune response to pathogens has been implicated in spondyloarthritis (SpA) pathogenesis, we analysed if the heterozygous C/T genotype was underrepresented in axial SpA compared with healthy controls. 204 patients with axial SpA and 175 population-matched controls were included. SNP C539T was determined with a sequence-specific polymerase chain reaction and direct sequencing. The frequency of the haplotypes was similar in cases and controls (87% for C and 13% for T in both groups). The C/T genotype, which attenuates TLR signalling, was not underrepresented in cases versus controls (19% in controls vs 24% in cases, p = 0.44). The T/T genotype, was slightly lower in cases than in controls, although this was not significant (3.4% in controls vs 1% in cases, p = 0.15). Within the cases, there were no differences in disease phenotype or activity between patients with the C/C or C/T genotype. This study did not show significant associations of SNP S180L of the TLR2/4 adaptor protein TIRAP with axial SpA.


Predictive value of neutrophil to lymphocyte ratio in outcomes of patients with acute coronary syndrome.
Acute coronary syndrome (ACS) is associated with many hereditary and acquired predisposing factors. It has been recently shown that inflammation may play a role in myocardial ischemia. Hence, the white blood cell (WBC) count provides a simple and inexpensive method for assessment of inflammatory status in patients with ACS. An elevated WBC count has been associated with cardiovascular risk, but which leukocyte subtype carries this risk is uncertain. The aim of this study was to investigate the utility of admission neutrophil/lymphocyte ratio (NLR) in predicting the likelihood of poor outcomes in patients with ACS. A total of 300 consecutive patients admitted to the Internal Medicine Department, Sohar Hospital, Oman with the diagnosis of ACS from June 2008 to May 2009 were included in this study. Patients were divided into tertile groups according to the NLR. The primary end point was all-cause in-hospital mortality at the end of 30 days. The mean age of patients included in this cohort was 61 years, with 63% of male patients. The mortality in the three groups based on NLR was 4, 10 and 19%, in the low-, middle- and high-risk groups, respectively (p <0.003; χ² test). Admission NLR is clearly an independent predictor of all-cause mortality in patients with ACS.


My experiences with kidney care: A qualitative study of adults in the Northern Territory of Australia living with chronic kidney disease, dialysis and transplantation.
Australian healthcare quality and safety accreditation standards recommend health services partner with health care users, to ensure the highest quality of care. Aboriginal Australians with chronic and end stage kidney disease have high health care access needs. To describe the experiences of health care users of a large government kidney healthcare service provider. Within a government renal health service in the Top-End of the Northern Territory, we undertook a qualitative study involving in-depth interviews with 26 adult clients from urban, regional and remote settings who were living with kidney health conditions. Client characteristics included a mean age of 55 years, 55% female and 81% identifying as Aboriginal. The kidney related conditions of client participants included CKD (11, 42.3%), haemodialysis (12, 46.2%), peritoneal dialysis (1, 3.9%), and transplant (2, 7.7%). Key themes emerging from patient interviews related to perceived gaps for clients and carers including: 1) knowledge gaps about the health condition, 2) the impact of relocation in order to access centrally-based renal care, 3) healthcare staff professionalism and qualities and 4) service environments. Overall, the experiences centred on a greater need for client-centred, respectful and culturally based healthcare support. Clients recommended the need for patient-led collective care, including sustaining an Indigenous Patient Reference Group to support ongoing healthcare service decision processes. Participants included in almost equal proportion, clients with CKD (without dialysis) and clients utilising renal replacement therapy, which adds significant weight to the client-identified recommendations for highest quality of kidney care across a wide spectrum of kidney function. Four major themes identified by clients related to their experience with renal care provided by this major regional health care provider: knowledge gaps of their own condition, the lived impacts of relocating to access health care, service environments, and Health Care Provider Quality. An Indigenous Patient Reference Group was one mechanism recommended to support the co-design of preferred care models.


Modification of digesta pH and intestinal morphology with the use of benzoic acid or phytobiotics and the effects on broiler chicken growth performance and energy and nutrient utilization.
Two experiments, each consisting of 2 trials, were conducted to investigate the effect of feeding benzoic acid (BA) and turmeric meal (TM) individually or in combination (Exp. 1) or garlic meal (GM) and TM individually or in combination (Exp. 2) on growth performance, digesta pH, gut morphology, and nutrient utilization in broiler chickens. Diets consisted of a nutrient-adequate control diet and the control diet with added BA (2 g/kg), TM (10 g/kg), BA (1 g/kg) plus TM (5 g/kg), and BA (2 g/kg) plus TM (10 g/kg) in Exp. 1. In Exp. 2, in addition to the same control diet as Exp. 1, the control diet with added GM (10 g/kg), TM (10 g/kg), GM plus TM at 5 g/kg each, and GM plus TM at 10 g/kg each were used. Each treatment had 6 replicate floor pens with 10 chickens per replicate. On d 14, 5 broiler chickens from each floor pen were transferred to metabolism cages and continued on their respective diets. Body weight and feed intake data were collected on d 0 and 21, excreta were collected from chickens in metabolism cages on d 19 and 20, and ileal digesta were collected on d 21. Digesta pH was measured at the crop, proventriculus, jejunum, and cecum. Jejunum sections were collected from chickens in Exp. 1 to study gut morphology. In Exp. 1, only the combination of BA and TM tended (P < 0.10) to improve weight gain but there were no effects on G:F. The combination of BA and TM at both inclusion rates decreased (P < 0.05) digesta pH in the crop, jenunum, and ceca. There were no treatment effects on ileal DM or total tract DM retention, but supplementation of BA or TM alone or in combination increased (P < 0.01) apparent ME (AME) and nitrogen-corrected AME (AMEn) relative to the control diet. In Exp. 2, TM alone or combined with GM improved (P < 0.05) weight gain and G:F compared to the control. Supplementation of TM alone or in combination with GM at the rate of 10 g/kg each reduced (P < 0.05) digesta pH in the crop, proventriculus, and ceca but had no effect at the jejunum. The combination of GM and TM improved (P < 0.01) ileal DE, AME, and AMEn. In conclusion, BA, TM, and GM individually or in combination with wheat-soybean meal based diets adequate in nutrients and energy selectively improved growth performance, modified digesta pH and intestinal growth, and increased the efficiency of dietary energy use.


A kinome RNAi screen identified AMPK as promoting poxvirus entry through the control of actin dynamics.
Poxviruses include medically important human pathogens, yet little is known about the specific cellular factors essential for their replication. To identify genes essential for poxvirus infection, we used high-throughput RNA interference to screen the Drosophila kinome for factors required for vaccinia infection. We identified seven genes including the three subunits of AMPK as promoting vaccinia infection. AMPK not only facilitated infection in insect cells, but also in mammalian cells. Moreover, we found that AMPK is required for macropinocytosis, a major endocytic entry pathway for vaccinia. Furthermore, we show that AMPK contributes to other virus-independent actin-dependent processes including lamellipodia formation and wound healing, independent of the known AMPK activators LKB1 and CaMKK. Therefore, AMPK plays a highly conserved role in poxvirus infection and actin dynamics independent of its role as an energy regulator.


Inconsistency in level of care assignment decisions in skilled nursing facilities.
In Arizona, a non-Medicaid state, we investigated the extent to which unregulated level of care assignments in Skilled Nursing Facilities consistently reflect level and nature of patient impairment. Using Multiple Discriminant Analysis (MDA) to develop optimal prediction functions, approximately 70 per cent of patients could be correctly classified. Factors identified by MDA as discriminating among patients at different levels of care are an Activities of Daily Living (ADL) impairment factor, and a factor defined by confusion, transitory contact with the social environment, and propensity to wander. Results are compared with those of studies using MDA to replicate Multidisciplinary Review Team (MRT) or other expert level of care assignments intended to develop patient classification functions for clinical use. MRT assignments appear to reflect patient impairment characteristics only slightly better than do unregulated institutional assignments, suggesting that such utilization review efforts may result in minimal net gains in appropriateness of placement.


