COMPARISON OF THE RADIOGRAPHIC AND TRACHEOSCOPIC APPEARANCE OF THE DORSAL TRACHEAL MEMBRANE IN LARGE AND SMALL BREED DOGS.
The etiology and clinical significance of increased radiographic opacity along the dorsal margin of the tracheal lumen has long been debated. Most often, this opacity is attributed to redundancy of the dorsal tracheal membrane (DTM), a condition that occurs with tracheal collapse. We hypothesized that the underlying etiology of this radiographic opacity differs between small breed dogs with tracheal collapse and small or large breed dogs without tracheal collapse. The purpose of this prospective, cross-sectional study was to compare the radiographic appearance of an increased opacity within the trachea to tracheoscopy findings in a group of small and large breed dogs. A total of 17 small breed dogs and 16 large breed dogs were included. Of these, only one did not have a radiographically visible DTM. Small breed dogs were divided into groups with tracheal collapse (n = 8) and those without (n = 9) based on tracheoscopy. Tracheal collapse was absent in larger breed dogs, however both large and small breed dogs demonstrated inward invagination of the DTM. In dogs with tracheal collapse, the DTM occupied a larger percentage of the tracheal luminal height on radiographs and a larger percentage of tracheal circumference on tracheoscopy vs. dogs with an invaginated DTM on tracheoscopy and dogs with no collapse and no invagination of the DTM. Findings supported the hypothesis that increased radiographic opacity along the dorsal margin of the trachea arises from different etiologies in dogs with and without tracheal collapse.


L1cam curbs the differentiation of adult-born hippocampal neurons.
L1 is an immunoglobulin domain (Ig)-containing protein essential for a wide range of neurodevelopmental processes highly conserved across species from worms to humans. L1 can act as a cell adhesion molecule by binding to other Ig-containing proteins or as a ligand for certain tyrosine kinase receptors such as FGFRs and TRKs, which are required not only during neurodevelopment but also in hippocampal neurogenesis. Yet, the role of L1 itself in adult hippocampal neurogenesis remains unaddressed. Here, we used several Cre-driver lines in mice to conditionally delete a floxed allele of L1cam at different points along the differentiation lineage of new neurons and in surrounding neurons in the adult dentate gyrus of the hippocampus. We found that L1cam deletion in stem/progenitor cells increased: 1) the differentiation of progenitors into new neurons, 2) the complexity of dendritic arbors in immature neurons, and 3) anxiety-related behavior. In addition, deletion of L1cam in neurons leads to an earlier age-related decline in hippocampal neurogenesis. These data suggest that L1 is not only important for normal nervous system development, but also for maintaining certain neural processes in adulthood.


Interstitial lung diseases associated with amyopathic dermatomyositis.
The aim of the present study was to clarify the clinical characteristics and prognosis of patients with interstitial lung disease (ILD) associated with amyopathic dermatomyositis (ILD-ADM). The study consisted of 14 consecutive patients with ILD-ADM. Patients were classified into two categories, acute/subacute and chronic forms, according to the clinical presentation of ILD. The clinical features, responsiveness to therapy, and prognosis between the two forms were compared. Nine ILD-ADM patients were categorised as the acute/subacute form, and five as the chronic form. Arterial oxygen tension was significantly lower in the acute/subacute ILD than chronic ILD patients. On high-resolution computed tomography, ground-glass opacities were frequently found in the two forms, but consolidation was more common in acute/subacute ILD than chronic ILD. Bronchoalveolar lavage analysis showed higher numbers of total cells and lymphocytes in acute/subacute ILD than chronic ILD. Histologically, the most common finding was nonspecific interstitial pneumonia in the two forms, while diffuse alveolar damage was only found in acute/subacute ILD. Acute/subacute ILD was generally resistant to therapy, while chronic ILD responded well. Notably, the mortality of acute/subacute ILD was much higher than that of chronic ILD (67 versus 0%, respectively). In conclusion, interstitial lung disease associated with amyopathic dermatomyositis includes two different forms, the acute/subacute and chronic forms, with distinct prognoses.


The efficacy of the systemic methotrexate treatment in caesarean scar ectopic pregnancy: A quantitative review of English literature.
To determine the efficacy and safety of primary medical treatment with systemic methotrexate (MTX) in caesarean scar ectopic pregnancy, we conducted a Medline/PubMed search on the relevant English literature from January 1978 to January 2012. The search yielded 27 publications of 40 cases of caesarean scar ectopic pregnancy. The literature search showed a very liberal use of systemic MTX treatment with unfavourable outcomes, although the major determinant of the clinical efficacy was found in here to be β-hCG level together with embryonic cardiac activity (ECA) status. A caesarean scar ectopic pregnancy presented with a serum β-hCG concentration of ≤ 12,000 mIU/ml (odds ratio, OR 5.68, 95% confidence interval, CI, 1.37-23.48) and absence of ECA (OR 4.80, 95% CI, 1.14-20.08) was found to be associated with higher efficacy rate of primary systemic MTX treatment. Administration of primary systemic MTX treatment was found to be ideal for a caesarean scar ectopic pregnancy presented before 8 weeks' gestation, with a β-hCG concentration of ≤ 12,000 mIU/ml together with an absent ECA (OR 14.52, 95% CI, 2.36-89.09).


Cross-referral between voluntary HIV counselling and testing centres and TB services, Maharashtra, India, 2003-2004.
India has a high tuberculosis (TB) burden, with 1.8 million new cases per year. Although an estimated 2.5 million people are infected with human immunodeficiency virus (HIV), the national HIV prevalence is <1%. India's size and diverse TB-HIV epidemiology pose a major challenge to the implementation of links between TB and HIV/AIDS programme services. A pilot cross-referral initiative was instituted between voluntary counselling and testing centres (VCT) and the diagnostic and treatment facilities of the Revised National TB Control Programme (RNTCP) in four districts of Maharashtra, India. To detect TB disease among VCT patients and selectively screen TB patients for referral to VCT services. Between July 2003 and June 2004, 336 (3%) of 9921 VCT patients were identified as TB suspects and 83 (29%) were diagnosed with TB disease. Of the 765 selectively referred TB cases, 181 (24%) were found to be HIV-positive, representing 11% of the newly detected persons living with HIV in the four districts. The pilot cross-referral initiative yielded significant numbers of active TB cases among VCT patients and HIV-positive persons among TB patients. Collaborative activities between HIV/AIDS and TB programmes need to be rapidly scaled up to other states in India.


