Coupled-cluster calculations of the lowest 0-0 bands of the electronic excitation spectrum of naphthalene.
Approximate singles and doubles coupled-cluster (CC2) calculations have been carried out for the 0-0 bands of the 1Ag→ 1B3u and 1Ag→ 1B2u transitions of naphthalene. The vertical excitation energies calculated for the 16 lowest excited singlet states have also been calculated using a sequence of large basis sets. The CC2 excitation energies extrapolated to the basis-set limit are in rather good agreement with values recently calculated at the multiconfiguration second-order perturbation theory (CASPT2) and at the singles, doubles and approximate triples (CC3) levels. Best values for the vertical excitation energies and the 0-0 transition energies have been obtained by adding higher-order correlation contributions to the basis-set extrapolated CC2 energies. For some of the states, the best estimated vertical excitation energies in this work deviate up to 0.3 eV from the previously best estimated energies, because larger basis sets have been employed in this study. The calculations of the 0-0 transitions show the importance of considering vibrational effects when aiming at reliable comparisons of calculated and measured excitation energies for assessing the accuracy of employed computational methods. Calculations at the density functional theory (DFT) level using Becke's three-parameter functional (B3LYP) yield less accurate excitation energies. At the B3LYP level, the two lowest states appear in reverse order with a deviation of 0.50 eV from experiment for the 0-0 transition energy of the 1B3u state.


Ploidy level determinations in high-grade and low-grade malignant variants of prostatic carcinoma.
Ploidy level determinations of prostatic carcinoma in 213 patients selected on the basis of survival time were analyzed. Two extreme groups were chosen: extreme group 1, 131 patients who died from prostatic cancer within 3 years of diagnosis; and extreme group 2, 82 patients who survived for more than 15 years after diagnosis. All patients were diagnosed by fine needle aspiration biopsy. The DNA measurements were performed on Feulgen stained, destained May-Grünwald-Giemsa smears. The DNA distribution patterns were studied in three benign prostatic lesions as a base for analyses of prostatic carcinoma. By choosing two extreme groups it was possible to evaluate in detail the optimal limits for defining the diploid 2c region and the tetraploid 4c region. Various limits were tested in order to determine those which most clearly separate extreme group 1 from extreme group 2. We found that the optimal upper diploid limit was 2.5c and the optimal tetraploid limits were 3.5c-4.5c. By using these limits to determine the percentage of aberrant tumor cells, i.e., non-2c and non-4c, and combining this with the modal value (in c units) of the tumor cell population the tumors could unambiguously be divided into D-, T-, and A-types. D/T-type tumors were found only in extreme group 2 and had less than 30% aberrant tumor cells, while A-type tumors (high-grade aneuploid) had greater than 50% non-2c and non-4c tumor cells. All A-type tumors were found in extreme group 1. In order to investigate whether the classification of tumors into D-, T-, and A-type was valid in general and could also be applied to patients with survival time between the two extreme groups (3-15 years), a material of 79 patients with a wide range of survival times was tested. The tumors were classified according to the above-mentioned criteria into A-, D-, and T-type tumors. All patients who died within 5 years of diagnosis had A-type tumors. All patients who lived greater than 5 years from diagnosis had D- or T-type tumors.


The emergence of tool use during the second year of life.
Despite a growing interest in the question of tool-use development in infants, no study so far has systematically investigated how learning to use a tool to retrieve an out-of-reach object progresses with age. This was the first aim of this study, in which 60 infants, aged 14, 16, 18, 20, and 22 months, were presented with an attractive toy and a rake-like tool. There were five conditions of spatial relationships between the toy and the tool, going from the toy and tool being connected to there being a large spatial gap between them. A second aim of the study was to evaluate at what age infants who spontaneously fail the task can learn this complex skill by being given a demonstration from an adult. Results show that even some of the youngest infants could spontaneously retrieve the toy when it was presented inside and touching the top part of the tool. In contrast, in conditions with a spatial gap, the first spontaneous successes were observed at 18 months, suggesting that a true understanding of the use of the tool has not been fully acquired before that age. Interestingly, it is also at 18 months that infants began to benefit from the demonstration in the conditions with a spatial gap. The developmental steps for tool use observed here are discussed in terms of changes in infants' ability to attend to more than one item in the environment. The work provides insight into the progressive understanding of tool use during infancy and into how observational learning improves with age.


Low Pretreatment CD4+:CD8+ T Cell Ratios and CD39+CD73+CD19+ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.
The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39-CD73-CD4+ T cells and reduced proportions of CD39-/+CD73+CD4+ T cells compared to the equivalent cells from HPV- patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted.


Comparison of factors influencing patient choice of community pharmacy in Poland and in the UK, and identification of components of pharmaceutical care.
Several factors, which are components of pharmaceutical care, can influence a patient's choice of a community pharmacy store and contribute to frequent visits to the same pharmacy. To compare factors that influence a patient's choice of pharmacy in Poland and in the UK, to identify which of them are components of pharmaceutical care, and to relate them to patient loyalty to the same pharmacy. A self-administered, anonymous questionnaire was distributed to clients visiting pharmacies in Poland and the UK January-August 2011. Comparisons were performed using chi-square tests and logistic regression. All statistical analyses were performed using SPSS 20.0. The response rate was 55.6% (n=417/750; 36 pharmacies) and 54.0% (n=405/750; 56 pharmacies) in Poland and in the UK, respectively. The most frequently reported factors, as defined by a percentage of responders, were in Poland: 1) location (84%); 2) professional and high-quality of service (82%); 3) good price of medicines (78%); and 4) promotions on medicines (66%). In the UK, the most commonly reported factors were: 1) professional and high quality of service (90%); 2) location (89%); 3) good advice received from the pharmacist (86%); and 4) option of discussing and consulting all health issues in a consultation room (80%). Good advice and an option of discussing personal concerns with a pharmacist are components of pharmaceutical care. Thirty-eight percent of patients in Poland and 61% in the UK declared visiting the same pharmacy. Components of pharmaceutical care are important factors influencing the patient's choice of pharmacy in the UK and, to a lesser degree, in Poland. Additionally, more patients in the UK than in Poland are committed to a single pharmacy. Therefore, implementing the full pharmaceutical care in Poland may contribute to an increase in patient loyalty and thus strengthen competitiveness of pharmacy businesses.


Alcohol drinking and the risk of colorectal cancer death: a meta-analysis.
A causal link between alcohol consumption and colorectal cancer (CRC) was established only recently by the International Agency for Research on Cancer. However, the quantitative association between alcohol drinking and CRC mortality is still an open question. We performed a systemic review and meta-analysis on epidemiological studies to quantify the risk for CRC mortality at different levels of alcohol consumption. A literature search was carried out in PubMed and Web of Science to identify all relevant studies published from January 1966 to June 2013. The pooled relative risk (RR) and the corresponding 95% confidence interval (CI) were estimated by categorical meta-analysis. A dose-risk relation was also analyzed. Nine cohort studies exploring the association between CRC mortality and alcohol drinking were identified. Compared with non/occasional drinkers, the pooled RR was 1.03 (95% CI, 0.93-1.15) for any, 0.97 (95% CI, 0.86-1.10) for light (≤12.5 g/day of ethanol), 1.04 (95% CI, 0.94-1.16) for moderate (12.6-49.9 g/day of ethanol), and 1.21 (1.01-1.46) for heavy drinkers (≥50 g/day of ethanol). For heavy drinkers, the pooled estimate was apparently higher for men (RR=1.28; 95% CI, 1.13-1.46) than for women (RR=0.79; 95% CI, 0.40-1.54; P(heterogeneity)=0.007). The dose-response analysis showed a J-shaped relationship between alcohol consumption and CRC mortality. The present meta-analysis provides the evidence for an association between heavy alcohol drinking (≥50 g/day of ethanol) and CRC mortality.


Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone.
Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).


Provision of HIV preexposure prophylaxis to female patients seeking family planning services in the United States.
We conducted a scoping review to assess barriers to and facilitators of integrating HIV preexposure prophylaxis (PrEP) and family planning (FP) at the patient, provider, and implementation levels, and to identify gaps in knowledge. We conducted a search of five bibliographic databases from database inception to March 2022: PubMed, CINAHL, Embase, Web of Science and Scopus. Two reviewers screened abstracts and full texts to determine eligibility based on a priori inclusion and exclusion criteria. We categorized studies by their relevance to patient, provider, and implementation barriers, and extracted data based on prespecified elements. Our initial search strategy yielded 1151 results, and 34 publications were included. Barriers to PrEP implementation in family planning settings included low PrEP knowledge among patients, hesitance to take PrEP due to perceived stigma, decreased willingness of providers unfamiliar with PrEP to prescribe PrEP, and limited financial and staffing resources that make prescribing and monitoring PrEP difficult. Facilitators included robust training for providers, stigma reduction efforts, leadership engagement, and increased resources specifically in settings with processes in place that ease the process of prescribing and monitoring PrEP. Advances in implementation strategy development, stigma reduction, and drug development will be essential to reinforcing PrEP care in family planning settings and thereby reducing the incidence of HIV in women through highly effective pharmacologic HIV prevention methods.