Direct measurement of perchlorate exposure biomarkers in a highly exposed population: a pilot study.
Exposure to perchlorate is ubiquitous in the United States and has been found to be widespread in food and drinking water. People living in the lower Colorado River region may have perchlorate exposure because of perchlorate in ground water and locally-grown produce. Relatively high doses of perchlorate can inhibit iodine uptake and impair thyroid function, and thus could impair neurological development in utero. We examined human exposures to perchlorate in the Imperial Valley among individuals consuming locally grown produce and compared perchlorate exposure doses to state and federal reference doses. We collected 24-hour urine specimen from a convenience sample of 31 individuals and measured urinary excretion rates of perchlorate, thiocyanate, nitrate, and iodide. In addition, drinking water and local produce were also sampled for perchlorate. All but two of the water samples tested negative for perchlorate. Perchlorate levels in 79 produce samples ranged from non-detect to 1816 ppb. Estimated perchlorate doses ranged from 0.02 to 0.51 µg/kg of body weight/day. Perchlorate dose increased with the number of servings of dairy products consumed and with estimated perchlorate levels in produce consumed. The geometric mean perchlorate dose was 70% higher than for the NHANES reference population. Our sample of 31 Imperial Valley residents had higher perchlorate dose levels compared with national reference ranges. Although none of our exposure estimates exceeded the U. S. EPA reference dose, three participants exceeded the acceptable daily dose as defined by bench mark dose methods used by the California Office of Environmental Health Hazard Assessment.


Breast cancer risk reduction--is it feasible to initiate a randomised controlled trial of a lifestyle intervention programme (ActWell) within a national breast screening programme?
Breast cancer is the most commonly diagnosed cancer and the second cause of cancer deaths amongst women in the UK. The incidence of the disease is increasing and is highest in women from least deprived areas. It is estimated that around 42% of the disease in post-menopausal women could be prevented by increased physical activity and reductions in alcohol intake and body fatness. Breast cancer control endeavours focus on national screening programmes but these do not include communications or interventions for risk reduction. This study aimed to assess the feasibility of delivery, indicative effects and acceptability of a lifestyle intervention programme initiated within the NHS Scottish Breast Screening Programme (NHSSBSP). A 1:1 randomised controlled trial (RCT) of the 3 month ActWell programme (focussing on body weight, physical activity and alcohol) versus usual care conducted in two NHSSBSP sites between June 2013 and January 2014. Feasibility assessments included recruitment, retention, and fidelity to protocol. Indicative outcomes were measured at baseline and 3 month follow-up (body weight, waist circumference, eating and alcohol habits and physical activity). At study end, a questionnaire assessed participant satisfaction and qualitative interviews elicited women's, coaches, and radiographers' experiences. Statistical analysis used Chi squared tests for comparisons in proportions and paired t tests for comparisons of means. Linear regression analyses were performed, adjusted for baseline values, with group allocation as a fixed effect. A pre-set recruitment target of 80 women was achieved within 12 weeks and 65 (81%) participants (29 intervention, 36 control) completed 3 month assessments. Mean age was 58 ± 5.6 years, mean BMI was 29.2 ± 7.0 kg/m(2) and many (44%) reported a family history of breast cancer. The primary analysis (baseline body weight adjusted) showed a significant between group difference favouring the intervention group of 2.04 kg (95% CI -3.24 kg to -0.85 kg). Significant, favourable between group differences were also detected for BMI, waist circumference, physical activity and sitting time. Women rated the programme highly and 70% said they would recommend it to others. Recruitment, retention, indicative results and participant acceptability support the development of a definitive RCT to measure long term effects. The trial was registered with Current Controlled Trials (ISRCTN56223933).


Molecular mechanisms of action of naringenin in chronic airway diseases.
Chronic airway inflammatory diseases are characterized by persistent proinflammatory responses in the respiratory tract. Although, several treatment strategies are currently available, lifelong therapy is necessary for most of these diseases. In recent years, phytophenols, namely, flavonoids, derived from fruits and vegetables have been gaining tremendous interest and have been extensively studied due to their low toxicological profile. Naringenin is a bioflavonoid abundantly found in citrus fruits. This substance has shown notable therapeutic potential in various diseases due to its promising diverse biological activities. In this review, we have attempted to review the published studies from the available literature, discussing the molecular level mechanisms of naringenin in different experimental models of airway inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis and cystic fibrosis. Current evidences have proposed that the anti-inflammatory properties of naringenin play a major role in ameliorating inflammatory disease states. In addition, naringenin also possesses several other biological properties. Despite the proposed mechanisms suggesting remarkable therapeutic benefits, the clinical use of naringenin is, however, hampered by its low solubility and bioavailability. Furthermore, this review also discusses on the studies that utilise nanocarriers as a drug delivery system to address the issue of poor solubility.


Overlapping effects of age on associative memory and the anterior hippocampus from middle to older age.
The anterior hippocampus has been implicated in associative memory, and along with hippocampal volume, this type of memory declines with age. However, few cross-sectional studies include middle-aged samples, making it unclear at what point these age-related changes occur. In addition, although men and women have been shown to differ in associative memory and rates of age-related hippocampal atrophy, sex-differences in aging are rarely studied. To address these issues, we assessed memory for word-pairs, hippocampal volume and activation during encoding and retrieval, across middle-aged (n=39) and older (n=44) participants, specifically in relation to sex. Older adults showed significantly poorer associative memory compared to middle-aged adults, paralleled by smaller anterior hippocampi and less activation during successful retrieval. The age-by-sex interaction observed in memory performance was also mirrored in the volume and activation of the hippocampus, indicating more pronounced age-effects in men as compared to women. These results indicate a specific role of the anterior hippocampus in verbal associative memory and suggest they both decline between middle-age and older age.


The sequences of the coenzyme-binding peptide in the cytoplasmic and the mitochondrial aspartate aminotransferases from sheep liver.
The sequences of the coenzyme-binding peptide of both cytoplasmic and mitochondrial aspartate aminotransferases from sheep liver were determined. The holoenzymes were treated with NaBH4 and digested with chymotrypsin; peptides containing bound pyridoxal phosphate were then isolated. One phosphopyridoxyl peptide was obtained from sheep liver cytoplasmic aspartate aminotransferase. Its sequence was Ser-Ne-(phosphopyridoxyl)-Lys-Asn-Phe. This sequence is identical with that reported for the homologous peptide from pig heart cytoplasmic aspartate aminotransferase. Two phosphopyridoxyl peptides with different RF values were isolated from the sheep liver mitochondrial isoenzyme. They had the same N-terminal amino acid and similar amino acid composition. The mitochondrial phosphopyridoxyl peptide of highest yield and purity had the sequence Ala-Ne-(phosphopyridoxyl)-Lys-Asx-Met-Gly-Leu-Tyr. The sequence of the first four amino acids is identical with that already reported for the phosphopyridoxyl tetrapeptide from the pig heart mitochondrial isoenzyme. The heptapeptide found for the sheep liver mitochondrial isoenzyme closely resembles the corresponding sequence taken from the primary structure of the pig heart cytoplasmic aspartate aminotransferase.


Red fox and tick-borne encephalitis (TBE) in humans: can predators influence public health?
Analysing datasets from hunting statistics and human cases of tick-borne encephalitis (TBE), we found a positive correlation between the number of human TBE cases and the number of red fox (Vulpes vulpes). Time lags were also present, indicating that high numbers of red fox in 1 y translated into high numbers of human TBE cases the following y. Results for smaller predators were mixed and inconsistent. Hares and grouse showed negative correlations with human TBE cases, suggesting that they might function as dilution hosts. Combining our findings with food web dynamics, we hypothesize a diversity of possible interactions between predators and human disease - some predators suppressing a given disease, others enhancing its spread, and still others having no effect at all. Larger-sized predators that suppress red fox numbers and activity (i.e. wolf, Canis lupus; European lynx, Lynx lynx) were once abundant in our study area but have been reduced or extirpated from most parts of it by humans. We ask what would happen to red foxes and TBE rates in humans if these larger predators were restored to their former abundances.