Intracortical lesions by 3T magnetic resonance imaging and correlation with cognitive impairment in multiple sclerosis.
Accurate classification of multiple sclerosis (MS) lesions in the brain cortex may be important in understanding their impact on cognitive impairment (CI). Improved accuracy in identification/classification of cortical lesions was demonstrated in a study combining two magnetic resonance imaging (MRI) sequences: double inversion recovery (DIR) and T1-weighted phase-sensitive inversion recovery (PSIR). To evaluate the role of intracortical lesions (IC) in MS-related CI and compare it with the role of mixed (MX), juxtacortical (JX), the sum of IC + MX and with total lesions as detected on DIR/PSIR images. Correlations between CI and brain atrophy, disease severity and disease duration were also sought. A total of 39 patients underwent extensive neuropsychological testing and were classified into normal and impaired groups. Images were obtained on a 3T scanner and cortical lesions were assessed blind to the cognitive status of the subjects. Some 238 cortical lesions were identified (130 IC, 108 MX) in 82% of the patients; 39 JX lesions were also identified. Correlations between CI and MX lesions alone (p = 0.010) and with the sum of IC + MX lesions (p = 0.030) were found. A correlation between severity of CI and Expanded Disability Status Scale was also seen (p = 0.009). Cortical lesions play an important role in CI. However, our results suggest that lesions that remain contained within the cortical ribbon do not play a more important role than ones extending into the adjacent white matter; furthermore, the size of the cortical lesion, and not the tissue-specific location, may better explain their correlation with CI.


Pregnancy mediated improvement of rheumatoid arthritis.
To investigate pregnancy related changes of rheumatoid factor (RF) isotypes and anti-citrullinated protein antibodies (ACPA) and their association with disease activity and therapy in patients with rheumatoid arthritis. In 22 rheumatoid arthritis patients disease activity (DAS28-CRP), therapy as well as the levels of rheumatoid factor isotypes (IgG, IgA, IgM) and ACPA were analysed longitudinally within 4 months before conception, once at each trimester and at 6,12 and 24 weeks postpartum. In addition, immunoglobulin isotypes (IgG, IgA, IgM) were measured in the pregnant rheumatoid arthritis patients as well as in 29 healthy pregnant women at the time points mentioned above. Our results showed that pregnancy significantly reduced systemic levels of the immunoglobulin isotypes IgG and IgA, but did not change the levels of IgG-RF, IgA-RF nor those of IgG-ACPA using assays with different antigen preparations. However, patients with active disease before and during pregnancy showed significantly higher levels of ACPA as compared to patients with low disease activity during pregnancy. Significantly more patients with low disease activity during pregnancy received pregnancy compatible disease modifying antirheumatic drugs or TNF-inhibitor therapy within four months before conception (P = 0.025). Our results suggest that treatment should be adjusted to pregnancy compatible drugs preconceptionally and continued until conception and beyond to allow for stable inactive disease during gestation and control the levels of autoantibodies.


Murine cytomegalovirus: reactivation in pregnancy.
Murine cytomegalovirus (MCMV) may be rapidly and reproducibly attenuated by passage in tissue culture. A high proportion of CDI mice neonatally infected with the virulent strain of CMV can be shown to have replicating virus in the kidneys for up to 90 weeks p.i. and this high rate of isolation is not altered in pregnancy. A much lower rate of isolation from the kidneys is seen in CDI mice neonatally infected with the attenuated strain. However, this isolation rate was significantly increased during pregnancy and higher titres of virus were recovered.


Detection of miRNA as non-invasive biomarkers of colorectal cancer.
Colorectal Cancer (CRC) is one of the deadliest cancers-ranking as the fourth most common cause of cancer-related deaths in the world. It is such a deadly disease because it is largely asymptomatic until the latter stages-oftentimes when the cancer has metastasized. Thus, a huge emphasis of cancer treatment is placed on early detection. Currently, there is a lack of a noninvasive, reliable, and cost-effective screening method for CRC. In recent years, microRNA (miRNA) diagnostic markers have been suggested as a viable new screening method for CRC. miRNAs play an important role in carcinogenesis, and has been observed to be dysregulated in many cancers including CRC. This review examines the diagnostic potential of circulatory and fecal miRNA markers in relation to CRC, as well as current techniques to detect them.


Bleeding gastric telangiectasia. Complication of Raynaud's phenomenon, esophageal motor dysfunction, sclerodactyly and telangiectasia (REST) syndrome.
Anemia and skin telangiectasia were the main presenting features of a patient with Raynaud's phenomenon, esophageal motor dysfunction, sclerodactyly and telangiectasia (REST) syndrome. Diffuse gastric telangiectasia with chronic intermittent blood loss were responsible for the anemia. The multisystemic and progressive character of this collagenopathy in our patient is described and the endoscopic picture is presented. Management difficulties and treatment alternatives are discussed.


Leu125Val polymorphism of platelet endothelial cell adhesion molecule-1 is associated with atherosclerotic cerebral infarction in Chinese Han population.
A total of 142 Atherosclerotic cerebral infarction (ACI) patients and 116 controls were enrolled in our study. The Leu125Val polymorphism of PECAM-1 was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The plasma sPECAM-1 level was measured by enzyme-linked immunosorbent assay (ELISA) method. We found a statistically significant difference in Leu125Val genotypic distribution between cases and controls (P < 0.05). The frequencies of the Val allele between ACI group and controls were significantly different (P < 0.05). Logistic regression analysis showed that the genotype Val/Val was associated with increased ACI risk (OR = 2.355, 95% CI = 1.153-4.809, P = 0.019). In both the ACI group and the control group, the plasma PECAM-1 levels of carriers of the Val/Val genotype were higher than those carrying Leu/Leu and Leu/Val genotypes. The plasma sPECAM-1 level is associated with ACI. Our study showed that Leu125Val polymorphism of PECAM-1 may be associated with ACI risk. Carrying the Val/Val genotype showed increased risk for ACI. The Leu125Val polymorphism of PECAM-1 may be associated with the plasma sPECAM-1 level, which is associated with Chinese ACI also. In conclusions, The Leu125Val polymorphism of the PECAM-1 gene is likely to be related to ACI, and the Val/Val genotype may be an independent risk factor for ACI. The plasma sPECAM-1 level may be associated with ACI risk.