Anal cancer incidence in men with HIV who have sex with men: are black men at higher risk?
To assess differences in anal cancer incidence between racial/ethnic groups among a clinical cohort of men with HIV who have sex with men. Clinical cohort study. We studied men who have sex with men (MSM) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who initiated antiretroviral therapy (ART) under HIV care in CNICS. We compared anal cancer incidence between Black and non-Black men and calculated hazard ratios controlling for demographic characteristics (age, CNICS site, year of ART initiation), HIV disease indicators (nadir CD4+, peak HIV RNA), and co-infection/behavioral factors including hepatitis B virus (HBV), hepatitis C virus (HCV), tobacco smoking and alcohol abuse. We studied 7473 MSM with HIV who contributed 41 810 person-years of follow-up after initiating ART between 1996 and 2014 in CNICS. Forty-one individuals had an incident diagnosis of anal cancer under observation. Crude rates of anal cancer were 204 versus 61 per 100 000 person-years among Black versus non-Black MSM. The weighted hazard ratio for anal cancer in Black MSM (adjusting for demographics, HIV disease factors, and co-infection/behavioral factors) was 2.37 (95% confidence interval: 1.17, 4.82) compared to non-Black MSM. In this large multicenter cohort, Black MSM were at significantly increased risk for anal cancer compared to non-Black MSM. Further detailed studies evaluating factors impacting anal cancer incidence and outcomes in Black men with HIV are necessary. Inclusion of more diverse study cohorts may elucidate modifiable factors associated with increased anal cancer risk experienced by Black MSM.


A novel rat microsurgical model to study the immunological characteristics of male genital tissue in the context of penile transplantation.
Penis transplantation represents an exciting new avenue for restoration of male genitalia and function after devastating tissue loss. This animal model is designed to fill a critical void to study immunologic aspects related to reconstructive transplantation of male genitalia. A rat penile graft dissection was designed based on the internal pudendal arteries and dorsal penile vein and includes the skin of the prepuce. A nonsuture cuff technique was used to anastomose the graft vessels to the recipient superficial epigastric and femoral vessels. Seventy-seven penile transplantations were performed. Graft design yields suitable caliber and length of vessels at the radix of the penis. Anastomosis of the dorsal penile vein and the internal pudendal arteries insures optimal graft perfusion. The nonsuture cuff technique allows for successful microvascular anastomosis by a single surgeon with an average overall operative time of 2.5 h. Long-term graft survival (>30 days) was observed in syngeneic transplants. We have established a robust murine model with ideal vascular perfusion of penile tissue to study the unique immunobiology of male genitourinary allotransplantation. Heterotopic inset further allows for visual monitoring of graft viability, while the native penis serves as an optimal control.


In honor of the Teratology Society's 50th anniversary: The role of Teratology Society members in the development and evolution of in vivo developmental toxicity test guidelines.
Members of the Teratology Society (established in 1960) were involved in the first governmental developmental and reproductive toxicity testing guidelines (1966) by FDA following the thalidomide epidemic, followed by other national and international governmental testing guidelines. The Segment II (developmental toxicity) study design, described in rodents and rabbits, has evolved with additional enhanced endpoints and better descriptions, mechanistic insights, range-finding studies, and toxico/pharmacokinetic ADME information (especially for pharmaceuticals). Society members were also involved in the development of the current screening assays and tests for endocrine disruptors (beginning in 1996) and are now involved with developing new testing guidelines (e.g., the extended one-generation protocol), and evaluating the current test guidelines and new initiatives under ILSI/HESI sponsorship. New initiatives include ToxCast from the U.S. EPA to screen, prioritize, and predict toxic chemicals by high throughput and high-content in vitro assays, bioinformation, and modeling to reduce (or eliminate) in vivo whole animal studies. Our Society and its journal have played vital roles in the scientific and regulatory accomplishments in birth defects research over the past 50 years and will continue to do so in the future. Happy 50th anniversary!


The vascular response to zinc varies seasonally: effect of pinealectomy and melatonin.
The effect of physiological concentrations of zinc on the in vitro pressor responses of male Wistar rat mesenteric preparations to norepinephrine was systematically studied over a 2-year period. A marked seasonal variation in the response of the preparations was observed over a range of zinc concentrations from 3.5 X 10(-11) to 3.5 X 10(-6) M. All concentrations of zinc inhibited pressor responses during the winter (November to March), but during the spring months (April to May) zinc became very much less effective and low concentrations of zinc potentiated the response. Inhibition of the pressor response at this time only occurred at zinc concentrations above 3.5 X 10(-7) M. In the summer months. (June to September) the zinc effect shifted back towards the winter situation with lower concentration of zinc potentiating and higher concentrations inhibiting vasoconstriction. Pinealectomy of the rats a week prior to preparation of the mesenteric beds very significantly enchanced pressor responses to norepinephrine in the winter months but had much less effect in the summer. The seasonal variation noted in preparations from control rats was maintained following pinealectomy but the amplitude was reduced. Perfusion of melatonin (4.3 X 10(-10) M through preparations from pinealectomized rats enhanced the inhibitory effect of zinc compared to the response to zinc from similarly perfused preparations from control rats. Thus, the rat mesenteric vascular bed is an in vitro model of seasonal variation in vascular reactivity which is sensitive to physiological concentrations of zinc. The origin of the seasonal rhythmicity remains speculative particularly in view of the fact that the rats were maintained under constant photoperiod. That the pineal may modulate the seasonal effect of zinc is suggested by the shift in response to zinc following pinealectomy. Melatonin reversed the effect of pinealectomy on this preparation implicating it as a possible mediator of normal vascular reactivity to zinc. A possible influence of magnetic radiation in evaluating the occurrence of seasonally varying phenomena in vitro should be considered.


Effect of Water Miscible Organic Solvents on p-Nitrophenol Hydroxylase (CYP2E1) Activity in Rat Liver Microsomes.
Organic solvents used for solubilization of the substrates/NCEs are known to affect the activity of cytochrome P450 enzymes. Further, this effect varies with the solvents used, the substrates and CYP450 isoforms in question. In the present study, we have investigated the effect of ten commonly used water miscible organic solvents (methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, dimethyl sulphoxide, N,N-dimethyl formamide, dioxane and polyethylene glycol 400) on p-nitrophenol hydroxylase activity at 0, 0.1, 0.25, 0.5, 0.75 and 1% v/v concentration in rat liver microsomes. All the solvents studied showed concentration dependent inhibition of the p-nitrophenol hydroxylase activity except acetonitrile which showed activation of the activity at concentration range studied. Out of ten solvents studied, dioxane was found to be the most inhibitory solvent (inhibition >90% at 0.25% v/v concentration). Overall, solvents like dimethyl sulphoxide, dimethyl formamide and dioxane appeared to be unsuitable for characterizing p-nitrophenol hydroxylase (CYP2E1-mediated) reactions due to a high degree of inhibition. On the other hand, methanol and acetonitrile at concentrations <0.5% v/v appeared to be appropriate solvents for substrate solubilization while evaluating CYP2E1-mediated catalysis. The results of this study imply that caution should be exercised while choosing solvents for dissolution of substrate during enzyme studies in liver microsomes.


NMR analysis of the structure and metal sequestering properties of metallothioneins.
Multinuclear 1 and 2 dimensional magnetic resonance methods have been used to investigate the structures and metal binding properties of metallothioneins (MTs) isolated from several different sources. 113Cd NMR studies have unambiguously shown that the 7 g-atoms of Cd2+ bound per mole of the mammalian MT are located in two separate metal clusters, one containing 4 metal ions and the other, 3 metal ions. In the invertebrate (Scylla serrata) MT, similar studies have revealed that the 6 g-atoms of bound Cd2+ are distributed in two distinct 3-metal clusters while in Neurospora MT, the 3 g-atoms of bound Cd2+ are arranged in a pseudo 3-metal cluster. With the exception of one of the Cd2+ sites in this latter cluster, all the Cd2+ ions are tetrahedrally coordinated to four cysteine thiolate ligands with single cysteinyl sulfurs bridging adjacent metals. These conclusions are based on the 113Cd chemical shift data and a detailed analysis of the observed 113Cd-113Cd scalar couplings by both homonuclear decoupling and 2D techniques. In addition, the 113Cd NMR studies have revealed significant differences in the affinity of different metal ions for the two mammalian metal clusters. For the 3-metal cluster, the affinity is found to decrease in the order Cu+ greater than Cd2+ greater than Zn2+ with Cd2+ greater than Zn2+ for the 4 metal cluster and Cd2+ (4-metal cluster) greater than Cd2+ (3-metal cluster). The 113Cd NMR data are currently being integrated with 500 MHz 2D 1H and 1H-113Cd chemical shift correlated multiple quantum data sets to more completely define the structural arrangement of the metal clusters in the tertiary structure of these proteins.


The high prevalence of poor physical health and unhealthy lifestyle behaviours in individuals with severe mental illness.
Recent mental health care policy has addressed the need for health care professionals to consider the physical health of consumers. Mental health nurses are particularly well-placed for this role. To provide mental health nurses with practical information, this narrative review summarises evidence from recent research on the physical health of individuals with Serious Mental Illness (SMI). In those with SMI, the international prevalence of obesity, the metabolic syndrome, diabetes mellitus, symptoms of cardiovascular disease, and respiratory disease all exceed that of the general population by at least two times, and HIV prevalence may be increased by as much as eight times. This increased prevalence of chronic disease may be largely responsible for an increased risk of death of up to five times, resulting in as much as 30 years of potential life lost. Of particular concern, the recent evidence suggests that for physical health and increased mortality, the gap between individuals with SMI and the general population is worsening. Unhealthy lifestyle behaviours undoubtedly play a role in the development of poor physical health and chronic disease, and the present review indicates that low physical activity, poor diet, smoking, alcohol and substance abuse, and risky sexual behaviour are common in individuals with SMI. This narrative review demonstrates that the prevalence of poor physical health and health behaviours in people with SMI far exceed that observed in the general population, and reinforces the urgent need for mental health nurses to address physical health concerns in patients.