Primary explant culture and collagen I substrate enhances corneal endothelial cell morphology.
Corneal endothelial cell (CEC) isolation and harvest aim to produce engineered grafts to solve donor corneal tissue shortage. To yield high amounts of CEC maintaining morphological and molecular characteristics, several isolation and culture conditions are reported. Here, we combined direct explant culture, with three different coating conditions and a two-step media approach to compare confluence efficiency, morphology, and specific molecular markers expression. Confluence was reached after 2 weeks in the three coating conditions (Matrigel, collagen I, and in uncoated plates) using a two-step approach (proliferative medium without pituitary extract, followed by stabilizer basal medium). Na/K-ATPase and GPC4 markers were detected by immunocytochemistry while GPC4, CD200, and TJP1 by RT-PCR in the three CEC coating culture conditions. CEC in proliferative medium showed spindle morphology in the three conditions. Polygonal morphology was seen in CEC cultures using basal medium under uncoated and collagen I coated plates. CEC cultured in Matrigel-coated plates remained with spindle morphology in basal medium.


Identification of Shared and Unique Serum Lipid Profiles in Diabetes Mellitus and Myocardial Infarction.
Diabetes mellitus (DM) and cardiovascular disease are associated with dyslipidemia, but the detailed lipid molecular pattern in both diseases remains unknown. We used shotgun mass spectrometry to determine serum levels of 255 molecular lipids in 316 controls, 171 DM, and 99 myocardial infarction (MI) events from a cohort derived from the Malmö Diet and Cancer study. Orthogonal projections to latent structures analyses were conducted between the lipids and clinical parameters describing DM or MI. Fatty acid desaturases (FADS) and elongation of very long chain fatty acid protein 5 (ELOVL5) activities were estimated by calculating product to precursor ratios of polyunsaturated fatty acids in complex lipids. FADS genotypes encoding these desaturases were then tested for association with lipid levels and ratios. Differences in the levels of lipids belonging to the phosphatidylcholine and triacylglyceride (TAG) classes contributed the most to separating DM from controls. TAGs also played a dominating role in discriminating MI from controls. Levels of C18:2 fatty acids in complex lipids were lower both in DM and MI versus controls (DM, P=0.004; MI, P=6.0E-06) at least due to an acceleration in the metabolic flux from C18:2 to C20:4 (eg, increased estimated ELOVL5: DM, P=0.02; MI, P=0.04, and combined elongase-desaturase activities: DM, P=3.0E-06; MI, P=2.0E-06). Minor allele carriers of FADS genotypes were associated with increased levels of C18:2 (P≤0.007) and lower desaturase activity (P≤0.002). We demonstrate a possible relationship between decreased levels of C18:2 in complex lipids and DM or MI. We thereby highlight the importance of molecular lipids in the pathogenesis of both diseases.


Molecularly imprinted polymers for ochratoxin a extraction and analysis.
Molecularly imprinted polymers (MIPs) are considered as polymeric materials that mimic the functionality of antibodies. MIPs have been utilized for a wide variety of applications in chromatography, solid phase extraction, immunoassays, and sensor recognition. In this article, recent advances of MIPs for the extraction and analysis of ochratoxins are discussed. Selection of functional monomers to bind ochratoxin A (OTA) with high affinities, optimization of extraction procedures, and limitations of MIPs are compared from different reports. The most relevant examples in the literature are described to clearly show how useful these materials are. Strategies on MIP preparation and schemes of analytical methods are also reviewed in order to suggest the next step that would make better use of MIPs in the field of ochratoxin research. The review ends by outlining the remaining issues and impediments.


Safety of symptom-limited cardiopulmonary exercise testing in patients with chronic heart failure due to severe left ventricular systolic dysfunction.
To assess the safety of symptom-limited exercise testing in patients with New York Heart Association class II-IV heart failure symptoms due to left ventricular systolic dysfunction, we investigated the frequency of all-cause fatal and nonfatal major cardiovascular (CV) events among subjects enrolled in a prospective clinical trial (HF-ACTION). We hypothesized that exercise testing would be safe, as defined by a rate for all-cause death of <0.1 per 1,000 tests and a rate of nonfatal CV events <1.0 per 1,000 tests. Before enrollment and at 3, 12, and 24 months after randomization, subjects were scheduled to complete a symptom-limited graded exercise test with open-circuit spirometry for analysis of expired gases. To ensure the accurate reporting of exercise test-related events, we report deaths and nonfatal major CV events per 1,000 tests at months 3, 12, or 24 after randomization. A total of 2,331 subjects were randomized into HF-ACTION. After randomization, 2,037 subjects completed 4,411 exercise tests. There were no test-related deaths, exacerbation of heart failure or angina requiring hospitalization, myocardial infarctions, strokes, or transient ischemic attacks. There was one episode each of ventricular fibrillation and sustained ventricular tachycardia. There were no exercise test-related implantable cardioverter defibrillator discharges requiring hospitalization. These findings correspond to zero deaths per 1,000 exercise tests and 0.45 nonfatal major CV events per 1,000 exercise tests (95% CI 0.11-1.81). In New York Heart Association class II-IV patients with severe left ventricular systolic dysfunction, we observed that symptom-limited exercise testing is safe based on no deaths and a rate of nonfatal major CV events that is <0.5 per 1,000 tests.


[Identification of the corn mosaic virus, a rhabdovirus, in Costa Rica].
Maize mosaic virus (MMV), a rhabdovirus, was identified associated to maize field plants, showing stunting and continuous chlorotic stripes uniformly distributed over the leaf blade. The virus was detected in field samples by agar-gel immunodifussion. Enveloped, bacilliform virus particles were observed by electron microscopy in thin sections of naturally infected leaf tissue.


Training and muscle ammonia and amino acid metabolism in humans during prolonged exercise.
We studied the responses of NH3 and amino acids (AA) to prolonged exercise (3 h) in trained (Tr; n = 6) and untrained (Utr; n = 6) men. Each subject exercised the knee extensor muscles of one leg at 60% of maximum capacity. Thigh blood flow and femoral arteriovenous differences (0, 30, 60, 120, 150, and 180 min) as well as muscle biopsies (0, 120, and 180 min) were taken for NH3 and AA measurements. In both groups, muscle Glu decreased (P < 0.05) and Asp increased (P < 0.05), but the intramuscular AA pool, including the essential AA, remained constant despite a total AA efflux of 22.4 +/- 8.3 and 24.4 +/- 6.8 mmol/kg wet wt in Tr and Utr, respectively. Tr had greater (P < 0.05) muscle Tau, Phe, Ala, and Glu. Both groups had a large Glu uptake and effluxes of NH3, Gln, and Ala as well as essential AA. The latter implies that there was a net protein catabolism. The efflux of NH3 and Gln was much greater than that expected from AMP deamination, suggesting that deamination of AA was occurring. Many of the AA responses use Glu, and Tr maintained the intramuscular Glu pool at a higher concentration (P < 0.05), implying that they derived more Glu from protein catabolism and/or AA transaminations. Under these conditions, prolonged dynamic knee extensor exercise is associated with a large release of alpha-amino moieties both as NH3 and as Gln as well as a net protein catabolism; these responses are similar in Tr and Utr.


Real-Time PCR Assay for Detection and Differentiation of Shiga Toxin-Producing Escherichia coli from Clinical Samples.
Timely accurate diagnosis of Shiga toxin-producing Escherichia coli (STEC) infections is important. We evaluated a laboratory-developed real-time PCR (LD-PCR) assay targeting stx1, stx2, and rfbEO157 with 2,386 qualifying stool samples submitted to the microbiology laboratory of a tertiary care pediatric center between July 2011 and December 2013. Broth cultures of PCR-positive samples were tested for Shiga toxins by enzyme immunoassay (EIA) (ImmunoCard STAT! enterohemorrhagic E. coli [EHEC]; Meridian Bioscience) and cultured in attempts to recover both O157 and non-O157 STEC. E. coli O157 and non-O157 STEC were detected in 35 and 18 cases, respectively. Hemolytic uremic syndrome (HUS) occurred in 12 patients (10 infected with STEC O157, one infected with STEC O125ac, and one with PCR evidence of STEC but no resulting isolate). Among the 59 PCR-positive STEC specimens from 53 patients, only 29 (54.7%) of the associated specimens were toxin positive by EIA. LD-PCR differentiated STEC O157 from non-O157 using rfbEO157, and LD-PCR results prompted successful recovery of E. coli O157 (n = 25) and non-O157 STEC (n = 8) isolates, although the primary cultures and toxin assays were frequently negative. A rapid "mega"-multiplex PCR (FilmArray gastrointestinal panel; BioFire Diagnostics) was used retrospectively, and results correlated with LD-PCR findings in 25 (89%) of the 28 sorbitol-MacConkey agar culture-negative STEC cases. These findings demonstrate that PCR is more sensitive than EIA and/or culture and distinguishes between O157 and non-O157 STEC in clinical samples and that E. coli O157:H7 remains the predominant cause of HUS in our institution. PCR is highly recommended for rapid diagnosis of pediatric STEC infections.