Wound Healing Effects of Curcumin: A Short Review.
Wound healing is a complex process that consists of several phases that range from coagulation, inflammation, accumulation of radical substances, to proliferation, formation of fibrous tissues and collagen, contraction of wound with formation of granulation tissue and scar. Since antiquity, vegetable substances have been used as phytotherapeutic agents for wound healing, and more recently natural substances of vegetable origin have been studied with the attempt to show their beneficial effect on wound treatment. Curcumin, the most active component of rhizome of Curcuma longa L. (common name: turmeric), has been studied for many years due to its bio-functional properties, especially antioxidant, radical scavenger, antimicrobial and anti-inflammatory activities, which play a crucial role in the wound healing process. Moreover, curcumin stimulated the production of the growth factors involved in the wound healing process, and so curcumin also accelerated the management of wound restoration. The aim of the present review is collecting and evaluating the literature data regarding curcumin properties potentially relevant for wound healing. Moreover, the investigations on the wound healing effects of curcumin are reported. In order to produce a more complete picture, the chemistry and sources of curcumin are also discussed.


Medical interventions during pregnancy and childbirth.
The right of the medical profession to intervene during childbirth, contrary to the wishes of the patient, has been the subject of considerable legal debate during the 1990s. However, recent judicial comment in R vs Louize Collins and others [1998] seems to have reached a clear conclusion on the rights of the pregnant woman, and also the steps that can be taken to treat when a pregnant woman has refused intervention.


Conserved structural and sequence elements implicated in the processing of gene-encoded circular proteins.
The cyclotides are the largest family of naturally occurring circular proteins. The mechanism by which the termini of these gene-encoded proteins are linked seamlessly with a peptide bond to form a circular backbone is unknown. Here we report cyclotide-encoding cDNA sequences from the plant Viola odorata and compare them with those from an evolutionarily distinct species, Oldenlandia affinis. Individual members of this multigene family encode one to three mature cyclotide domains. These domains are preceded by N-terminal repeat regions (NTRs) that are conserved within a plant species but not between species. We have structurally characterized peptides corresponding to these NTRs and show that, despite them having no sequence homology, they form a structurally conserved alpha-helical motif. This structural conservation suggests a vital role for the NTR in the in vivo folding, processing, or detoxification of cyclotide domains from the precursor protein.


[Combined heart and kidney transplantation in terminal myocardial and renal insufficiency].
In a 38-year-old man combined heart and kidney transplantation was performed successfully in one operation. Both organs have functioned well postoperatively: the patient was discharged from hospital on the 19th postoperative day and has remained in functional class I (New York Heart Association) eight months later. Only two episodes of cardiac rejection have been observed during this period, responding to treatment, and there was no evidence of rejection of the kidney. Such combined heart-kidney transplantation from one donor seems to be a promising form of treatment for patients in end-stage myocardial and renal failure. The frequency of cardiac rejections my be lower after combined heart-kidney transplantation than after cardiac transplantation alone.


Supervisor assessment of clinical and professional competence of medical trainees: a reliability study using workplace data and a focused analytical literature review.
Even though rater-based judgements of clinical competence are widely used, they are context sensitive and vary between individuals and institutions. To deal adequately with rater-judgement unreliability, evaluating the reliability of workplace rater-based assessments in the local context is essential. Using such an approach, the primary intention of this study was to identify the trainee score variation around supervisor ratings, identify sampling number needs of workplace assessments for certification of competence and position the findings within the known literature. This reliability study of workplace-based supervisors' assessments of trainees has a rater-nested-within-trainee design. Score variation attributable to the trainee for each competency item assessed (variance component) were estimated by the minimum-norm quadratic unbiased estimator. Score variance was used to estimate the number needed for a reliability value of 0.80. The trainee score variance for each of 14 competency items varied between 2.3% for emergency skills to 35.6% for communication skills, with an average for all competency items of 20.3%; the "Overall rating" competency item trainee variance was 28.8%. These variance components translated into 169, 7, 17 and 28 assessments needed for a reliability of 0.80, respectively. Most variation in assessment scores was due to measurement error, ranging from 97.7% for emergency skills to 63.4% for communication skills. Similar results have been demonstrated in previously published studies. In summary, overall supervisors' workplace based assessments have poor reliability and are not suitable for use in certification processes in their current form. The marked variation in the supervisors' reliability in assessing different competencies indicates that supervisors may be able to assess some with acceptable reproducibility; in this case communication and possibly overall competence. However, any continued use of this format for assessment of trainee competencies necessitates the identification of what supervisors in different institutions can reliably assess rather than continuing to impose false expectations from unreliable assessments.


The platelet cytoskeleton regulates the affinity of the integrin alpha(IIb)beta(3) for fibrinogen.
Agonist-generated inside-out signals enable the platelet integrin alpha(IIb)beta(3) to bind soluble ligands such as fibrinogen. We found that inhibiting actin polymerization in unstimulated platelets with cytochalasin D or latrunculin A mimics the effects of platelet agonists by inducing fibrinogen binding to alpha(IIb)beta(3). By contrast, stabilizing actin filaments with jasplakinolide prevented cytochalasin D-, latrunculin A-, and ADP-induced fibrinogen binding. Cytochalasin D- and latrunculin A-induced fibrinogen was inhibited by ADP scavengers, suggesting that subthreshold concentrations of ADP provided the stimulus for the actin filament turnover required to see cytochalasin D and latrunculin A effects. Gelsolin, which severs actin filaments, is activated by calcium, whereas the actin disassembly factor cofilin is inhibited by serine phosphorylation. Consistent with a role for these factors in regulating alpha(IIb)beta(3) function, cytochalasin D- and latrunculin A-induced fibrinogen binding was inhibited by the intracellular calcium chelators 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid acetoxymethyl ester and EGTA acetoxymethyl ester and the Ser/Thr phosphatase inhibitors okadaic acid and calyculin A. Our results suggest that the actin cytoskeleton in unstimulated platelets constrains alpha(IIb)beta(3) in a low affinity state. We propose that agonist-stimulated increases in platelet cytosolic calcium initiate actin filament turnover. Increased actin filament turnover then relieves cytoskeletal constraints on alpha(IIb)beta(3), allowing it to assume the high affinity conformation required for soluble ligand binding.