Preliminary treatment of MSW fly ash as a way of improving electrodialytic remediation.
In the current work electrodialytic remediation (EDR) was applied to remove heavy metals from municipal solid waste (MSW) fly ash, a hazardous waste collected during flue gas treatment. Tests were conducted to evaluate if EDR could be improved by introducing a preliminary treatment in which very soluble salts were removed. Three different preliminary treatments were conducted with different L:S ratios and pH. Treatment in which metal release and L/S ratio were lower was selected for EDR. Electrodialytic remediation was performed at a constant current of 38 mA, for 14 days, using gluconate as a solubilisation enhancement agent. Conductivity and pH were monitored and electrolyte samples were collected every 4 days to evaluate metal release over time. It was found that the preliminary treatment reduces fouling of the ion-exchange membranes used in EDR and drastically increases the removal of metals. Remediation time was also considerably reduced. Additionally, preliminary washing reduces energy consumption during EDR, since electric current is not wasted in the transport of soluble salts. Sequential extraction was performed in the untreated and treated samples to help identify how metals are bond to the fly ash. It was seen that at the end metals are mainly found in the strongly bonded and residual phases. This indicates that the combined treatment (washing + EDR) is successful in reducing the environmental risk posed by fly ash.


[The Thymic Hormone Thymosin-1α Reduces the Pro-Inflammatory Response of Raw 264.7 Cells Induced by Endotoxin].
The aim of this work was to study the effects of thymosin-1 alpha (Tα1) on the anti-inflammatory response of RAW 264.7 macrophages cultured in the presence of lipopolysaccharide (LPS) from the walls of gram-negative bacteria. As well, we evaluated production of pro-inflammatory cytokines and the activity of the NF-κB and SAPK/JNK signaling pathways. In addition, the level of expression of a number of genes that regulate cell apoptosis, as well as the activity of receptors involved in the pro-inflammatory response, was determined. First, the addition of Tα1 normalized the level of cytokine production to varying degrees, with a particularly noticeable effect on IL-1β and IL-6. Second, the addition of Tα1 normalized the activity of the NF-κB and SAPK/JNK signaling cascades and the expression of the Tlr4 gene. Third, Tα1 significantly reduced p53 and the activity of the P53 gene, which is a marker of cell apoptosis. Fourth, it was shown that the increase in Ar-1 gene expression under the influence of LPS was significantly reduced using Tα1. Thus, it was found that the presence of Tα1 in the RAW 264.7 cell culture medium significantly reduced the level of the pro-inflammatory response of cells.


Audit of transthoracic fine needle aspiration of the lung: cytological subclassification of bronchogenic carcinomas and diagnosis of tuberculosis.
Transthoracic fine-needle aspiration cytology (FNAC) is a useful tool for evaluating neoplastic and inflammatory lung nodules. In view of the relative paucity of published audit studies regionally, such a study was undertaken to assess the use of the technique in our centre. One hundred and fourteen FNACs were performed during 1997-1999. Immediate assessment for specimen adequacy was done. Diagnoses were correlated with clinical-pathological information and selective blind review performed. Cytologically, 65.8% of cases were malignant, 1.8% were atypical, 25.4% were inflammatory/non-malignant and 7% were inadequate. Cytological-histological tumour diagnostic concordance was 94.4%. Diagnostic sensitivity for malignancy: 93.4%, specificity: 95.8%, accuracy: 94%. Eight inadequate/ benign cases (7%) proved to be malignant with clinical-pathological follow-up. Tuberculosis was confirmed (acid-fast bacilli detected) in six cases (5.3%) and suggested in a further 10 cases (8.8%). The cytological review showed 96% concordance with the original benign/malignant diagnoses. Pneumothorax rate was 18%. FNAC is an accurate and safe method for the evaluation of lung nodules and it enables subclassification of bronchogenic carcinomas in the vast majority of cases. It is also useful for the diagnosis of tuberculous pulmonary nodules. Immediate assessment optimises specimen adequacy; inadequate/non-malignant smears in particular, need clinical correlation, close follow-up and re-biopsy, if necessary.


alpha7 nicotinic acetylcholine receptors and modulation of gabaergic synaptic transmission in the hippocampus.
The present report provides new findings regarding modulation of gamma-aminobutyric acid (GABA) transmission by alpha7 nicotinic receptor activity in CA1 interneurons of rat hippocampal slices. Recordings were obtained from tight-seal cell-attached patches of the CA1 interneurons, and agonists were delivered to the neurons via a modified U-tube. Application for 6 s of the alpha7 nicotinic receptor-selective agonist choline (> or =1 mM) to all CA1 interneurons tested triggered action potentials that were detected as fast current transients. The activity triggered by choline terminated well before the end of the agonist pulse, was blocked by the alpha7 nicotinic receptor antagonist methyllycaconitine (50 nM) and was concentration dependent; the higher the concentration of choline the higher the frequency of events and the shorter the delay for detection of the first event. In 40% of the neurons tested, choline-triggered action potentials decreased in amplitude progressively until no more events could be detected despite the presence of the agonist. Primarily, this finding could be explained by Na(+)-channel inactivation associated with membrane depolarization induced by alpha7 nicotinic receptor activation. In 60% of the neurons, the amplitude of choline-induced action potentials was sustained at the intial level, but again the activity did not last as long as the agonist pulse, in this case apparently because of agonist-induced receptor desensitization. These results altogether demonstrate that agonists interacting with alpha7 nicotinic receptors, including the natural transmitter acetylcholine and its metabolite choline, influence GABAergic transmission, not only by activating these receptors, but also by controlling the rate of Na(+)-channel inactivation and/or by inducing receptor desensitization.


First measurements of spin-dependent double-differential cross sections and the Gerasimov-Drell-Hearn Integrand from 3He(γ,n)pp at incident photon energies of 12.8 and 14.7 MeV.
The first measurement of the three-body photodisintegration of longitudinally polarized (3)He with a circularly polarized γ-ray beam was carried out at the High Intensity γ-ray Source facility located at Triangle Universities Nuclear Laboratory. The spin-dependent double-differential cross sections and the contributions from the three-body photodisintegration to the (3)He Gerasimov-Drell-Hearn integrand are presented and compared with state-of-the-art three-body calculations at the incident photon energies of 12.8 and 14.7 MeV. The data reveal the importance of including the Coulomb interaction between protons in three-body calculations.


A Cross-National Comparison of Attributional Patterns Toward Students With and Without Learning Disabilities.
Claims of the importance of having positive perceptions and expectations of students with learning disabilities (LD) have been repeatedly made over recent years. This article aims to raise awareness of the importance of attributional beliefs in relation to the educational outcomes of students with LD in Australia and China. Australian and Chinese trainee teachers ( N = 240) who were at the end of their training were surveyed with vignettes and Likert-scale questions to ascertain their responses to students with and without LD. Overall, the findings suggest that Chinese trainee teachers' attributional pattern is more positive than that of their Australian counterparts. Implications and recommendations for research and practice are also presented.


Glucagon-like and insulin-like hormones of the insect neurosecretory system.
Aqueous extracts of corpus cardiacum-corpus allatum complexes of the adult tobacco hornworm Manduca sexta produced both glycogenolysis and hypoglycaemia when injected into the larval form of the same species. Application of specific radioimmuno assays to similar extracts showed also that these gland complexes contain both glucagon-like and insulin-like peptides. Further, the partially purified immunoreactive peptides had the expected biological activities. The former decreased the glycogen content of the fatbody and the latter the circulating trehalose levels in recipient animals. These results suggest the existence of hormones in these invertebrates having both biological and structural similarities to vertebrate insulin and glucagon.


Mechanisms of methane activation and transformation on molybdenum oxide based catalysts.
We present a comprehensive survey of different C-H activation pathways over various kinds of active sites of terminal oxygens [=O] and bridge oxygens [-O-] by using Mo3O9 model systems. This allows us to provide some insights into fundamental issues concerning C-H activation by metal oxo species involved in many heterogeneous, homogeneous, and enzymatic processes. We show that H abstraction is the most feasible reaction pathway for the activation of a C-H bond on molybdenum oxides; and that [=O] is more active than [-O-]. Our calculations also suggest that (2+2) can be an alternative if M=O bond possesses a high polarity, while (5+2) can provide another effective pathway if two M=O bonds are in close proximity. Implications for the related heterogeneous, homogeneous, and enzymatic processes are discussed.


Ionotropic glutamate receptor biology: effect on synaptic connectivity and function in neurological disease.
Glutamate receptor signaling is essential to normal synaptic function in the central nervous system. The major ionotropic glutamate receptors (AMPA, Kainic, and NMDA) have different synaptic functions depending upon cellular and subcellular localization, subunit composition, and second messenger systems linked to the receptors. In this review, we examine major advances in glutamate receptor biology whose physiology plays a central role in neurologic disease such as epilepsy and stroke. A key feature of glutamate receptor activation in neurologic disease is the downstream effects on cell survival, genetic expression of axon guidance cues, synaptic connectivity/formation of networks, and neuronal excitability. Identification of therapeutic pharmacologic targets and development of antagonists specific to the disease process remain central themes in epilepsy and stroke research.