A mitotic kinesin-6, Pav-KLP, mediates interdependent cortical reorganization and spindle dynamics in Drosophila embryos.
We investigated the role of Pav-KLP, a kinesin-6, in the coordination of spindle and cortical dynamics during mitosis in Drosophila embryos. In vitro, Pav-KLP behaves as a dimer. In vivo, it localizes to mitotic spindles and furrows. Inhibition of Pav-KLP causes defects in both spindle dynamics and furrow ingression, as well as causing changes in the distribution of actin and vesicles. Thus, Pav-KLP stabilizes the spindle by crosslinking interpolar microtubule bundles and contributes to actin furrow formation possibly by transporting membrane vesicles, actin and/or actin regulatory molecules along astral microtubules. Modeling suggests that furrow ingression during cellularization depends on: (1) a Pav-KLP-dependent force driving an initial slow stage of ingression; and (2) the subsequent Pav-KLP-driven transport of actin- and membrane-containing vesicles to the furrow during a fast stage of ingression. We hypothesize that Pav-KLP is a multifunctional mitotic motor that contributes both to bundling of interpolar microtubules, thus stabilizing the spindle, and to a biphasic mechanism of furrow ingression by pulling down the furrow and transporting vesicles that deliver new material to the descending furrow.


Tubulin bond energies and microtubule biomechanics determined from nanoindentation in silico.
Microtubules, the primary components of the chromosome segregation machinery, are stabilized by longitudinal and lateral noncovalent bonds between the tubulin subunits. However, the thermodynamics of these bonds and the microtubule physicochemical properties are poorly understood. Here, we explore the biomechanics of microtubule polymers using multiscale computational modeling and nanoindentations in silico of a contiguous microtubule fragment. A close match between the simulated and experimental force-deformation spectra enabled us to correlate the microtubule biomechanics with dynamic structural transitions at the nanoscale. Our mechanical testing revealed that the compressed MT behaves as a system of rigid elements interconnected through a network of lateral and longitudinal elastic bonds. The initial regime of continuous elastic deformation of the microtubule is followed by the transition regime, during which the microtubule lattice undergoes discrete structural changes, which include first the reversible dissociation of lateral bonds followed by irreversible dissociation of the longitudinal bonds. We have determined the free energies of dissociation of the lateral (6.9 ± 0.4 kcal/mol) and longitudinal (14.9 ± 1.5 kcal/mol) tubulin-tubulin bonds. These values in conjunction with the large flexural rigidity of tubulin protofilaments obtained (18,000-26,000 pN·nm(2)) support the idea that the disassembling microtubule is capable of generating a large mechanical force to move chromosomes during cell division. Our computational modeling offers a comprehensive quantitative platform to link molecular tubulin characteristics with the physiological behavior of microtubules. The developed in silico nanoindentation method provides a powerful tool for the exploration of biomechanical properties of other cytoskeletal and multiprotein assemblies.


Study protocol--diabetes and related conditions in urban indigenous people in the Darwin, Australia region: aims, methods and participation in the DRUID Study.
Diabetes mellitus is a serious and increasing health problem in Australia and is a designated national health priority. Diabetes and related conditions represent an even greater health burden among Indigenous Australians (Aborigines and Torres Strait Islanders), but there are critical gaps in knowledge relating to the incidence and prevalence, aetiology, and prevention of diabetes in this group, including a lack of information on the burden of disease among Indigenous people in urban areas. The DRUID Study (Diabetes and Related conditions in Urban Indigenous people in the Darwin region) was designed to address this knowledge gap. The study was conducted in a specified geographic area in and around Darwin, Australia. Eligible participants underwent a health examination, including collection of blood and urine samples, clinical and anthropometric measurements, and administration of questionnaires, with an additional assessment for people with diabetes. The study was designed to incorporate local Indigenous leadership, facilitate community engagement, and provide employment and training opportunities for local Indigenous people. A variety of recruitment methods were used. A total of 1,004 eligible people gave consent and provided at least one measurement. When compared with census data for the Indigenous population living in the study area, there was a marked under-representation of males, but no substantial differences in age, place of residence, Indigenous group, or household income. Early participants were more likely than later participants to have previously diagnosed diabetes. Despite lower than anticipated recruitment, this is, to our knowledge, the largest study ever conducted on the health of Indigenous Australians living in urban areas, a group which comprises the majority of Australia's Indigenous population but about whose health and wellbeing relatively little is known. The study is well-placed to provide new information that can be used by policy makers and service providers to improve the delivery of services and programs that affect the health of Indigenous people. It also represents a valuable opportunity to establish an urban Indigenous cohort study, provided participants can be followed successfully over time.


Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver.
CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.


Preoperative planning of airway management in critical care patients.
The aim of this article is to review aspects of airway evaluation that may affect the care of the critical care patient whose airway is to be managed. This information must then be incorporated into the decision-making process of the "airway manager." Literature review. Historically used indexes of airway evaluation suffer from low sensitivity and only modest specificity in identifying the difficult-to-intubate patient. Using each index in isolation of others contributes to their poor predictive power. An understanding of anatomical relationships that these indexes measure should help the clinician in evaluating the airway. The clinician's impression of the airway, as well as the likelihood of trouble with supraglottic ventilation, the patient's inability to take food orally, and the patient's general condition can be used to formulate a management plan. This plan should be consistent with the American Society of Anesthesiologist's difficult airway algorithm. Rote decision making on airway management, based on commonly used indexes, is not adequate. The vital role of airway in anesthetic management of the critical care patient demands thoughtful consideration. Patient conditions including the need for airway control, the likelihood of difficult laryngoscopy or supraglottic ventilation, the patient's inability to take food orally, and the medical state of the patient must be incorporated.


Canine echinococcosis: genetic diversity of Echinococcus granulosus sensu stricto (s.s.) from definitive hosts.
Canids, particularly dogs, constitute the major source of cystic echinococcosis (CE) infection to humans, with the majority of cases being caused by Echinococcus granulosus (G1 genotype). Canine echinococcosis is an asymptomatic disease caused by adult tapeworms of E. granulosus sensu lato (s.l.). Information on the population structure and genetic variation of adult E. granulosus is limited. Using sequenced data of the mitochondrial cytochrome c oxidase subunit 1 (cox1) we examined the genetic diversity and population structure of adult tapeworms of E. granulosus (G1 genotype) from canid definitive hosts originating from various geographical regions and compared it to that reported for the larval metacestode stage from sheep and human hosts. Echinococcus granulosus (s.s) was identified from adult tapeworm isolates from Kenya, Libya, Tunisia, Australia, China, Kazakhstan, United Kingdom and Peru, including the first known molecular confirmation from Gaza and the Falkland Islands. Haplotype analysis showed a star-shaped network with a centrally positioned common haplotype previously described for the metacestode stage from sheep and humans, and the neutrality indices indicated population expansion. Low Fst values suggested that populations of adult E. granulosus were not genetically differentiated. Haplotype and nucleotide diversities for E. granulosus isolates from sheep and human origin were twice as high as those reported from canid hosts. This may be related to self-fertilization of E. granulosus and/or to the longevity of the parasite in the respective intermediate and definitive hosts. Improved nuclear single loci are required to investigate the discrepancies in genetic variation seen in this study.