Pharmacokinetics of Dexketoprofen Trometamol in Healthy Volunteers After Single and Repeated Oral Doses.
The pharmacokinetics of dexketoprofen trometamol were evaluated in two studies using healthy volunteers. In the first study, the relative bioavailability of a single oral capsule of dexketoprofen free acid 25 mg or dexketoprofen trometamol 25 mg (given as 37 mg of the trometamol salt) was compared to ketoprofen 50 mg in 18 healthy volunteers. In the second study, the pharmacokinetics and tolerability of oral dexketoprofen trometamol in tablet form were evaluated after either a single 25 mg dose (24 volunteers) or a repeated dose of 25 mg twice daily for 7 days (12 volunteers). The absorption of dexketoprofen from dexketoprofen trometamol capsules was bioequivalent to that of ketoprofen. On the other hand, the extent of absorption of dexketoprofen free acid was significantly lower than that for ketoprofen. Dexketoprofen trometamol showed the most rapid absorption rate, with highest Cmax and shortest tmax values, whereas dexketoprofen free acid had the slowest absorption rate, and ketoprofen had an intermediate absorption rate. After repeated-dose administration of dexketoprofen trometamol, the pharmacokinetic parameters were similar to those obtained after single doses, indicating that no drug accumulation occurred. Dexketoprofen trometamol was well tolerated, with no clinically relevant adverse events reported.


Contributions of Nrf2 to Puerarin Prevention of Cardiac Hypertrophy and its Metabolic Enzymes Expression in Rats.
Previous evidence has suggested that puerarin may attenuate cardiac hypertrophy; however, the potential mechanisms have not been determined. Moreover, the use of puerarin is limited by severe adverse events, including intravascular hemolysis. This study used a rat model of abdominal aortic constriction (AAC)-induced cardiac hypertrophy to evaluate the potential mechanisms underlying the attenuating efficacy of puerarin on cardiac hypertrophy, as well as the metabolic mechanisms of puerarin involved. We confirmed that puerarin (50 mg/kg per day) significantly attenuated cardiac hypertrophy, upregulated Nrf2, and decreased Keap1 in the myocardium. Moreover, puerarin significantly promoted Nrf2 nuclear accumulation in parallel with the upregulated downstream proteins, including heme oxygenase 1, glutathione transferase P1, and NAD(P)H:quinone oxidoreductase 1. Similar results were obtained in neonatal rat cardiomyocytes (NRCMs) treated with angiotensin II (Ang II; 1 μM) and puerarin (100 μM), whereas the silencing of Nrf2 abolished the antihypertrophic effects of puerarin. The mRNA and protein levels of UGT1A1 and UGT1A9, enzymes for puerarin metabolism, were significantly increased in the liver and heart tissues of AAC rats and Ang II-treated NRCMs. Interestingly, the silencing of Nrf2 attenuated the puerarin-induced upregulation of UGT1A1 and UGT1A9. The results of chromatin immunoprecipitation-quantitative polymerase chain reaction indicated that the binding of Nrf2 to the promoter region of Ugt1a1 or Ugt1a9 was significantly enhanced in puerarin-treated cardiomyocytes. These results suggest that Nrf2 is the key regulator of antihypertrophic effects and upregulation of the metabolic enzymes UGT1A1 and UGT1A9 of puerarin. The autoregulatory circuits between puerarin and Nrf2-induced UGT1A1/1A9 are beneficial to attenuate adverse effects and maintain the pharmacologic effects of puerarin.


Evaluation of anticancer activities of Poria cocos ethanol extract in breast cancer: In vivo and in vitro, identification and mechanism.
Poria cocos Wolf (P. cocos), a well-known traditional East-Asian medicinal and edible fungus, is one of the most important components in Chinese medicine formulas like "Guizhi fuling wan" to treat hyperplasia of mammary glands and breast cancer. In this study, we attempted to verify the anticancer efficacy of the ethanol extract of P. cocos (PC) on the breast cancer as well as to investigate its most active compound and its underlying molecular mechanism in vivo and in vitro. The key anti-cancer components were separated and purified through chromatography and identified by spectral analyses. The in vivo anti-breast cancer efficacy and side effects of PC were evaluated in BALB/c nude mice that have been subcutaneously injected with breast cancer cells MDA-MB-231. Cytotoxicity, apoptosis and cell cycle arrest of PC were evaluated in vitro by cell viability assays and flow cytometry. The protein levels were examined via western blotting. Pachymic acid (PA), separated and identified as the most active compound, induced the significant cytotoxicity on breast cancer cells MDA-MB-231(IC50 value, 2.13 ± 0.24 μg/mL) and was not active against the normal breast epithelium cells MCF-10A. The in vivo experiment revealed that PC could significantly inhibit the tumor development and the final mean tumor weight of the mice in the PC group (0.51 ± 0.12g) was significantly lower than that in the model group (1.22 ± 0.45g). Notably, compared to the first-line anticancer drug cisplatin, PC showed less side effects on the function of the vital organs and the muscle strength of the mice. Among in vitro study, PC significantly inhibited the cell growth of MDA-MB-231 by inducing cell apoptosis and cell cycle arrested at G0/G1 phase in a dose-dependent manner. The expression of cell cycle-associated cyclin D1, cyclin E, CDK2, and CDK4 were downregulated, while p53 and p21 expression were upregulated following the PA treatment. In addition, PA downregulated the apoptotic regulator Bcl-2, increased the expression of pro-apoptotic protein Bax, and promoted the release of cytochrome c and the activation of cleaved caspase-3, -9 and caspase -8 via mitochondria-mediated and death receptor-mediated signaling pathways. This study verified the anticancer efficacy of PC on breast cancer in vivo and in vitro through induction of cell apoptosis and G0/G1 cell cycle arrest. The data also suggested that PA could be developed as an efficacious agent for breast cancer treatment with less side effects.