Clinicopathological characteristics of extrahepatic biliary neuroendocrine neoplasms in the gallbladder, extrahepatic biliary tract, and ampulla of Vater: A single-center cross-sectional study.
In 2019, the grading and staging system for neuroendocrine neoplasms (NENs) was significantly changed. In this study, we report the clinicopathological characteristics and surgical outcomes of patients with extrahepatic biliary NENs who underwent curative resection with or without adjuvant treatment. We retrospectively reviewed a database of 16 patients who developed NENs, neuroendocrine carcinoma (NEC), and mixed endocrine non-endocrine neoplasms (MiNENs) after curative resection. Among them, eight patients had ampulla of Vater (AoV) tumors, and eight patients had non-AoV tumors. G1 and G2 were more frequently observed in the AoV group than in the non-AoV group (12.5% and 62.5%, respectively). In contrast, NEC and MiNEN were more common in the non-AoV group (50.0%). High Ki-67 index (> 20%) and perineural invasion (PNI) were more frequently observed in the non-AoV group. Advanced age (> 65 years), mitotic count > 20 per 2 mm2, and Ki-67 index > 20% were strongly correlated with patient survival (p = 0.018, 0.009, and 0.044, respectively). Advanced age (> 65 years) and mitotic count > 20 per 2 mm2 were significantly correlated with disease recurrence (p = 0.033 and 0.010, respectively). AoV and non-AoV tumors had significant differences in the histologic grade, Ki67, and PNI. Patients with non-AoV tumors had an increased risk for survival and recurrence than those in the AoV group. For extrahepatic biliary NENs, early detection of tumors, adequate surgery, and aggressive adjuvant treatment for high-risk patients are important to achieve long-term survival and prevent disease recurrence.


Comic worksheets for integrated disaster risk reduction learning in the subject of Geography.
Indonesian students have limited visual learning capacity. Low literacy of such students has gained the researcher's attention in developing their literacy through comic worksheets. The researcher created comic worksheets with blank speech bubbles to help high school students build their conceptual framework about disaster risk mitigation. This study attempts to investigate the effectiveness of comic worksheets in helping high school students learn disaster risk reduction (DRR) in the subject of Geography. This study followed the research and development (R&D) approach to develop comic worksheets with blank speech bubbles. A paired sample t-test was used to analyse the mean difference between the pre-and post-test scores of 103 students. The results show a significant difference between both means. It indicates that using comic worksheets could improve student learning outcomes. It could also effectively be used as an assessment instrument for the students' affective aspects. Dialogues among comic characters compiled by students record their attitudes and behaviour in their everyday life. Collaboration between teachers, learning media developers, and artists is needed to create comic packages for learning Geography.


Cooperative Self-Assembly of Pyridine-2,6-Diimine-Linked Macrocycles into Mechanically Robust Nanotubes.
Nanotubes assembled from macrocyclic precursors offer a unique combination of low dimensionality, structural rigidity, and distinct interior and exterior microenvironments. Usually the weak stacking energies of macrocycles limit the length and mechanical strength of the resultant nanotubes. Imine-linked macrocycles were recently found to assemble into high-aspect ratio (>103 ), lyotropic nanotubes in the presence of excess acid. Yet these harsh conditions are incompatible with many functional groups and processing methods, and lower acid loadings instead catalyze macrocycle degradation. Here we report pyridine-2,6-diimine-linked macrocycles that assemble into high-aspect ratio nanotubes in the presence of less than 1 equiv of CF3 CO2 H per macrocycle. Analysis by gel permeation chromatography and fluorescence spectroscopy revealed a cooperative self-assembly mechanism. The low acid concentrations needed to induce assembly enabled nanofibers to be obtained by touch-spinning, which exhibit higher Young's moduli (1.33 GPa) than many synthetic polymers and biological filaments. These findings represent a breakthrough in the design of inverse chromonic liquid crystals, as assembly under such mild conditions will enable the design of structurally diverse and mechanically robust nanotubes from synthetically accessible macrocycles.


Soft tissue sealing around dental implants based on histological interpretation.
The aim of this study was to provide an overview on the biology and soft tissue sealing around dental implants and teeth. This is a narrative review performed through scientific articles published between 1977 and 2014, indexed in MEDLINE and PubMed databases. The study selected articles that focused on epithelial sealing around dental implant or teeth with cell biology and histology of soft tissue. Implant therapy has been widely applied in dental rehabilitation for many years, with predictable long-term results. The longevity and functionality of dental implants is dependent on both osseointegration around the implant body and the establishment of a soft tissue barrier that protects the underlying hard tissue structures and the implant itself. The health and stability of the peri-implant mucosa also affects the esthetics of the implant. The healing and maintenance of the epithelial and connective tissues around implants are increasingly recognized as being fundamental to implant success. However, there has been little research into the function or formation of the soft tissue seal around dental implants, and the roles of this unique mucosal interface remain unclear. This narrative review explores the extent of the current knowledge of soft tissue barriers around implants from both a basic and clinical perspective, and aims to consolidate this knowledge and highlight the most pertinent questions relating to this area of research.


Island life shapes the physiology and life history of eastern bluebirds (Sialia sialis).
Abstract Island organisms face a range of extrinsic threats to their characteristically small populations. Certain biological differences between island and continental organisms have the potential to exacerbate these threats. Understanding how island birds differ from their continental relatives may provide insight into population viability and serve as a predictive tool for conservation efforts. We compared an eastern bluebird population in Ohio with a threatened population in Bermuda in terms of the birds' development, morphology, immunology, and reproduction. These comparisons revealed that island nestlings had shorter wings and island adults had longer wings than their continental analogs. Island nestlings also had shorter tarsi than continental nestlings at day 8 posthatch, but this difference was absent at day 15 and in adults. Adults weighed less in Bermuda than in Ohio, and both nestlings and adults in Bermuda exhibited higher levels of two immunological indexes (concentrations of an acute-phase protein and titers of nonspecific antibodies). Clutch sizes and hatch rates did not differ between the island and continental populations; however, as the breeding season progressed, brood sizes declined in Bermuda, whereas no such decline occurred in Ohio. Despite these differences and differences in nestling development, island and continental parents fed their nestlings at equal rates. Overall, our results suggest that the Bermuda phenotype may be adjusted to certain aspects of the island environment but not to others. Efforts to conserve the bluebirds of Bermuda may be improved by focusing on the intraseasonal patterns in nestling mortality and, more generally, the survival probabilities of different age classes.


[Analysis of retinal nerve fiber layer thickness in superior segmental optic hypoplasia (SSOH)].
To evaluate the clinical characteristics of patients with superior segmental optic hypoplasia (SSOH) and quantitatively assess the structural characteristics using optical coherence tomography (OCT). Forty-three eyes of 43 subjects with SSOH and 30 eyes of 30 normal subjects as controls (mean age; 40.2 +/- 14.1, 42.9 +/- 9.9 years, mean refraction; - 4.6 +/- 3.7 D, -3.6 +/- 2.7 D, mean intraocular pressure; 14.6 +/- 2.5 mmHg, 14.3 +/- 3.2 mmHg, Humphrey visual field mean deviation; -4.31 +/- 4.3 dB, 0.01 +/- 1.2 dB) were enrolled. Forty-three eyes of the 43 patients with SSOH were examined by OCT for the quantitative assessment of the RNFL thickness (RNFLT). For the comparison of RNFLT, total average thickness, four quadrants and clock hour-based (12 equal 30 degree sectors) RNFLT were analyzed using OCT. OCT showed that the eyes with SSOH had significantly thinner RNFL than the normal subjects in total average thickness (SSOH 81.2 mm vs. 105.0 mm, p < 0.0001). Except for the temporal guadrant (p = 0.31), RNFL was thinner in superior, nasal(both p < 0.0001) and inferior (p = 0.002) guadrant. A comparison between the SSOH group and the normal control group for the 12 clock-hour segments in the OCT demonstrated that the patients with SSOH had decreased peripapillary RNFL thickness; the difference was statistically significant, except for the 7, 8, 9 and 10 o'clock segments. The area under the receiver operator characteristic curve (AUC) was greatest for the RNFL thickness of the 12 o'clock segment (AUC = 0.93), followed by the 1 o'clock segment (AUC = 0.90), and the 2 o'clock segment (AUC- = 0.87), as measured by the OCT. More generalized thinning of the RNFL and decreasing total average thickness except for the RNFL from 7 o'clock to 10 o'clock were identified in the eyes with SSOH with a relatively superior entrance of the central retinal artery and thinning of the superior retinal nerve fiber layer. It was also demonstrated that segments 12, 1 and 2 o'clock of the SSOH were highly useful for differential diagnosis.


Psychological, muscular and kinematic factors mediate performance under pressure.
It is well established that performance is influenced by pressure, but the underlying mechanisms of the pressure-performance relationship are poorly understood. To address this important issue, the current experiment evaluated psychological, physiological, and kinematic factors as mediators of the pressure-performance relationship. Psychological, physiological, and kinematic responses to three levels of competitive pressure were measured in 23 males and 35 females during a golf putting task. Pressure manipulations impaired putting performance. Self-reported anxiety, effort, and perceived pressure were increased. Heart rate, heart rate variability, muscle activity, and lateral clubhead acceleration were also elevated. Mediation analyses revealed that effort, muscle activity, and lateral acceleration partially mediated the decline in performance. Results confirmed that pressure elicits effects on performance through multiple pathways.