Treatment of obesity.
For primary care physicians, obesity is one of the most challenging problems confronted in office practice. The disorder is Increasing in prevalence despite the efforts of both patients and physicians. Treatment requires a multimodality approach that addresses diet, physical activity, and behavioral issues. Medication and surgical approaches may be appropriate as well. This review outlines the evidence for each approach, suggests how primary care physicians can best help obese patients, and provides practical tips for weight loss.


Experience and choice shape expected aversive outcomes.
The value assigned to aversive events is susceptible to contextual influences. Here, we asked whether a change in the valuation of negative events is reflected in an altered neuronal representation of their expected aversive outcome. We show that experiencing an aversive event in the past, and choosing to experience it in the future, reduces its aversive value. This psychological change is mirrored in an altered neural representation of aversive value in the caudate nucleus and anterior cingulate cortex. Our findings indicate that subcortical regions known to track expected value such as the caudate nucleus, together with anterior cingulate cortical regions implicated in emotional modulation, mediate a revaluation in expectancies of aversive states. The results provide a striking example of a contextual sensitivity in how the brain ascribes value to events, in a manner that may foster resilience in the face of adversity.


Three-dimensional chiral photonic superlattices.
We investigate three-dimensional photonic superlattices composed of polymeric helices in various spatial checkerboard-like arrangements. Depending on the relative phase shift and handedness of the chiral building blocks, different circular-dichroism resonances appear or are suppressed. Samples corresponding to four different configurations are fabricated by direct laser writing. The measured optical transmittance spectra are in good agreement with numerical calculations.


Slow cycling of unphosphorylated myosin is inhibited by calponin, thus keeping smooth muscle relaxed.
A key unanswered question in smooth muscle biology is whether phosphorylation of the myosin regulatory light chain (RLC) is sufficient for regulation of contraction, or if thin-filament-based regulatory systems also contribute to this process. To address this issue, the endogenous RLC was extracted from single smooth muscle cells and replaced with either a thiophosphorylated RLC or a mutant RLC (T18A/S19A) that cannot be phosphorylated by myosin light chain kinase. The actin-binding protein calponin was also extracted. Following photolysis of caged ATP, cells without calponin that contained a nonphosphorylatable RLC shortened at 30% of the velocity and produced 65% of the isometric force of cells reconstituted with the thiophosphorylated RLC. The contraction of cells reconstituted with nonphosphorylatable RLC was, however, specifically suppressed in cells that contained calponin. These results indicate that calponin is required to maintain cells in a relaxed state, and that in the absence of this inhibition, dephosphorylated cross-bridges can slowly cycle and generate force. These findings thus provide a possible framework for understanding the development of latch contraction, a widely studied but poorly understood feature of smooth muscle.


Low-molecular-weight heparin in the treatment of patients with venous thromboembolism.
Low-molecular-weight heparin is known to be safe and effective for the initial treatment of patients with proximal deep-vein thrombosis. However, its application to pulmonary embolism or previous episodes of thromboembolism has not been studied. We randomly assigned 1021 patients with symptomatic venous thromboembolism to fixed-dose, subcutaneous low-molecular-weight heparin (reviparin sodium) or adjusted-dose, intravenous unfractionated heparin. Oral anticoagulant therapy with a coumarin derivative was started concomitantly and continued for 12 weeks. Approximately one third of the patients had associated pulmonary embolism. The outcome events studied over the 12 weeks were symptomatic recurrent venous thromboembolism, major bleeding, and death. We sought to determine whether low-molecular-weight heparin is at least equivalent to unfractionated heparin in patients with venous thromboembolism. Twenty-seven of the 510 patients assigned to low-molecular-weight heparin (5.3 percent) had recurrent thromboembolic events, as compared with 25 of the 511 patients assigned to unfractionated heparin (4.9 percent). The difference of 0.4 percentage point indicates that the two therapies have equivalent value according to our predetermined definition of equivalence. Sixteen patients assigned to low-molecular-weight heparin (3.1 percent) and 12 patients assigned to unfractionated heparin (2.3 percent) had episodes of major bleeding (P= 0.63), and the mortality rates in the two groups were 7.1 percent and 7.6 percent, respectively (P=0.89). Fixed-dose, subcutaneous low-molecular-weight heparin is as effective and safe as adjusted-dose, intravenous unfractionated heparin for the initial management of venous thromboembolism, regardless of whether the patient has pulmonary embolism or a history of venous thromboembolism.


Preterm or not--an evaluation of estimates of gestational age in a cohort of women from Rural Papua New Guinea.
Knowledge of accurate gestational age is required for comprehensive pregnancy care and is an essential component of research evaluating causes of preterm birth. In industrialised countries gestational age is determined with the help of fetal biometry in early pregnancy. Lack of ultrasound and late presentation to antenatal clinic limits this practice in low-resource settings. Instead, clinical estimators of gestational age are used, but their accuracy remains a matter of debate. In a cohort of 688 singleton pregnancies from rural Papua New Guinea, delivery gestational age was calculated from Ballard score, last menstrual period, symphysis-pubis fundal height at first visit and quickening as well as mid- and late pregnancy fetal biometry. Published models using sequential fundal height measurements and corrected last menstrual period to estimate gestational age were also tested. Novel linear models that combined clinical measurements for gestational age estimation were developed. Predictions were compared with the reference early pregnancy ultrasound (<25 gestational weeks) using correlation, regression and Bland-Altman analyses and ranked for their capability to predict preterm birth using the harmonic mean of recall and precision (F-measure). Average bias between reference ultrasound and clinical methods ranged from 0-11 days (95% confidence levels: 14-42 days). Preterm birth was best predicted by mid-pregnancy ultrasound (F-measure: 0.72), and neuromuscular Ballard score provided the least reliable preterm birth prediction (F-measure: 0.17). The best clinical methods to predict gestational age and preterm birth were last menstrual period and fundal height (F-measures 0.35). A linear model combining both measures improved prediction of preterm birth (F-measure: 0.58). Estimation of gestational age without ultrasound is prone to significant error. In the absence of ultrasound facilities, last menstrual period and fundal height are among the more reliable clinical measures. This study underlines the importance of strengthening ultrasound facilities and developing novel ways to estimate gestational age.


Shared decision-making based on different features of risk in the context of diabetes mellitus and rheumatoid arthritis.
There is an increased awareness about patients' involvement in the clinical decision process where uncertainty is an unavoidable condition. The impact of psychological factors like risk aversion, risk aversion and time, asymmetry in risk aversion, and risk and control on shared decision-making is discussed. In addition to differences in risk estimates, doctors and patients may exhibit a difference in perception of time perspectives, and losses versus gains.A summary of valuation factors in shared decision-making is presented: (a) the doctors tend to follow expected value combinations more closely, while the patient is more risk aversive; (b) unwillingness to take risks increases for rare outcomes; (c) there is an increased tendency to take risks with delayed outcomes of the decisions; (d) the doctor is generally well informed about risk and time aspects for different diseases, whereas this might not always be the case with the patient; (e) rheumatoid arthritis and diabetes mellitus are chronic diseases, and both create a vulnerability to a variety of complications over time; (f) rheumatoid arthritis demands different combinations of treatments sequentially over time, whereas diabetes mellitus is treated with insulin; (g) many diseases, like rheumatoid arthritis and diabetes mellitus, are not completely affected by control, as the disease may constantly progress.


Challenges of a HL7 CDA Guideline for Telehealth Based DMP Systems.
Disease management programs (DMP) are a modern way of treating health conditions and are becoming a part of standard care. One telehealth DMP service has been in regular operation since 2017, named "HerzMobil Tirol". This paper investigates, if the electronic health record standard HL7 CDA, which is widely accepted in the health care industry, could be used for telehealth DMP services as well. It is already in use in a legally required integrated element of healthcare in Austria called ELGA. An official guideline from the Austrian Ministry of Health sets the standard for telemonitoring with data logging. After the background knowledge was built up, requirements have been gathered through existing official guidelines and interviews and existing documentation by "HerzMobil Tirol". Twenty-five requirements were collected, categorized and analyzed to determine if the existing CDA guidelines are suitable or a new standard must be designed. Based on the requirements, it was established that seven specific sections and two different CDA documents are needed.