Antiarrhythmic therapy in the elderly: pacemakers and drugs.
Investigations of syncope often fail to demonstrate any abnormality. However, in view of the ease of permanent pacemaker implantation and the potential dangers of recurrent syncope, patients with this symptom should receive pacemaker therapy. In general, acute therapy of any tachyarrhythmia associated with hemodynamic collapse consists of DC cardioversion, but skillful use of drug therapy and, occasionally, pacemaking are also highly important in preventing recurrences.


Implementing potentially better practices to reduce lung injury in neonates.
Adherence to basic quality improvement principles enhances the implementation of potentially better practices (PBPs) and requires extensive planning and education. Even after PBPs have been identified and acknowledged as desirable, effective implementation of these practices does not occur easily. The objective of this study was to identify and assess implementation strategies that facilitate quality improvements in the respiratory care of extremely low birth weight infants. The 9 members of the Neonatal Intensive Care Quality Improvement Collaborative Year 2000 Reducing Lung Injury focus group identified 9 PBPs in a evidence-based manner to decrease chronic lung disease in extremely low birth weight newborns. Each site implemented several or all PBPs based on a site-specific selection process. Each site was asked to submit 1 or more examples of experiences that highlighted effective implementation strategies. This article reports these examples and emphasizes the principles on which they are based. The 9 participating institutions implemented a total of 57 PBPs (range: 1-9; median: 5). Including previous implementation, the 9 participating institutions implemented a total of 70 of a possible 81 PBPs before or during the study period (range: 5-9; median: 8). We report 7 approaches that facilitated PBP implementation: information availability, feedback, perseverance, collaboration, imitation, recognition of implementation complexity, and tracking of process indicators. Quality improvement efforts are enhanced by identifying and then implementing PBPs. In our experience, implementation of these PBPs can be difficult. Implementation strategies, such as those identified in this article, can improve the chances that quality improvement efforts will be effective.


Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes.
AMP-activated protein kinase (AMPK) is a cellular energy sensor that is conserved in eukaryotes. Although AMPK is traditionally thought to play a major role in the regulation of cellular lipid and protein metabolism, recent discoveries reveal that AMPK inhibits mammalian target of rapamycin (mTOR) signaling and connects with several tumor suppressors such as liver kinase B1 (LKB1), p53, and tuberous sclerosis complex 2 (TSC2), indicating that AMPK may be a potential target for cancer prevention and treatment. For the first time, we demonstrated that apigenin, a naturally occurring nonmutagenic flavonoid, induced AMPK activation in human keratinocytes (both cultured HaCaT cell line and primary normal human epidermal keratinocytes). Through experiments with over-expression of constitutively active Akt and knockdown of LKB1 expression by siRNAs, we further found that the activation of AMPK by apigenin was not dependent on its inhibition of Akt, and was independent of the activation of upstream kinase LKB1. Instead, another upstream kinase of AMPK, calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ), was required for apigenin-induced AMPK activation. We have demonstrated that knockdown of CaMKKβ expression by siRNA or inhibition of CaMKKβ activity by either CaMKK inhibitor STO-609 or BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester; a chelator of intracellular Ca(2+)) prevented apigenin-induced AMPK activation. Apigenin-induced AMPK activation inhibited mTOR signaling and further induced autophagy in human keratinocytes. These results suggest that one of the mechanisms by which apigenin exerts its chemopreventive action may be through activation of AMPK and induction of autophagy in human keratinocytes.


[Isolation and characterization of individual tRNA Leu 1,2,and 4 from the bovine udder].
tRNA-Leu 1, tRNA-Leu 2 and tRNA-Leu 4 were isolated from a lactating cow mammary gland by combination of several chromatographic methods. Chromatography on a Sepharose 4B column with a reverse salt gradient was used as the first step. Individual tRNAsLeu were further purified by RPC-5 column chromatography at pH 4.5 and 7.5. For isolation of tRNA-Leu 2 a RPC-5 column was additionally used at pH 3.3 in the presence of 7 M urea. Using micro-column chromatography of Ti-RNAases digests, it was demonstrated that tRNA-Leu 1 and tRNA-Leu 2+ are similar in their primary structure and differ essentially from tRNA-Leu 4.


A longitudinal integration of identity styles and educational identity processes in adolescence.
Identity formation is a main adolescent psychosocial developmental task. The complex interconnection between different processes that are at the basis of one's identity is a research and applied intervention priority. In this context, the identity style model focuses on social-cognitive strategies (i.e., informational, normative, and diffuse-avoidant) that individuals can use to deal with identity formation. The 3-factor identity dimensional model examines the interplay between identity processes of commitment, in-depth exploration, and reconsideration of commitment in different life domains. Theoretical integrations between these models have been proposed, but there is a dearth of studies unraveling their longitudinal links in specific identity domains. We addressed this gap by testing in a 3-wave longitudinal study the bidirectional associations between identity styles and educational identity processes measured during 1 academic year. Participants were 1,151 adolescents (58.7% female). Results highlighted that the informational style was related over time to higher levels of educational commitment and in-depth exploration, whereas the diffuse-avoidant style was related to lower levels of commitment and higher levels of reconsideration of commitment. Educational commitment was positively related to the informational and normative styles; in-depth exploration was positively related to the informational style; and reconsideration of commitment was positively related to the diffuse-avoidant style. These relations were not moderated by adolescents' gender and age. Hence, identity styles and educational identity processes reinforce each other during 1 academic year. Theoretical integrations between these models, suggestions for integration with other identity approaches (e.g., narrative identity models), and practical implications are discussed. (PsycINFO Database Record


Effect of chewing Azadirachta indica (neem) and Ocimum sanctum (tulsi) leaves on salivary acidogenicity: A comparative study.
Dental caries is an infectious disease affecting majority of children in the modern world. An acidogenic diet brings down plaque pH, leading to dental caries. However, certain foods bring about rapid reversal of plaque pH after an acidogenic challenge. Azadirachta indica and Ocimum sanctum leaves which are anticariogenic show promise in this regard. The aim of this study was to evaluate the salivary pH reversal phenomenon by chewing A. indica and O. sanctum leaves after an acidogenic challenge. Forty caries-free children were selected and randomly divided into two groups. The resting salivary pH and salivary pH after eating chocolate was measured using a pH meter at time intervals of 5, 30 and 60 min. The children were then instructed to chew A. indica and O. sanctum leaves after chocolate consumption, and salivary pH was again measured at 5, 30 and 60 min. The change in salivary pH was assessed. The data obtained were analyzed using Student's t-test (two tailed, dependent) to find the significance of the study parameters. The level of significance was set at P < 0.05. Chewing A. indica and O. sanctum leaves after chocolate consumption increased salivary pH to statistically significant values at 5, 30 and 60 min. The observations of the study show that chewing of A. indica and O. sanctum leaves reversed the drop in salivary pH levels after an acidogenic challenge.