Fever and hypothermia in systemic inflammation: recent discoveries and revisions.
Systemic inflammation is accompanied by changes in body temperature, either fever or hypothermia. Over the past decade, the rat and mouse have become the predominant animal models, and new species-specific tools (recombinant antibodies and other proteins) and genetic manipulations have been applied to study fever and hypothermia. Remarkable progress has been achieved. It has been established that the same inflammatory agent can induce either fever or hypothermia, depending on several factors. It has also been established that experimental fevers are generally polyphasic, and that different mechanisms underlie different febrile phases. Signaling mechanisms of the most common pyrogen used, bacterial lipopolysaccharide (LPS), have been found to involve the Toll-like receptor 4. The roles of cytokines (such as interleukins-1beta and 6 and tumor necrosis factor-alpha) have been further detailed, and new early mediators (e.g., complement factor 5a and platelet-activating factor) have been proposed. Our understanding of how peripheral inflammatory messengers cross the blood-brain barrier (BBB) has changed. The view that the organum vasculosum of the lamina terminalis is the major port of entry for pyrogenic cytokines has lost its dominant position. The vagal theory has emerged and then fallen. Consensus has been reached that the BBB is not a divider preventing signal transduction, but rather the transducer itself. In the endothelial and perivascular cells of the BBB, upstream signaling molecules (e.g., pro-inflammatory cytokines) are switched to a downstream mediator, prostaglandin (PG) E2. An indispensable role of PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing enzymes or PGE2 receptors. The PGE2-synthesizing enzymes include numerous phospholipases (PL) A2, cyclooxygenases (COX)-1 and 2, and several newly discovered terminal PGE synthases (PGES). It has been realized that the "physiological," low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes. The "inflammatory" set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "fever receptor." The effector pathways of fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vaso-constriction are located. The rapid progress in our understanding of how thermoeffectors are controlled has revealed the inadequacy of set point-based definitions of thermoregulatory responses. New definitions (offered in this review) are based on the idea of balance of active and passive processes and use the term balance point. Inflammatory signaling and thermoeffector pathways involved in fever and hypothermia are modulated by neuropeptides and peptide hormones. Roles for several "new" peptides (e.g., leptin and orexins) have been proposed. Roles for several "old" peptides (e.g., arginine vasopressin, angiotensin II, and cholecystokinin) have been detailed or revised. New pharmacological tools to treat fevers (i.e., selective inhibitors of COX-2) have been rapidly introduced into clinical practice, but have not become magic bullets and appeared to have severe side effects. Several new targets for antipyretic therapy, including mPGES-1, have been identified.


The N-allyl substituted effect on wormlike micelles and salt tolerance of a C22-tailed cationic surfactant.
Wormlike micelles (WLMs) have been observed in a wide variety of cationic surfactants. Here we developed WLMs based on an N-allyl substituted cationic surfactant with an unsaturated C22-tail, N-erucamidopropyl-N,N-dimethyl-N-allyl-ammonium bromide (EDAA), and compared them with UC22AMPM at the same concentration. The viscoelasticity, aggregate microstructure and salt tolerance of EDAA solutions were investigated by rheology, surface tension and Cryo-TEM measurements. It was found that EDAA exhibited a higher viscosity and a high salt tolerance. Upon increasing the concentration of NaCl, the viscosity of wormlike micelles in the solutions continuously increased and reached ∼1.10 × 106 mP s at 200 mM. On further increasing the NaCl concentration to 2000 mM, the viscosity remained at ∼106 mP s without any reduction. But the viscosity of UC22AMPM solutions showed a drastic change with the increase of NaCl concentration. This drastic variation in rheological behavior is attributed to the presence of the N-allyl substituent. Besides, the EDAA also shows some advantages such as low overlapping concentration(∼2.2 mM) and stable viscosity over the whole pH range.


Mapping of Morphine-Induced OPRM1 Gene Expression Pattern in the Adult Zebrafish Brain.
Morphine is a potent analgesic opiate commonly used in treating pain, and it is also a substance of abuse and highly addictive. Hence, it is vital to discover the action sites of morphine in the brain to increase its efficacy of treatment. In the present study, we aimed at identifying comprehensive neuroanatomical locations that are sensitive to morphine in the adult zebrafish (Danio rerio). We performed in situ hybridization to localize the mu opioid receptor (oprm1) gene and to map the morphine sensitive brain areas using neuronal PAS domain-containing protein 4a (npas4a), an early gene marker. Real-time PCR was used to detect changes in mRNA levels of oprm1 and npas4a in control and acute morphine treated fish (2 mg/L; 20 min). Intense positive oprm1 signals were seen in the telencephalon, preoptic area, habenula, hypothalamic area and periventricular gray zone of the optic tectum. Acute morphine exposure significantly increased oprm1 and npas4a mRNA levels in the medial zone of dorsal telencephalon (Dm), ventral region of the ventral telencephalon (Vv), preoptic area, and in the hypothalamus but a decrease in oprm1 and npas4a signals in the dorsal habenula. This study provides a detailed map of oprm1 localization in the brain, which includes previously unreported oprm1 in the habenula of teleost. Presence of oprm1 in multiple brain sites implies multiple action targets of morphine and potential brain functions which could include reward, cognitive and negative emotions.


Calpains: potential targets for alternative chemotherapeutic intervention against human pathogenic trypanosomatids.
The treatment for both leishmaniasis and trypanosomiasis, which are severe human infections caused by trypanosomatids belonging to Leishmania and Trypanosoma genera, respectively, is extremely limited because of concerns of toxicity and efficacy with the available anti-protozoan drugs, as well as the emergence of drug resistance. Consequently, the urgency for the discovery of new trypanosomatid targets and novel bioactive compounds is particularly necessary. In this context, the investigation of changes in parasite gene expression between drug resistant/sensitive strains and in the up-regulation of virulence-related genes in infective forms has brought to the fore the involvement of calpain-like proteins in several crucial pathophysiological processes performed by trypanosomatids. These studies were encouraged by the publication of the complete genome sequences of three human pathogenic trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, which allowed in silico analyses that in turn directed the identification of numerous genes with interesting chemotherapeutic characteristics, including a large family of calpain-related proteins, in which to date 23 genes were assigned as calpains in T. brucei, 40 in T. cruzi and 33 in L. braziliensis. In the present review, we intend to add to these biochemical/biological reports the investigations performed upon the inhibitory capability of calpain inhibitors against human pathogenic trypanosomatids.


Genomic Alterations of Signaling and DNA Damage Repair Pathways in Non-Muscle Invasive Bladder Cancer.
The aim of the study was to demonstrate the most common genetic alterations and evaluate possible targets involving phosphatidylinositol-3-OH kinase (PIK3)/AKT/mammalian target of rapamycin (mTOR) signaling and DNA damage repair (DDR) pathways for personalized treatment in patients with non-muscle invasive bladder cancer (NMIBC). Alterations of these pathways were observed in 89.5% and 100% of patients, respectively. Among them, BARD1 was more frequently altered in low/intermediate-risk cases, but PARP4 was more frequently affected in intermediate/high-risk patients. The possible target feasibility of BARD1 and PARP4 alterations should be evaluated for personalized treatment using PARP-inhibitors in NMIBC. It is important to detect high tumor mutation burden (TMB) in patients in terms of immunotherapy.


Neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level are increased in the hypothalamus of mouse bearing a human oral squamous cell carcinoma.
We examined gene expression of corticotropin-releasing hormone and neuropeptide Y level in the hypothalamic paraventricular nucleus of mouse bearing a human oral squamous cell carcinoma. A cell line derived from a human oral squamous cell carcinoma was inoculated into the lower dorsal area of nude mice. Body weight, tumor size and daily food intake were recorded every morning. Mice were sacrificed for corticotropin-releasing hormone mRNA in situ hybridization and neuropeptide Y immunohistochemistry, when the tumor ratio reached to 11-13% of real body weight. The results were compared with the age-matching non-tumor controls injected with saline instead of carcinoma cell. Body weight gain was significantly reduced in tumor bearing mice, however, no compensatory hyperphagia was found, i.e. daily food intake of the tumor mice did not differ from the non-tumor mice. Both neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level were significantly increased in the hypothalamic paraventricular nucleus of tumor mice. These results suggest that a human oral squamous cell carcinoma may induce anorexia, at least partly, via increasing the hypothalamic expression of corticotropin-releasing hormone in the tumor subjects. Additionally, neuropeptide Y-induced feeding appears to be inhibited in this tumor anorexia model, and this may correlate with increased expression of corticotropin-releasing hormone.


InstantLabs® Salmonella species detection method: matrix extension.
The performance of InstantLabs® Salmonella Species Food Safety Kit to detect Salmonella in four food matrixes was validated against the International Organization for Standardization (ISO) reference method 6579:2002. The matrixes (raw ground beef, raw chicken breast, raw ground chicken, and lettuce) were inoculated with low levels of Salmonella (<1 CFU/test portion) to generate fractional positives (5-15) in 20 inoculated samples. These matrixes were co-inoculated with Escherichia coli O157:H7 at two to five times the level of Salmonella. Samples were validated using 375 g (meat) or 25 g (lettuce and poultry) test portions enriched in FASTGRO TM SE at 42±1 °C for 12 h and 10 h, respectively. All samples were confirmed using the ISO reference method, regardless of initial-screen result. The InstantLabs test method was shown to perform as well as or better than the reference method for the detection of Salmonella species in ground beef, chicken breast, ground chicken, and lettuce. Inclusivity and exclusivity testing revealed no false negatives among the 100 Salmonella serovars and no false positives among the 30 non-Salmonella species examined, respectively.


Effect of Resveratrol on Preventing Steroid-induced Osteonecrosis in a Rabbit Model.
Prevention of osteonecrosis (ON) has seldom been addressed. The purpose of this study was to evaluate the effect of resveratrol on preventing steroid-induced ON in rabbits. Seventy-two rabbits were divided into four groups: (1) NEC (ON) group: thirty rabbits were treated with lipopolysaccharide (LPS) once, then with methylprednisolone (MPS) daily for 3 days; (2) PRE (prevention) group: thirty rabbits were given one dose of LPS, then MPS daily for 3 days, and resveratrol on day 0 and daily for 2 weeks; (3) RES (resveratrol) group: six rabbits were given resveratrol for 2 weeks but without LPS/MPS; (4) CON (control) group: six rabbits were given alcohol for 2 weeks but without LPS/MPS. Levels of plasma tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), thrombomodulin (TM), vascular endothelial growth factor (VEGF), maximum enhancement (ME) by magnetic resonance imaging, and ON incidence were evaluated. The PRE group had a lower ON incidence than the NEC group, but with no significant differences at 2 weeks and 12 weeks. The RES and CON groups did not develop ON. TM and VEGF were significantly higher in the NEC group compared with the PRE group at weeks 1, 2, and 4 (TM: 1 week, P = 0.029; 2 weeks, P = 0.005; and 4 weeks, P = 0.047; VEGF: 1 week, P = 0.039; 2 weeks, P = 0.021; 4 weeks, P = 0.014), but the difference disappeared at 12 weeks. The levels of t-PA and PAI-1 were not significantly different between the NEC and PRE groups. The TM, t-PA, PAI-1, and VEGF concentrations in the RES and CON groups did not change over time. Compared to the baseline, ME in the NEC group decreased significantly (P = 0.025) at week 1, increased significantly (P = 0.021) at week 2, and was decreased at week 12. The variance was insignificant in the PRE group. Resveratrol may improve blood supply to bone in a rabbit model of ON of the femoral head via anti-inflammatory effects to protect the vascular endothelium and reduce thrombosis.