Flexophore, a new versatile 3D pharmacophore descriptor that considers molecular flexibility.
A novel pharmacophore descriptor Flexophore is presented, which considers molecular flexibility when comparing descriptor similarities. The descriptor is a complete reduced graph of the underlying molecule. Its nodes are represented by enhanced MM2 atom types, while the edge descriptions encode the molecular flexibility by means of a histogram of node distances in a diverse conformer distribution. For comparing two descriptor nodes, a statistical function derived from the Cambridge Crystallographic Database is implemented. To assess the capability of the descriptor to describe the bioactivity space, 350 test data sets with 1000 molecules each are compiled. The data sets were spiked with molecules active on one of 18 different targets. In 175 of the 350 data sets, all molecules chemically similar to the query molecules were removed. Virtual screening on these data sets showed that the Flexophore descriptor detects active molecules despite chemical dissimilarity, whereas the results for the screening of the complete data sets show enrichments comparable to chemical fingerprint descriptors. The diversity analysis of the enriched compounds demonstrates that the Flexophore descriptor describes the chemical space orthogonal to chemical fingerprint descriptors.


Comforting touch in the very preterm hospitalized infant: an integrative review.
Infants born prematurely lose the protection of the uterus at a time of fetal development when the brain is growing and organizing exponentially. Environmental factors such as stress in the neonatal intensive care unit (NICU) may play a role in altered brain maturation and neurobehavioral outcomes. Strategies aimed at reducing stress and promoting infant well-being are essential to improve neurologic and behavioral outcomes. Infant massage is a developmentally supported strategy aimed at promoting relaxation. However, despite the well-documented benefits of infant massage, infants born very preterm (≤30 weeks' gestation) are often excluded from these studies, leaving neonatal clinicians and families without guidance in how to provide a stress-reducing supplemental touch. Much of the touch in the NICU is a procedural touch, and infants born very preterm often miss out on comforting touch stimulation. A systematic review of the literature is presented with an aim to explore the research that examines the various comforting touch therapies used on hospitalized NICU infants born very preterm within the first few days of postnatal life. The purpose of this review was to identify appropriate stress-reducing comforting touch techniques for physiologically fragile very preterm infants in order to inform and provide guidance to neonatal clinicians and families.


Neurons projecting from the entopeduncular nucleus to the thalamus receive convergent synaptic inputs from the subthalamic nucleus and the neostriatum in the rat.
The two major afferents of the entopeduncular nucleus are the subthalamic nucleus and the neostriatum, which have opposing physiological effects on entopeduncular neurons. Experiments were performed to test the hypothesis that individual entopeduncular neurons that project to the thalamus receive convergent synaptic input from both the subthalamic nucleus and the neostriatum in the rat. This was achieved using double anterograde tracing combined with retrograde tracing. In the electron microscope anterogradely labelled subthalamic (Subthalamic Type 1) and neostriatal terminals were observed to form asymmetrical and symmetrical synaptic contacts respectively, with all parts of entopeduncular neurons. Labelled subthalamic and neostriatal terminals were observed in convergent synaptic contact with entopeduncular neurons, some of which were retrogradely labelled from the thalamus. A second rarer type of terminal was labelled (Subthalamic Type 2) which formed symmetrical synaptic contacts with the proximal regions of unlabelled and retrogradely labelled entopeduncular neurons. These terminals are believed to be derived from the globus pallidus. It is concluded that the topographical and synaptic organization of the so-called direct (neostriatum to entopeduncular nucleus) and indirect pathways (involving the subthalamus and the globus pallidus) is capable of mediating the inhibition and excitation of output neurons in the entopeduncular nucleus that occur following neostriatal stimulation.


A Spatiotemporal Map of Reading Aloud.
Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans (26 male, 20 female) as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband γ activity varies with multiple word attributes critical to reading speed: lexicality, word frequency, and orthographic neighborhood. We found that lexicality is encoded earliest in mid-fusiform (mFus) cortex, and precentral sulcus, and is represented reliably enough to allow single-trial lexicality decoding. Word frequency is first represented in mFus and later in the inferior frontal gyrus (IFG) and inferior parietal sulcus (IPS), while orthographic neighborhood sensitivity resides solely in IPS. We thus isolate the neural correlates of the distributed reading network involving mFus, IFG, IPS, precentral sulcus, and motor cortex and provide direct evidence for parallel processes via the lexical route from mFus to IFG, and the sublexical route from IPS and precentral sulcus to anterior IFG.SIGNIFICANCE STATEMENT Reading aloud depends on multiple complex cerebral computations: mapping from a written letter string on a page to a sequence of spoken sound representations. Here, we used direct intracranial recordings in a large cohort while they read aloud known and novel words, to track, across space and time, the progression of neural representations of behaviorally relevant factors that govern reading speed. We find, concordant with cognitive models of reading, that known and novel words are differentially processed through a lexical route, sensitive to frequency of occurrence of known words in natural language, and a sublexical route, performing letter-by-letter construction of novel words.


Cirrus cloud optical and microphysical property retrievals from eMAS during SEAC4RS using bi-spectral reflectance measurements within the 1.88 μm water vapor absorption band.
Previous bi-spectral imager retrievals of cloud optical thickness (COT) and effective particle radius (CER) based on the Nakajima and King (1990) approach, such as those of the operational MODIS cloud optical property retrieval product (MOD06), have typically paired a non-absorbing visible or near-infrared wavelength, sensitive to COT, with an absorbing shortwave or midwave infrared wavelength sensitive to CER. However, in practice it is only necessary to select two spectral channels that exhibit a strong contrast in cloud particle absorption. Here it is shown, using eMAS observations obtained during NASA's SEAC4RS field campaign, that selecting two absorbing wavelength channels within the broader 1.88 μm water vapor absorption band, namely the 1.83 and 1.93 μm channels that have sufficient differences in ice crystal single scattering albedo, can yield COT and CER retrievals for thin to moderately thick single-layer cirrus that are reasonably consistent with other solar and IR imager-based and lidar-based retrievals. A distinct advantage of this channel selection for cirrus cloud retrievals is that the below-cloud water vapor absorption minimizes the surface contribution to measured cloudy TOA reflectance, in particular compared to the solar window channels used in heritage retrievals such as MOD06. This reduces retrieval uncertainty resulting from errors in the surface reflectance assumption, as well as reduces the frequency of retrieval failures for thin cirrus clouds.


A novel Gli3 enhancer controls the Gli3 spatiotemporal expression pattern through a TALE homeodomain protein binding site.
The zinc finger transcription factor Gli3 is an essential mediator of hedgehog signaling. Gli3 has a dynamic expression pattern during embryonic development. In the neural tube, Gli3 transcripts are patterned along the anteroposterior and dorsoventral axes such that the initial broad expression in the posterior neural tube becomes dorsally restricted as neurogenesis takes place. Little is known about the molecular mechanisms that regulate this dynamic expression. Here, we report on a phylogenetic analysis of the Gli3 locus that uncovered a novel regulatory element, HCNE1. HCNE1 contains a compound Pbx/Meis binding site that binds Pbx and Meis/Prep proteins in vitro and in vivo. We show that HCNE1 recapitulates Gli3 expression in the developing neural tube and that mutations in the Pbx/Meis binding site affect the spatiotemporal control of HCNE1 transcriptional activity. Ectopic expression or loss of function of Pbx and Meis/Prep proteins in the chick and mouse embryo results in aberrant expression of endogenous Gli3 transcripts. We propose a novel role for TALE proteins in establishing the correct spatiotemporal expression pattern of Gli3 in the vertebrate spinal cord, thus implicating TALE transcription factors in early embryonic patterning events controlled by Sonic hedgehog signaling.