Three-Dimensional Super-resolution Imaging of Single Nanoparticles Delivered by Pipettes.
Controlled three-dimensional positioning of nanoparticles is achieved by delivering single fluorescent nanoparticles from a nanopipette and capturing them at well-defined regions of an electrified substrate. To control the position of single nanoparticles, the force of the pressure-driven flow from the pipette is balanced by the attractive electrostatic force at the substrate, providing a strategy by which nanoparticle trajectories can be manipulated in real time. To visualize nanoparticle motion, a resistive-pulse electrochemical setup is coupled with an optical microscope, and nanoparticle trajectories are tracked in three dimensions using super-resolution fluorescence imaging to obtain positional information with precision in the tens of nanometers. As the particles approach the substrate, the diffusion kinetics are analyzed and reveal either subdiffusive (hindered) or superdiffusive (directed) motion depending on the electric field at the substrate and the pressure-driven flow from the pipette. By balancing the effects of the forces exerted on the particle by the pressure and electric fields, controlled, real-time manipulation of single nanoparticle trajectories is achieved. The developed approach has implications for a variety of applications such as surface patterning and drug delivery using colloidal nanoparticles.


Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth.
Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


[The significance of distal obstructions and stenoses of the vertebral artery].
3 patients with intracranial infarctions as consequence of obstructive lesions of the distal vertebral artery are presented. The first patient, with a unilateral occlusion of the distal intracranial portion of the vertebral artery and contralateral high grade stenosis at the same site, suffered bilateral cerebellar infarctions. Predominantly occipital infarction occurred in the second patient, with unilateral occlusion of the vertebral artery, the infarction being probably caused by embolization from the distal stump. In the third patient traumatic injury of the vertebral artery at the C1/C2 level was followed by embolic occipital lobe infarction. The discussion covers pathogenetic significance of hemodynamic and thromboembolic factors for cerebellar and occipital infarctions and the possible therapeutic options.


Graph analysis of dream reports is especially informative about psychosis.
Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that "dreams are the royal road to the unconscious" is clinically useful, after all.


Differential transcription directed by discrete gamma interferon promoter elements in naive and memory (effector) CD4 T cells and CD8 T cells.
Acquisition of the ability to produce gamma interferon (IFN-gamma) is a fundamental property of memory T cells and enables one subset (T helper 1 [TH1]) to deliver its effector functions. To examine regulation of IFN-gamma gene expression in a model system which recapitulates TH1 differentiation, we prepared reporter transgenic mice which express the luciferase gene under the control of proximal and distal regulatory elements (prox.IFN gamma and dist.IFN gamma) from the IFN-gamma promoter. Memory T cells, but not naive T cells, secreted IFN-gamma and expressed both prox.IFN gamma and dist.IFN gamma transcriptional activities. Naive T cells required priming to become producers of IFN-gamma and to direct transcription by these elements. While both CD4+ and CD8+ T cells produced IFN-gamma, only CD4+ T cells expressed prox.IFN gamma transcriptional activity. Induction of transcriptional activity was inhibited by known antagonists of effector T-cell populations. Cyclosporin A inhibited transcriptional activity directed by both elements in effector T cells. Elevated cyclic AMP inhibited transcriptional activity directed by prox.IFN gamma in primed CD4+ T cells but enhanced transcriptional activity directed by dist.IFN gamma in primed CD8+ T cells. Taken together, these data show that prox.IFN gamma and dist.IFN gamma transcriptional activities mirror IFN-gamma gene expression in naive and memory CD4+ T cells but suggest that differences exist in regulation of IFN-gamma gene expression in CD4+ and CD8+ T-cell subsets.


Development and application of a specific radioimmunoassay for trifluoperazine N4'-oxide to a kinetic study in humans.
A hapten derivative of prochlorperazine N4'-oxide, 7-(3-carboxy-propionyl)-prochlorperazine N4'-oxide, was synthesized and coupled to bovine serum albumin. Immunization of New Zealand White rabbits with this conjugate generated antibodies which were utilized to develop a radioimmunoassay (RIA) for the quantitation of trifluoperazine N4'-oxide (TFPNO). This assay enabled for the first time the quantitation of TFPNO in plasma, and 20 pg can be measured in a 200-microliter plasma sample with a coefficient of variation less than 5%. Statistically, indistinguishable results were obtained by the assay procedure with or without the selective extraction of TFPNO, and also in the presence or absence of an excess of trifluoperazine (TFP) and other major metabolites, such as trifluoperazine sulfoxide and 7-hydroxytrifluoperazine. This RIA and a previously reported RIA for TFP were used to directly determine plasma concentrations of TFP and TFPNO after administration of a single 5-mg p.o. dose of TFP to six healthy male volunteers. The mean +/- S.D. for the peak concentration, time to peak concentration, area under the curve from 0 to 72 hr and the elimination T1/2 for the terminal portion of the plasma concentration vs. time curve for TFPNO were found to be 3.7 +/- 0.7 ng/ml, 3.2 +/- 0.4 hr, 51.1 +/- 9.8 ng X hr/ml and 26.9 +/- 14.0 hr, respectively, whereas the corresponding values for TFP were found to be 2.7 +/- 0.7, 3.1 +/- 0.8, 42.2 +/- 6.9 and 21.9 +/- 6.5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Which component of sulphasalazine is active in rheumatoid arthritis?
Sulphasalazine is known to be effective as a second line agent in the treatment of rheumatoid arthritis. The two chemical constituents of sulphasalazine (sulphapyridine and 5-aminosalicylic acid) were assessed separately in the treatment of rheumatoid arthritis. Over 24 weeks sulphapyridine showed a pronounced second line effect comparable with sulphasalazine and with a similar toxicity profile, whereas 5-aminosalicylic acid showed only a weak first line effect. Thus sulphapyridine appears to be the active moiety responsible for the second line effect of sulphasalazine in rheumatoid arthritis. The efficacy of the antibacterial component of sulphasalazine yet again permits speculation about the role of a bacterial pathogen in the aetiopathogenesis of rheumatoid disease.