Identification of DNA Viruses in Ancient DNA from Herbarium Samples.
Herbaria encompass millions of plant specimens, mostly collected in the nineteenth and twentieth centuries that can represent a key resource for investigating the history and evolution of phytopathogens. In the last years, the application of high-throughput sequencing technologies for the analysis of ancient nucleic acids has revolutionized the study of ancient pathogens including viruses, allowing the reconstruction of historical genomic viral sequences, improving phylogenetic based molecular dating, and providing essential insight into plant virus ecology. In this chapter, we describe a protocol to reconstruct ancient plant and soil viral sequences starting from highly fragmented ancient DNA extracted from herbarium plants and their associated rhizospheric soil. Following Illumina high-throughput sequencing, sequence data are de novo assembled, and DNA viral sequences are selected, according to their similarity with known viruses.


Uptake of advance care planning and its circumstances: An nationwide survey in Australian general practice.
There are potential benefits associated with advance care planning (ACP), and general practitioners (GPs) are well placed to coordinate ACP initiatives with their patients. Few studies have reported on the uptake of different forms of advance care plan conducted by GPs and how this affects patients' place of death. The primary aims of the study were to examine uptake of verbal (conversations regarding care preferences) and written (documented care preferences) advance care plans and their associated factors from the perspective of Australian GPs. The secondary aim was to determine the impact of different types of advance care plans on place of death. Sixty-one GPs from three Australian states used a validated clinic-based data collection process to report on care provided for decedents in the last year of life, including provision of services, place of death, and uptake of ACP. We found that 58 (27.9%), 91 (43.7%) and 59 (28.4%) reported decedents had no advance care plans, verbal plans or written plans, respectively. There were increased uptake of both verbal plans (relative risk ratio [RRR] = 13.10, 95% confidence interval [CI]: 2.18-77.34) and written plans (RRR = 10.61, 95% CI: 1.72-65.57) if GPs foresaw the death for >90 days versus <7 days. Palliative care training history for GPs predicted uptake of verbal plans (RRR = 5.83, 95% CI: 1.46-31.93). Patients with verbal plans versus no plans were more likely to die at a private residence (odds ratio = 4.97, 95% CI: 1.32-18.63). Our findings suggest that expectation of death for at least three months prior to the event (where clinically possible) and palliative care training for GPs improve the uptake of ACP in general practice. Larger pragmatic trials are required to determine the impact of ACP on patients' place of death.


Risk factors for stroke outcomes in adults: Stroke in China.
This study aimed to determine the possible risk factors for stroke outcomes based on prospective cohort study in China. A total of 146 stroke patients were recruited and divided into 2 groups, which assessed using the modified Rankin Scale (mRS), good outcomes (mRS <= 2) and poor outcomes group (mRS > 2). Demographic, clinical, and laboratory characteristics of participants were obtained from the medical record. The multivariable logistic regression analysis was employed to assess the risk factors for stroke outcomes. Of 146 participants, 28 (19.18%) were presented with poor outcomes at day 90. As a result of multivariable logistic regression analysis, a significantly increased risk of stroke outcomes was found in patients with Barthel Index (BI) score (stroke (OR 1.50, 95% CI 1.21 ~ 1.85, P < .001) and IS (OR 1.48, 95% CI 1.20 ~ 1.83, P < .001)).


Protein-protein docking with F(2)Dock 2.0 and GB-rerank.
Computational simulation of protein-protein docking can expedite the process of molecular modeling and drug discovery. This paper reports on our new F(2) Dock protocol which improves the state of the art in initial stage rigid body exhaustive docking search, scoring and ranking by introducing improvements in the shape-complementarity and electrostatics affinity functions, a new knowledge-based interface propensity term with FFT formulation, a set of novel knowledge-based filters and finally a solvation energy (GBSA) based reranking technique. Our algorithms are based on highly efficient data structures including the dynamic packing grids and octrees which significantly speed up the computations and also provide guaranteed bounds on approximation error. The improved affinity functions show superior performance compared to their traditional counterparts in finding correct docking poses at higher ranks. We found that the new filters and the GBSA based reranking individually and in combination significantly improve the accuracy of docking predictions with only minor increase in computation time. We compared F(2) Dock 2.0 with ZDock 3.0.2 and found improvements over it, specifically among 176 complexes in ZLab Benchmark 4.0, F(2) Dock 2.0 finds a near-native solution as the top prediction for 22 complexes; where ZDock 3.0.2 does so for 13 complexes. F(2) Dock 2.0 finds a near-native solution within the top 1000 predictions for 106 complexes as opposed to 104 complexes for ZDock 3.0.2. However, there are 17 and 15 complexes where F(2) Dock 2.0 finds a solution but ZDock 3.0.2 does not and vice versa; which indicates that the two docking protocols can also complement each other. The docking protocol has been implemented as a server with a graphical client (TexMol) which allows the user to manage multiple docking jobs, and visualize the docked poses and interfaces. Both the server and client are available for download. Server: http://www.cs.utexas.edu/~bajaj/cvc/software/f2dock.shtml. Client: http://www.cs.utexas.edu/~bajaj/cvc/software/f2dockclient.shtml.


Sequence Effects in Conjugated Donor-Acceptor Trimers and Polymers.
To investigate the sequence effect on donor-acceptor conjugated oligomers and polymers, the trimeric isomers PBP and BPP, comprising dialkoxy phenylene vinylene (P), benzothiadiazole vinylene (B), and alkyl endgroups with terminal olefins, are synthesized. Sequence effects are evident in the optical/electrochemical properties and thermal properties. Absorption maxima for PBP and BPP differ by 41 nm and the electrochemical band gaps by 0.1 V. The molar emission intensity is five times greater in PBP than BPP. Both trimers are crystalline and the melting points differ by 17 °C. The PBP and BPP trimers are used as macromonomers in an acyclic diene metathesis polymerization to give PolyPBP and PolyBPP. The optical and electrochemical properties are similar to those of their trimer precursors-sequence effects are still evident. These results suggest that sequence is a tunable variable for electronic materials and that the polymerization of oligomeric sequences is a useful approach to introducing sequence into polymers.


Interposition Tendon Graft and Tension in the Repair of Closed Rupture of the Flexor Digitorum Profundus in Zone III or IV.
We report the results of interposition tendon grafts using the ipsilateral palmaris longus tendon in 12 patients with closed flexor digitorum profundus tendon ruptures in zone III or IV of 14 digits between June 2006 and October 2015. Before surgery, 2 patients were diagnosed with closed tendon ruptures that occurred after nonunion of hamate hook fractures. The other 10 patients were diagnosed with spontaneous tendon ruptures of unknown cause. In 2 of the 10 patients with spontaneous tendon rupture, the cause of the rupture was not found. In the other 8 patients, there was rough surface with deficient overlying soft tissue on the radial side of the hamate hook. In all cases, the ruptured flexor digitorum profundus was reconstructed by applying overtension on the tendon graft, causing greater flexion than for the other normal digits. Hamate hook excision was also performed on 10 subjects with abnormalities. Postoperatively, the patients were followed for an average of 22.5 months (range, 12-64 months). At the final follow-up, the mean Disabilities of the Arm, Shoulder, and Hand questionnaire score was 5.7 (range, 3.3-8.3). There were excellent results in all 14 digits according to Strickland and Glogovac criteria. The mean total active motion was 167 degrees (range, 160-180 degrees). There were no surgical complications, including infection, adhesions, or tendon rerupture. There were excellent clinical results with the interposition tendon graft using palmaris longus for closed tendon rupture in zone III or IV of the hand. Applying overtension to the grafted tendon appears to be beneficial.


The synthesis of 5-alpha-dihydrotestosterone from androgens by human gingival tissues and fibroblasts in culture in response to TGF-beta and PDGF.
The effects of TGF-beta and PDGF on the metabolic conversion of 14C-testosterone by human gingival tissue (HGT) from 5 subjects was investigated. The metabolic conversions in response to TGF-beta and PDGF were also studied in 4-6 cell-lines of cultured gingival fibroblasts, using 14C-testosterone and 14C-4-androstenedione as substrates. Duplicate incubations of HGT were performed in Eagle's MEM + 10% FCS and optimal stimulatory concentrations of TGF-beta/PDGF for 24 h. Similar incubations were performed in duplicate with cell-lines of cultured gingival fibroblasts, TGF-beta/PDGF, 14C-testosterone/14C-4-androstenedione in Eagle's MEM + 10% FCS. The radioactive metabolites were extracted, separated and quantified. With HGT, TGF-beta and PDGF caused 2.5/2-fold increases in DHT synthesis (p < 0.1; Wilcoxon signed rank test) and 3.4/2-fold increases in 4-androstenedione formation (p < 0.1) from 14C-testosterone. PDGF increased DHT and testosterone synthesis from 14C-4-androstenedione by 3-fold in gingivae (p < 0.1). With cell-lines, average values of duplicate incubations showed 2.8/2-fold increases in DHT synthesis from 14C-testosterone in response to TGF-beta/PDGF (p < 0.1; p < 0.2) and 2.4/2-fold increases in 4-androstenedione synthesis (p < 0.1; p < 0.2). With 14C-4-androstenedione as substrate, TGF-beta/PDGF caused 1.6/1.9-fold increases in DHT synthesis compared with controls (p < 0.05; p < 0.1) and 1.7/1.5-fold increases in testosterone formation from this substrate (p < 0.05; p < 0.1). Due to the strong implications of TGF-beta/PDGF and anabolic androgens on matrix repair, significant increases in DHT synthesis from 2 androgenic substrates in response to TGF-beta and PDGF are of particular relevance to inflammatory repair processes.