Impact of Liraglutide on Amylase, Lipase, and Acute Pancreatitis in Participants With Overweight/Obesity and Normoglycemia, Prediabetes, or Type 2 Diabetes: Secondary Analyses of Pooled Data From the SCALE Clinical Development Program.
To describe amylase/lipase activity levels and events of acute pancreatitis (AP) in the SCALE (Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes) weight-management trials. Secondary analyses were performed on pooled data from four trials (N = 5,358 with BMI ≥30, or 27 to <30 kg/m2 with ≥1 comorbidity). Of these, 1,723 had normoglycemia, 2,789 had prediabetes, and 846 had type 2 diabetes. Participants were randomized to liraglutide 3.0 mg (n = 3,302), liraglutide 1.8 mg (n = 211, only type 2 diabetes), or placebo (n = 1,845). Relationships between baseline characteristics and amylase/lipase activity at baseline and during treatment were investigated. Over 56 weeks, liraglutide 3.0 mg versus placebo was associated with increases in mean levels of 7% (amylase) and 31% (lipase), respectively. Similar changes in amylase/lipase levels were observed with liraglutide 1.8 mg. More participants receiving liraglutide 3.0 mg versus placebo experienced amylase (9.4% vs. 5.9%) and lipase (43.5% vs. 15.1%) elevations greater than or equal to the upper limit of normal (ULN); few had elevations ≥3 × ULN for amylase (<0.1% with liraglutide 3.0 mg or placebo) or lipase (2.9% vs. 1.5%, respectively). After liraglutide discontinuation, enzymes returned to baseline levels. Thirteen participants developed AP: 12 on (n = 9, 0.3%) or after (n = 3, 0.1%) liraglutide 3.0 mg treatment and one (0.1%) with placebo. A total of 6/13 participants with AP (5/12 liraglutide; 1 placebo) had gallstone disease evident at AP onset. Amylase/lipase elevations either 1 × ULN or ≥3 × ULN before AP onset had very low positive predictive value for AP (<1%). Liraglutide resulted in dose-independent, reversible increases in amylase/lipase activity, unrelated to baseline characteristics, not predicting AP onset. Gallstones possibly contributed to 50% of AP cases. Data provide no basis for amylase/lipase level monitoring in liraglutide treatment except in suspected AP.


Self-referenced method for optical path difference calibration in low-coherence interferometry.
A simple method for the calibration of optical path difference modulation in low-coherence interferometry is presented. Spectrally filtering a part of the detected interference signal results in a high-coherence signal that encodes the scan imperfections and permits their correction. The method is self-referenced in the sense that no secondary high-coherence light source is necessary. Using a spectrometer setup for spectral filtering allows for flexibility in both the choice of calibration wavelength and the maximum scan range. To demonstrate the method's usefulness, it is combined with a recently published digital spectral shaping technique to measure the thickness of a pellicle beam splitter with a white-light source.


Non-contiguous finished genome sequence of plant-growth promoting Serratia proteamaculans S4.
Serratia proteamaculans S4 (previously Serratia sp. S4), isolated from the rhizosphere of wild Equisetum sp., has the ability to stimulate plant growth and to suppress the growth of several soil-borne fungal pathogens of economically important crops. Here we present the non-contiguous, finished genome sequence of S. proteamaculans S4, which consists of a 5,324,944 bp circular chromosome and a 129,797 bp circular plasmid. The chromosome contains 5,008 predicted genes while the plasmid comprises 134 predicted genes. In total, 4,993 genes are assigned as protein-coding genes. The genome consists of 22 rRNA genes, 82 tRNA genes and 58 pseudogenes. This genome is a part of the project "Genomics of four rapeseed plant growth-promoting bacteria with antagonistic effect on plant pathogens" awarded through the 2010 DOE-JGI's Community Sequencing Program.


Robust fringe density and direction estimation in noisy phase maps.
A method for automated fringe analysis is presented. It robustly estimates local fringe density and direction in noisy wrapped phase maps. Such information can be used to improve the performance of two-dimensional phase unwrapping methods, to construct phase-jump-preserving filtering strategies, and also to perform robust segmentation of phase data. The method, which is highly insensitive to noise, is model based and performs the estimation in the Fourier domain.


An investigation into the thermal behaviour of an amorphous drug using low frequency dielectric spectroscopy and modulated temperature differential scanning calorimetry.
The objective of the study was to investigate the use of low frequency dielectric spectroscopy as a means of characterizing the thermal transitions of an amorphous drug substance, indometacin, with particular emphasis on modelling the response using the Dissado-Hill function. The low frequency dielectric behaviour of indometacin was measured over a temperature range of 10-160 degrees C and a frequency range of 10(-3)-10(6) Hz. Modulated temperature differential scanning calorimetry (MTDSC) studies were also performed on equivalent samples, showing a glass transition, recrystallization and melting. Isothermal low frequency dielectric spectra of the sample at temperatures below recrystallization showed the dynamic dielectric relaxation associated with the amorphous phase, while changes in the real and imaginary permittivities were observed that were associated with recrystallization and subsequent melting. A small discontinuity was observed immediately above the recrystallization process in the MTDSC and dielectric data, suggested to correspond to a solid state transformation. The use of the Dissado-Hill function as a means of modelling the dielectric behaviour has also been described. The study suggests that low frequency dielectric spectroscopy, used in conjunction with MTDSC and Dissado-Hill modelling, may be a useful tool for the characterization of amorphous and crystalline drugs.


Determinants of antibiotic-associated hypoprothrombinemia.
Hypoprothrombinemia is a relatively uncommon event in the hospitalized patient. When it does occur, it often is associated with surgery, dietary vitamin K deficiency, renal dysfunction, malignancy, and broad-spectrum antibiotic therapy. Several mechanisms have been proposed to account for antibiotic-associated hypoprothrombinemia, including eradication of gastrointestinal bacteria, direct inhibition of vitamin K-dependent coagulation, and indirect inhibition of coagulation. The anecdotal reports and comparative studies of antibiotic-associated hypoprothrombinemia were reviewed; these usually implicated broad-spectrum or the use of several antibiotics. The increased frequency of hypoprothrombinemia associated with moxalactam and cefoperazone also raises questions about the role of their N-methylthiotetrazole (NMTT) side chains. The hypoprothrombinemia associated with NMTT antibiotics does not occur in healthy volunteers and is rare in patients without complicating conditions. Although NMTT inhibits vitamin K-dependent carboxylation in vitro, the parent cephalosporins do not. It is not clear whether NMTT-containing antibiotics liberate sufficient amounts of NMTT in vivo to antagonize clotting in patients. Thus, although moxalactam, and possibly cefoperazone, may in some cases be responsible for increases in prothrombin time, most important question for further study is whether the newer NMTT-containing antibiotics pose a risk of hypoprothrombinemia that is greater than that of antibiotics lacking this side chain.


Comparing protein behaviour in vitro and in vivo, what does the data really tell us?
The recent advancement in moving 'biophysical' analysis of proteins in vivo has finally brought us to a position where we can start to make quantitative comparisons with existing in-vitro data. A striking observation is that protein behaviour in live cells seems, after all, not that different from in test tubes, not even at the level of complex mechanisms like protein aggregation. The example examined in this review is the ALS associated protein SOD1 that apparently retains its in-vitro properties in vivo. Does this mean that the protocols for studying proteins in vivo are somehow oversimplified, or that the macromolecular properties and interplay - despite being intrinsically malleable - are evolutionary more 'streamlined' than previously anticipated? Whatever the answer may be the time is now right to put these data to critical biological test.


Cross-dimensional magnitude interactions arise from memory interference.
Magnitudes from different dimensions (e.g., space and time) interact with each other in perception, but how these interactions occur remains unclear. In four experiments, we investigated whether cross-dimensional magnitude interactions arise from memory interference. In Experiment 1, participants perceived a constant-length line consisting of two line segments of complementary lengths and presented for a variable stimulus duration; then they received a cue about which of the two segment lengths to later reproduce. Participants were to first reproduce the stimulus duration and then the cued length. Reproduced durations increased as a function of the cued length if the cue was given before duration was retrieved from memory for reproduction (i.e. before duration reproduction; Experiment 1) but not if it was given after the duration memory had been retrieved from memory (i.e. after the start of duration reproduction; Experiment 2). These findings demonstrate that space-time interaction arises as a result of memory interference when length and duration information co-exist in working memory. Experiment 3 further demonstrated spatial interference on duration memories from memories of filled lengths (i.e. solid line segments) but not from noisier memories of unfilled lengths (demarcated empty spatial intervals), thus highlighting the role of memory noise in space-time interaction. Finally, Experiment 4 showed that time also exerted memory interference on space when space was presented as (relatively noisy) unfilled lengths. Taken together, these findings suggest that cross-dimensional magnitude interactions arise as a result of memory interference and the extent and direction of the interaction depend on the relative memory noises of the target and interfering dimensions. We propose a Bayesian model whereby the estimation of a magnitude is based on the integration of the noisily encoded percept of the target magnitude and the prior knowledge that magnitudes co-vary across dimensions (e.g., space and time). We discuss implications for cross-dimensional magnitude interactions in general.