Human T-lymphotropic virus type 1 infection is frequent in rural communities of the southern Andes of Peru.
To evaluate the presence of human T-lymphotropic virus type 1 (HTLV-1) infection in isolated rural communities in the southern Andes of Peru. We conducted a cross-sectional study in five communities located in three provinces in Ayacucho, Peru. The five communities are located at >3000 meters above sea level and are mainly rural, and more than 85% of the population speaks Quechua. Volunteers aged 12 years and older were included. Clinical and epidemiological data were collected, along with a blood sample for serological testing. We included 397 participants; their median age was 41 years (interquartile range 31-57 years) and 69% were women. According to our definitions, 98% were of Quechua origin. HTLV-1 was diagnosed in 11 people: 0/164 in Cangallo, 3/154 (2%) in Vilcashuaman, and 8/79 (10%) in Parinacochas. There were no cases of HTLV-2. All the HTLV-1-positive participants were born in Ayacucho and were of Quechua origin; they ranged in age from 29 to 87 years (median 56 years) and 10/11 were women. Ten were apparently healthy, and one woman was diagnosed with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Three out of 11 had a family member with a lower limb impairment compatible with HAM/TSP. The fact that HTLV-1 infection was present in two out of three provinces suggests that HTLV-1 could be highly endemic in the southern Andes in the Quechua population.


Surface structural dynamics of enzymatic cellulose degradation, revealed by combined kinetic and atomic force microscopy studies.
Highly heterogeneous and usually weakly defined substrate morphologies complicate the study of enzymatic cellulose hydrolysis. The cellulose surface has a non-uniform shape in particular, with consequent impacts on cellulase adsorption and activity. We have therefore prepared a cellulosic model substrate which is shown by atomic force microscopy (AFM) to display a completely smooth surface, the residual squared mean roughness being 10 nm or lower, and applied it for kinetic analysis of cellulase action. The substrate consists of an amorphous cellulose matrix into which variably sized crystalline fibers are distributed in apparently irregular fashion. Its conversion into soluble sugars by Trichoderma sp. cellulase at 50 °C proceeded without apparent limitation up to 70% completion and was paralleled by a steady increase in cellulase adsorption to the cellulose. Individual cellulase components (CBH I, CBH II, EG) also showed strongly enhanced adsorption with progressing cellulose conversion, irrespective of their preference for degrading the amorphous or crystalline substrate parts as revealed by AFM. The specific activity of the adsorbed cellulases, however, decreased concomitantly. Cellulose surface morphologies evolving as a consequence of cellulase action were visualized by AFM. Three-dimensional surface degradation by the cellulases resulted in a large increase in cellulose surface area for enzyme adsorption. However, the decline in enzyme specific activity during conversion was caused by factors other than surface ablation and disruption. Based on kinetic evidence for enzymatic hydrolyses of the smooth-surface model substrate and microcrystalline cellulose (Avicel), we hypothesize that, due to gradual loss of productive dynamics in their interactions with the cellulose surface, individual cellulases get progressively confined to substrate parts where they are no longer optimally active. This eventually leads to an overall slow-down of hydrolysis.


[Low-threshold potential-controlled calcium channels--their properties and functions].
Low voltage-activated calcium channels discovered 15 year ago are unique molecular structures which play a specific role in the functioning of different types of excitable cells. This conclusion is supported by recent identification of special channel-forming 1- subunits which after expression in artificial cellular systems generate transmembrane currents characteristic for low-voltage-activated calcium channels. At the same time, analysis of recent experimental data indicate the existence of several subtypes of low voltage-activated channels which differ in the characteristics of their permeability, kinetics and pharmacological sensitivity. The expression of different subtypes of low-voltage activated channels is found to be highly coordinated, on one hand, with different phases of the ontogenetic development of excitable cells and, on the other, with their fulfillment of specific functions. Therefore the search for selective modulators of the activity of these channels is an extremely important goal for modern investigations.


The epidemiology of laryngeal cancer in Brazil.
The city of São Paulo exhibits one of the highest incidences of laryngeal cancer in world and Brazil presents remarkable occurrence, compared with other Latin American countries. Around 8,000 new cases and 3,000 deaths by laryngeal cancer occur annually in the Brazilian population. In the city of São Paulo, incidence rates for laryngeal cancer among males have been decreasing since the late 1980s while, among females, the rates have shown a stable trend. This phenomenon is probably the expression of changes in gender behavior related to tobacco smoking. Several risk factors are involved in the genesis of laryngeal cancer. The most important are tobacco smoking and alcohol intake, but occupational hazards have also been associated with the disease, such as asbestos, strong inorganic acids, cement dust and free crystalline silica. Additionally, salted meat and total fat intake have been linked to elevated risk of laryngeal cancer. Conversely, several studies have confirmed that fruits, raw leaf vegetables and legumes protect against this cancer. Some researchers have postulated a possible association between laryngeal squamous cell carcinoma and human papilloma virus (HPV), but this is not universally accepted. Gastroesophageal reflux disease is weakly, but consistently correlated with laryngeal cancer. Familial cancer clusters, particularly of head and neck tumors, seem to increase the risk of laryngeal cancer. Some genetic polymorphisms, such as of genes that code for xenobiotic-metabolizing enzymes, have shown elevated risk for laryngeal cancer according to recent studies. Public health policies regarding the control of tobacco smoking and alcohol consumption, and also surveillance of carcinogen exposure in occupational settings, could have an impact on laryngeal cancer. No proposals for screening have been recommended for laryngeal cancer, but one diagnostic goal should be to avoid treatment delay when suspected symptoms have been observed.