Characteristics and treatment patterns in older patients with locally advanced head and neck cancer (KCSG HN13-01).
Treatment decisions for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are complicated, and multi-modal treatments are usually indicated. However, it is challenging for older patients to complete treatments. Thus, we investigated disease characteristics, real-world treatment, and outcomes in older LA-HNSCC patients. Older patients (aged ≥ 70 years) were selected from a large nationwide cohort that included 445 patients with stage III-IVB LA-HNSCC from January 2005 to December 2015. Their data were retrospectively analyzed and compared with those of younger patients. Older patients accounted for 18.7% (83/445) of all patients with median age was 73 years (range, 70 to 89). Proportions of primary tumors in the hypopharynx and larynx were higher in older patients and older patients had a more advanced T stage and worse performance status. Regarding treatment strategies of older patients, 44.5% of patients received concurrent chemoradiotherapy (CCRT), 41.0% underwent surgery, and 14.5% did not complete the planned treatment. Induction chemotherapy (IC) was administered to 27.7% (23/83) of older patients; the preferred regimen for IC was fluorouracil and cisplatin (47.9%). For CCRT, weekly cisplatin was prescribed 3.3 times more often than 3-weekly cisplatin (62.2% vs. 18.9%). Older patients had a 60% higher risk of death than younger patients (hazard ratio, 1.6; p = 0.035). Oral cavity cancer patients had the worst survival probability. Older LA-HNSCC patients had aggressive tumor characteristics and received less intensive treatment, resulting in poor survival. Further research focusing on the older population is necessary.


The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats.
Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure-induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.


Functional specialization within the vacuolar sorting receptor family: VSR1, VSR3 and VSR4 sort vacuolar storage cargo in seeds and vegetative tissues.
Two different gene families have been proposed to act as sorting receptors for vacuolar storage cargo in plants: the vacuolar sorting receptors (VSRs) and the receptor homology-transmembrane-RING H2 domain proteins (RMRs). However, functional data on these genes is scarce and the identity of the sorting receptor for storage proteins remains controversial. Through a genetic screen we have identified the mtv2 mutant, which is defective in vacuolar transport of the storage cargo VAC2 in shoot apices. Map-based cloning revealed that mtv2 is a loss of function allele of the VSR4 gene. We show that VSR1, VSR3 and VSR4, but not the remaining VSRs or RMRs, participate in vacuolar sorting of VAC2 in vegetative tissues, and 12S globulins and 2S albumins in seeds, an activity that is essential for seedling germination vigor. Finally, we demonstrate that the functional diversification in the VSR family results from divergent expression patterns and also from distinct sorting activities of the family members.


Vitamin B12 excretion in patients with various skin diseases.
The excretion in the urine of (58)Co after an oral dose of (58)Co vitamin B(12) given together with intrinsic factor has been found to be reduced in a number of patients with psoriasis, eczema, and other less common dermatoses. There is a correlation between the abnormality and the extent of the rash. A reduced glomerular filtration rate was found in a few of the patients in whom it was measured, and this must have been responsible, at least in part, for the reduced excretion of vitamin B(12) in these patients, but abnormal vitamin B(12) excretion also occurred in the absence of impaired renal function. Our evidence is insufficient to show whether malabsorption or increased tissue utilization of vitamin B(12) was the explanation in other cases. Certainly a number of patients had steatorrhoea, and in these it is most likely that malabsorption was the major factor. In patients without steatorrhoea a lone malabsorption of vitamin B(12) cannot be excluded. A decreased serum concentration of vitamin B(12) was found in only one of the patients.


Emergence of resistance to biocides during differentiation of Acanthamoeba castellanii.
A synchronous encystment method was used to study the order of development of resistance of Acanthamoeba castellanii to a range of biocides. The emerging resistance during encystation to short-term exposure to the minimum amoebicidal concentrations of each biocide tested was recorded during the first 36 h of the differentiation process. Hydrochloric acid and moist heat were tested as possible resistance markers. Development of the acid-insoluble, proteincontaining, ectocyst wall and the cellulose endocyst wall was followed by quantification of the acid- and alkali-insoluble residues of cell samples removed from synchronous encystment cultures up to 36 h. Resistance to chemical agents (polyhexamethylene biguanide, benzalkonium chloride, propamidine isethionate, pentamidine isethionate, dibromopropamidine isethionate, hydrogen peroxide) and to moist heat was seen to develop between 14 and 24 h after trophozoites were inoculated into the encystment media. Resistance to hydrochloric acid developed between 0 and 2 h and to chlorhexidine diacetate between 24 and 36 h. Levels of acid-insoluble residues began to increase after 8 h and alkali-insoluble residues (cellulose) were detected after 16 h and coincided with the emergence of resistance to all the agents tested except hydrochloric acid. The results suggest that resistance to the biocides tested probably results largely from the physical barrier of the cyst walls rather than as a consequence of a metabolically dormant cyst.


Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature.
Aspirin-exacerbated respiratory disease (AERD) is manifested by adult-onset asthma, nasal polyposis, chronic rhinosinusitis, and aspirin sensitivity. Previously reported prevalence rates have been widely variable based on the population studied, method of diagnosis, and definition of aspirin sensitivity. We sought to determine the prevalence of AERD among asthmatic adults. A systematic review of databases was performed to identify all clinical trials published on or before June 16, 2013, that evaluated the prevalence of AERD. The studies were clustered into 7 different groups based on underlying disease (asthma, nasal polyps or chronic rhinosinusitis, or both), as well as on the methodology of prevalence determination. A total of 1770 articles were identified, with 27 considered appropriate for inclusion. Prevalence rates of AERD ranged from 5.5% to 12.4% based on study type. Among all studies in asthmatic patients, regardless of method, the prevalence of AERD was 7.15% (95% CI, 5.26% to 9.03%). The prevalence of AERD was highest among patients with severe asthma (14.89% [95% CI, 6.48% to 23.29%]). Among patients with nasal polyps and chronic rhinosinusitis, the prevalence was 9.69% (95% CI, 2.16% to 17.22%) and 8.7% (95% CI, -1.02% to 18.34%), respectively. AERD is a distinct and important subtype of asthma and polypoid sinus disease. The prevalence of AERD is 7% in typical adult asthmatic patients and twice that number in patients with severe asthma, which underscores the importance of recognizing this disorder. Early identification of this syndrome is critical in view of the increased morbidity and costs associated with asthma exacerbations and the option to treat patients with AERD with long-term aspirin treatment after desensitization.


Long-range surface modes of metal-clad four-layer waveguides.
The surface modes of metal-clad four-layer waveguides were theoretically analyzed. We showed that the long-range surface modes can be excited in such waveguides. The long-range surface modes were experimentally studied with the angle scanning attenuated-total-reflection method; the dependence of wave vector and loss of these modes on the waveguide parameters were measured. Experimental results were in good agreement with theoretical calculations.


Examining the Association Between Affordable Care Act Medicaid Expansion and Sexually Transmitted Infection Testing Among U.S. Women.
Sexually transmitted infection (STI) rates are rising among women in the United States, increasing the importance of routine STI testing. Beginning in 2014, some states expanded Medicaid under the Affordable Care Act, providing health coverage to most individuals in and near poverty. Here, we investigate whether Medicaid expansion changed rates of STI testing among U.S. women. We analyzed nationally representative 2011-2017 National Survey of Family Growth data from U.S. women ages 15-44. Using difference-in-differences analysis, we assessed whether Medicaid expansion was associated with within-state changes in the prevalence of STI testing in the past 12 months, among women overall and by race/ethnicity and sexual orientation, during each year following Medicaid expansion. Models were adjusted for individual- and state-level demographic and socioeconomic factors. Our sample included 14,196 U.S. women. Medicaid expansion was associated with higher STI testing rates, which increased over time. By 3 years post-expansion, expansion states had increased STI testing by 12.7 percentage points more than nonexpansion states (95% confidence interval [CI] [2.5, 23.0], p = .016). This association was imprecisely estimated within racial/ethnic and sexual orientation subgroups, but trended strongest among White, Latina, and heterosexual women, followed by Black and bisexual women (who tested more often at baseline). Medicaid expansion is associated with increased STI testing among U.S. women; these benefits grew over time but varied by both race/ethnicity and sexual orientation. State governments that fail to expand Medicaid may harm their residents' health by allowing more spread of STIs.