Alpha-2-adrenoceptor control of cortisol and ACTH in normal volunteers: preliminary open trial of the effects of acute and chronic idazoxan.
To examine the role of alpha 2-adrenoceptors in the control of cortisol and ACTH, hormone responses to the selective alpha 2-antagonist idazoxan were studied in 12 normal volunteers. Plasma cortisol and ACTH were measured from 0930h-1230h on three occasions: before, on the 1st day, and on the 22nd day of an open treatment trial with idazoxan 40 mg administered three times per day. Compared with pretreatment cortisol levels, acute but not chronic idazoxan treatment attenuated the normal diurnal fall in plasma cortisol. Plasma ACTH concentrations were not altered by either dose of idazoxan. The attenuation of the diurnal fall in cortisol after acute idazoxan may be mediated through increased central availability of norepinephrine, and is similar to responses after high doses of the less selective alpha 2-antagonist yohimbine. Activity of central noradrenergic neurons appears to be reduced or normalized by chronic idazoxan, indicated by restoration of the normal diurnal fall in cortisol.


Interactions of glucocorticoids and beta 2-agonists.
Beta 2-adrenoreceptor agonists and glucocorticosteroids are the two most effective treatments for asthma and are often used in combination. Glucocorticoids mediate their anti-inflammatory effects through the action of activated glucocorticoid receptors (GRs). Many of the effects of GRs on the synthesis of cytokines and other inflammatory mediators are due to a direct interaction with other deoxyribonucleic acid (DNA)-binding proteins belonging to the basic leucine zipper (bZIP) group of transcription factors, such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B). Beta 2-agonists are potent bronchodilators at low doses and at high doses can activate gene transcription via a bZIP protein, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Activated GRs and CREB can interact with each other within the nucleus to modulate both DNA-binding and gene transcription in either a positive or inhibitory manner, depending on cell type. In lung cells, high doses of beta 2-agonists reduce the ability of GR to bind DNA, a process which is mediated by CREB activation. Inhibition of GR DNA-binding by CREB raises the possibility that high-dose beta 2-agonists could have functional antiglucocorticoid activity and may be a basis for the reported increase in asthma morbidity and mortality in industrialized countries, which have increasing per capita beta 2-agonist use.


Gene expression profiling of sex differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia.
Although physiological responses to chronic hypoxia, including pulmonary hypertension and right ventricular hypertrophy, have been well described, the molecular mechanisms involved in cardiopulmonary adaptations are still not fully understood. We hypothesize that adaptive responses to chronic hypoxia are the result of altered transcriptional regulations in the right and left ventricles. Here we report results from the gene expression profiling of adaptive responses in a chronically hypoxic heart. Of 11 analyzed candidate genes, the expression of seven and four genes, respectively, was significantly altered in the right ventricle of hypoxic male and female mice. In the transcriptional profile of the left ventricle, we identified a single expression change in hypoxic males (Vegfa gene). To directly test the role of HIF1, we analyzed the expression profile in Hif1a partially deficient mice exposed to moderate hypoxia. Our data showed that Hif1a partial deficiency significantly altered transcriptional profiles of analyzed genes in hypoxic hearts. The expression changes were only detected in two genes in the right ventricle of Hif1a(+/-) males and in one gene in the right ventricle of Hif1a(+/-) females. First, our results suggest that hypoxia mainly affects adaptive expression profiles in the right ventricle and that each ventricle can respond independently. Second, our findings indicate that HIF1a plays an important role in adaptive cardiopulmonary responses and the dysfunction of HIF1 pathways considerably affects transcriptional regulation in the heart. Third, our data reveal significant differences between males and females in cardiac adaptive responses to hypoxia and indicate the necessity of optimizing diagnostic and therapeutic procedures in clinical practice, with respect to sex.


Lymphocyte to Monocyte Ratio and Modified Glasgow Prognostic Score Predict Prognosis of Lung Adenocarcinoma Without Driver Mutation.
Neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR) and modified Glasgow prognostic score (mGPS) are useful prognostic markers based on host-related systemic inflammatory response. They have been shown as independent prognostic biomarkers in various cancers, including non-small cell lung cancer. However, there has been little evidence for a specific population of pulmonary adenocarcinoma without active epidermal growth factor receptor (EGFR) mutation. We retrospectively reviewed 159 patients who met the following criteria: histologically or cytologically diagnosed adenocarcinoma, confirmed wild-type EGFR, started first-line cytotoxic chemotherapy between July 2007 and March 2017 at our hospital, and c-stage IIIB or IV. We compared overall survival (OS) between dichotomized groups by the optimal cut-off points of NLR and LMR, and mGPS 0 - 1 vs. 2. Univariate and multivariate Cox proportional hazard analyses also detected prognostic factors for OS. As favorable prognostic factors for OS, multivariate analysis detected Eastern Cooperative Oncology Group performance status (ECOG PS) 0 - 1 (hazard ratio (HR) 3.43, 95% confidence interval (CI): 2.12 - 5.53; P < 0.01), LMR ≥ 1.97 (HR 0.39, 95% CI: 0.21 - 0.72; P < 0.01) and mGPS 0 - 1 (HR 1.95, 95% CI: 1.20 - 3.16; P < 0.01). The OS of LMR ≥ 1.97 and mGPS 0 - 1 groups were significantly longer than those of LMR < 1.97 and mGPS 2 groups, respectively. We divided 159 patients into three groups, both LMR ≥ 1.97 and mGPS 0 - 1, either LMR ≥ 1.97 or mGPS 0 - 1 and both LMR < 1.97 and mGPS 2. The OS of both LMR < 1.97 and mGPS 2 was significantly shorter than the other two groups. After adjustment for age, sex, ECOG PS, sodium, alkaline phosphatase and NLR, multivariate analysis found both LMR < 1.97 and mGPS 2 as an independent poor prognostic combination in comparison with both LMR ≥ 1.97 and mGPS0-1 (HR 5.98, 95% CI: 2.64 - 13.5; P < 0.01). LMR and mGPS are independent prognostic markers for pulmonary adenocarcinoma with wild-type EGFR. Combination of LMR and mGPS can stratify patients according to prognosis.


Acquired granulocyte abnormality during drug allergic reactions: possible role of complement activation.
A profound defect in granulocyte chemotaxis was documented in an otherwise healthy 21-yr-old man who failed to localize granulocytes to an area of cellulitis during an allergic reaction to cephalothin. During the period of drug allergy, characterized by urticaria, eosinophilia, and profound hypocomplementemia, in vitro migration of the patient's granulocytes in the Boyden chamber was markedly impaired. Although devoid of hemolytic complement activity, the patient's serum possessed supranormal chemotactic activity, even following heat inactivation, suggesting the presence of chemotactically active complement split products. Chemotactic function improved concomitantly with steroid therapy and normalization of serum complement levels, and was entirely normal following clinical recovery and cessation of steroid therapy. The chemotactic abnormality noted in the patient's cells was reproduced in normal granulocytes by preincubation either with patient serum or with cobra venom-activated fresh (but not heated) normal serum, suggesting that in vivo exposure of granulocytes to activated complement was responsible for the patient's abnormal chemotactic response. This mechanism may contribute to the increased infection propensity noted in other conditions characterized by in vivo complement activation, such as rheumatoid arthritis and systemic lupus erythematosis.