Impact of MRI on high grade Ductal Carcinoma Insitu (HG DCIS) management, are we using the full scope of MRI?
Preoperative assessment of pure Ductal Carcinoma Insitu (DCIS) is essential in the surgical planning. The role of Magnetic resonance imaging (MRI) has long been debated. The impact of MRI on the management of High Grade (HG) DCIS was assessed, whether it accurately captures the true size of this entity in comparison to conventional imaging, and, if MRI use would reduce the number of re-excision surgery. Ninety-one consecutive patients with HG DCIS, who were identified from a prospectively collected data at Kettering General Hospital between April 2011 and December 2015. All patients had preoperative MRI scan in addition to the standard breast imaging. This was compared to a control group of consecutive patients (n=52) which was obtained from a period just before 2011. Impact on surgical planning and number of surgeries for each patient was compared. The size of HG DCIS estimated by MRI was compared to the final histological size. Secondary outcomes included change of initial surgical plan and detection of occult contralateral breast cancer. MRI group had 91 patients with median age of 63. Seventy percent of which presented through the screening program. The overall sensitivity of MRI to detect HG DCIS was 77% (70/91) with a false negative rate FNR of 23% (21/91). Therefore, 70 patients only were included in the data analysis. The control group included 52 screening patients with comparable baseline characteristics. Re-excision (or completion mastectomy) rates were higher in the control group 26% compared to 8% in the MRI group (P-value 0.012). MRI use correctly converted the initial plan of breast conservation to mastectomy in 9 patients (13%). Five patients had additional ipsilateral malignant features (7%).Occult contra lateral disease, was diagnosed in 2 patients (3%). This study suggests that MRI could be an important tool in reducing the re-excision rates in the surgical management of HG DCIS. Although still controversial, selective MRI imaging can be useful in the preoperative diagnosis and evaluation of HG DCIS. Case by case discussion at MDT is crucial. Wider adaptation of MRI when indicated in the assessment of breast lesions with proper correlation to histology postoperatively is a key in improving our MRI interpretation skills, helping us to exploit the full scope of this useful tool.


Acute Kidney Injury Pharmacokinetic Changes and Its Impact on Drug Prescription.
Acute kidney injury (AKI) is a common problem in hospitalized patients that is associated with significant morbid-mortality. The impact of kidney disease on the excretion of drugs eliminated by glomerular filtration and tubular secretion is well established, as well as the requirement for drug dosage adjustment in impaired kidney function patients. However, since impaired kidney function is associated with decreased activity of several hepatic and gastrointestinal drug-metabolizing enzymes and transporters, drugs doses adjustment only based on kidney alteration could be insufficient in AKI. In addition, there are significant pharmacokinetics changes in protein binding, serum amino acid levels, liver, kidney, and intestinal metabolism in AKI, thus the determination of plasma drug concentrations is a very useful tool for monitoring and dose adjustment in AKI patients. In conclusion, there are many pharmacokinetics changes that should be taken into account in order to perform appropriate drug prescriptions in AKI patients.


The metabolic impact of small intestinal nutrient sensing.
The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes.


Chronic oral administration of Passiflora incarnata extract has no abnormal effects on metabolic and behavioral parameters in mice, except to induce sleep.
Although the number of prescriptions and dependence on sleeping pills are increasing, the associations with unexpected abnormal behaviors and metabolic diseases caused by the overuse of sleeping pills are not well understood. In particular, such as abnormal eating-behavior and the occurrence of metabolic disorders caused by psychological unstable states are reported. For this reason, herbal medicine, which has not had such side effects in recent years, is attracting attention as an alternative medicine/food for sleeping inducer. We have used ethanol extracts from Passiflora incarnata (PI) to steadily obtain positive effects on sleep and brain microenvironment. However, as mentioned earlier, sleep-inducing efficacy can only be used safely if the behavioral and metabolic abnormalities do not appear. Thus, in this study, we used Phenomaster equipment to continuously monitor the movement, feeding, water consumption, gas changes, etc. in C57BL/6 mice at a dose of 500 mg/kg/day for 5 consecutive days with PI extract group compared with the control group. Before sacrifice, differences in body composition of mice were also compared. Monitoring of 24 h/5 days through the equipment showed no change in PI-treated group in anything except for significant decrease in blood melatonin levels and activity after PI administration. Taken together, the statistically insignificance of any behavioral and metabolic phenomenon produced by repeated treatment of PI are not only expected to have an accurate sleep effect, but are also free of side effects of the prescribed sleeping pills. This study has given us greater confidence in the safety of the PI extracts we use for sleep-inducer.


Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket.
The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects. Inspired by the hypothesis that structural changes that are associated with events initiating unfolding in DBD are likely to present opportunities for inhibition, we investigate the dynamics of the wild type (WT) and some aggregating mutants through extensive all atom explicit solvent MD simulations. Simulations reveal differential conformational sampling between the WT and the mutants of a turn region (S6-S7) that is contiguous to a known aggregation-prone region (APR). The conformational properties of the S6-S7 turn appear to be modulated by a network of interacting residues. We speculate that changes that take place in this network as a result of the mutational stress result in the events that destabilize the DBD and initiate unfolding. These perturbations also result in the emergence of a novel pocket that appears to have druggable characteristics. FDA approved drugs are computationally screened against this pocket.


[Views of GPs and patients on use of computers during consultation].
The aim of this study was to describe how Danish patients and their general practitioners (GPs) perceive physician's use of computers during consultation. Data were collected between November 2006 and February 2007 at five primary care clinics. Nine GPs and 253 of their patients completed complementary questionnaires concerning the consultation as a whole and their perceptions of computer use during consultation. Patients were generally satisfied with their GP's use of computers during consultations. Compared to their practitioners, patients more often perceived computer use to be extensive. 28% of patients reported their GP's computer use as extensive. These patients more often reported discomfort with their GP's computer use (OR 1.09), or stated that they did not get help with the problem they most wanted solved (OR 0.83), compared with patients who perceived their GP's computer use as less extensive. Men (OR 2.21) and patients over 55 years of age (OR 2.45) were also overrepresented in this group. Overall, patients were satisfied with their consultations. Patients generally perceived computer use as more extensive than doctors did. Where patients perceived their GP's computer use as extensive, they tended to rate selected consultation quality indicators lower. Further study in this field of general practice is therefore needed.


Active and passive maternal smoking during pregnancy and the risks of low birthweight and preterm birth: the Generation R Study.
The objective of this study was to examine the associations between active and passive smoking in different periods of pregnancy and changing smoking habits during pregnancy, with low birthweight and preterm birth. The study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards in Rotterdam, The Netherlands. Active and passive smoking were assessed by questionnaires in early, mid- and late pregnancy. Analyses were based on 7098 pregnant women and their children. Active smoking until pregnancy was ascertained and was not associated with low birthweight and preterm birth. Continued active smoking after pregnancy was also recorded and was associated with low birthweight (adjusted odds ratio 1.75 [95% CI 1.20, 2.56]) and preterm birth (adjusted odds ratio 1.36 [95% CI 1.04, 1.78]). The strongest associations were found for active maternal smoking in late pregnancy. Passive maternal smoking in late pregnancy was associated with continuously measured birthweight (P for trend <0.001). For all active smoking categories in early pregnancy, quitting smoking was associated with a higher birthweight than continuing to smoke. Tendencies towards smaller non-significant beneficial effects on mean birthweight were found for reducing the number of cigarettes without quitting completely. This study shows that active and passive smoking in late pregnancy are associated with adverse effects on weight and gestational age at birth. Smoking in early pregnancy only, seems not to affect fetal growth adversely. Health care strategies for pregnant women should be aimed at quitting smoking completely rather than reducing the number of cigarettes.


Concerted cell and in vivo screen for pancreatic ductal adenocarcinoma (PDA) chemotherapeutics.
PDA is a major cause of US cancer-related deaths. Oncogenic Kras presents in 90% of human PDAs. Kras mutations occur early in pre-neoplastic lesions but are insufficient to cause PDA. Other contributing factors early in disease progression include chronic pancreatitis, alterations in epigenetic regulators, and tumor suppressor gene mutation. GPCRs activate heterotrimeric G-proteins that stimulate intracellular calcium and oncogenic Kras signaling, thereby promoting pancreatitis and progression to PDA. By contrast, Rgs proteins inhibit Gi/q-coupled GPCRs to negatively regulate PDA progression. Rgs16::GFP is expressed in response to caerulein-induced acinar cell dedifferentiation, early neoplasia, and throughout PDA progression. In genetically engineered mouse models of PDA, Rgs16::GFP is useful for pre-clinical rapid in vivo validation of novel chemotherapeutics targeting early lesions in patients following successful resection or at high risk for progressing to PDA. Cultured primary PDA cells express Rgs16::GFP in response to cytotoxic drugs. A histone deacetylase inhibitor, TSA, stimulated Rgs16::GFP expression in PDA primary cells, potentiated gemcitabine and JQ1 cytotoxicity in cell culture, and Gem + TSA + JQ1 inhibited tumor initiation and progression in vivo. Here we establish the use of Rgs16::GFP expression for testing drug combinations in cell culture and validation of best candidates in our rapid in vivo screen.


In vitro potency of moxifloxacin, clinafloxacin and sitafloxacin against 248 genetically defined clinical isolates of Staphylococcus aureus.
The in vitro potency of three newer fluoroquinolones, moxifloxacin, clinafloxacin and sitafloxacin was tested against 248 genetically defined Staphylococcus aureus isolates, comprising 116 unrelated S. aureus, seven heterogeneous intermediate vancomycin-resistant S. aureus strains as well as 125 clonally related methicillin-resistant S. aureus. All strains were susceptible to clinafloxacin and sitafloxacin based on an investigational breakpoint of 1 mg/L and were less influenced by mutations within the grl and gyr gene loci. In one-quarter to one-third of the strains tested, reserpine decreased slightly the MICs of moxifloxacin, clinafloxacin and sitafloxacin. Compared with moxifloxacin, clinafloxacin and sitafloxacin showed a significantly increased anti-staphylococcal potency.