Examining the efficacy of video-based microinterventions for improving risk and protective factors for disordered eating among young adult women.
Brief self-guided activities designed for focused and immediate benefits, termed microinterventions, have the potential to aid reach and engagement in mental health interventions; however further validation is needed. This study evaluated effects of two microinterventions for responding to appearance-ideal media on risk and protective factors for disordered eating. Undergraduate women (N = 202, Mage = 19.90, SD = 2.75) were allocated quasi-randomly to one of three 15-min video-based microinterventions (mindfulness, cognitive dissonance, educational control) in the lab and assessed on state outcomes at baseline and immediate posttest. One week later, trait factors were assessed and participants underwent an appearance-ideal media exposure task. Both mindfulness and dissonance groups reported significant immediate benefits to state appearance-ideal internalization, perceived sociocultural pressures and related distress, and mood, compared to educational control (Glass's Δ effect sizes = .40-.94), but not state weight or appearance satisfaction. At 1-week follow-up, mindfulness and dissonance groups demonstrated improved trait appearance-ideal internalization (Δ = .40 and .42), weight and shape concerns (Δ = .27 [ns] and .44), and body appreciation (Δ = .39 and .46) compared to the educational control. There were no effects on trait perceived pressures, negative affect, or body image psychological flexibility, and no differential changes in state outcomes from premedia to postmedia exposure. Microinterventions using mindfulness and dissonance techniques show promise for improving some risk and potential protective factors for disordered eating in the immediate and short-term. Further research is required to substantiate their place within the spectrum of eating disorder prevention, early intervention and treatment techniques.


Associations of an empirical dietary pattern with cardiometabolic risk factors in Malaysian adolescents.
This study aimed to identify a dietary pattern (DP) characterised mainly by high intakes of free sugar and other nutrients hypothesised to be associated with obesity such as dietary energy density (DED), percentage of energy from total fat and fibre density in adolescents from three southern states of Peninsular Malaysia, and its associations with cardiometabolic risk factors. This is a cross-sectional study among 335 adolescents who provided both dietary information assessed using a validated food frequency questionnaire (FFQ) and biochemical parameters including lipid profile, blood glucose, serum insulin and homeostatic model assessment-insulin resistance (HOMA-IR). Anthropometric measurements included weight (kg), height (cm) and waist circumference (cm), while body mass index (BMI) in kg/m2 was estimated, respectively. Reduced rank regression (RRR) identified a DP with percentage of energy from sugar and total fat, DED and fibre density intake as response variables. The identified 'high sugar, high fibre, high DED and low fat' DP was characterised by high intakes of sugar-sweetened beverages, fruits, sweets and low intakes of meat and cereal. Adolescents in the highest tertile of the identified DP had about 3.0 (OR = 2.7; 95%CI: 1.3, 5.6) and 2.0 (OR = 1.9; 95%CI: 1.0, 3.5) times higher odds of having dyslipideamia or elevated total cholesterol and LDL-cholesterol level, respectively compared to adolescents in the lowest tertile DP after adjusting for sex, school location, maternal education, physical activity, dietary misreporting and BMI z-score. This DP was not significantly associated with overweight and obesity. Higher adherence to a DP characterised mainly by free sugars and DED was associated with greater odds of having dyslipideamia, elevated total cholesterol and LDL-cholesterol levels in Malaysian adolescents.


Uncovering Emotions: A Pilot Study on Classifying Moods in the Valence-Arousal Space using In-the-Wild Passive Data.
Mood classification from passive data promises to provide an unobtrusive way to track a person's emotions over time. In this exploratory study, we collected phone sensor data and physiological signals from 8 individuals, including 5 healthy participants and 3 depressed patients, for a maximum of 35 days. Participants were asked to answer a digital questionnaire three times daily, resulting in a total of 334 self-reported mood state samples. Gradient-boosting classification was applied to the collected passive data to categorize 4 mood states in the Valence-Energetic Arousal space. The cross-validation results showed better classification performance compared to a baseline model, which always predicts the majority class. The classifier using passive data had an area under the precision-recall curve of 0.39 (SD = 0.1) while the baseline had 0.26 (SD = 0.03), suggesting the presence of information in the collected features that support the classification process. The model identified the entropy of the heart rate and the average physical activity in the preceding 8 hours, along with the max normal-to-normal (NN) sinus beat interval and the NN low frequency-high frequency ratio during the questionnaire completion, as the most important features in its analysis. Additionally, the time range of data collection was considered a contextual factor.


The life and work of Ksenija Atanasijević (1894-1981)--psychology and anthropology as the inevitability and necessity of philosophy.
Ksenja Atanasijević (1894-1981) was the first woman in Serbia to obtain a Ph.D. in philosophy. Going through numerous psychological metamorphoses in her lifetime and confronted with numerous challenges, Ksenija Atanasijević developed a specific philosophical-psychological system of consolation prominently featuring the concepts of happiness, bliss, moderation, courage and wisdom. Modifying the original teachings of Democritus and Epicurus, Ksenija Atanasijević developed a distinctive anthropology based on confrontation with but equally the overcoming of obstacles, both internal (spiritual) as well as external ones. The philosopheress developed a reflexive and indeed metaphysical defensive psychotherapeutical skill at the root of which was cleansing the soul, as well as dedication to the realm of fancy, fantasy and imagination. Ksenija Atanasijević also had precious literary talent which was best expressed in her analyses of the poetry and prose of great Serbian writers (Pandurović, Njegos, Nastasijević, etc.). It is quite certain that this, with Anica Savić-Rebac, definitely greatest Serbian philosopheress, through personal suffering, creative solitude and shrouded desperation built an utterly authentic and harmonious system of philosophical comfort.


Low quality of reporting adverse drug reactions in paediatric randomised controlled trials.
Randomised controlled trials (RCT) offer an opportunity to learn about frequency and character of adverse drug reactions. To improve the quality of reporting adverse effects, the Consort group published recommendations. The authors studied the application of these recommendations in RCTs performed in children. Literature search. The authors found 107 articles on paediatric RCTs written in English and published between 1 January 2006 and 1 April 2009. 83 articles (78%) mentioned adverse drug reactions, 36 articles (34%) used standardised methods for the disclosure of adverse drug reactions, 33 articles (31%) tabulated the reactions, and 27 (25%) stated numbers of and reasons for withdrawal. Registration of the RCT did not influence reporting. Sponsoring did lead to better reporting. According to the Consort guidelines, 19 (18%) reported safety data adequately. Reporting of adverse drug reactions in RCTs is often inadequate. Authors should anticipate and define adverse drug reactions. During research all adverse events should be monitored and assessed actively. Monitoring and assessment should be described in articles in accordance with the extended Consort recommendations. Both authors and editors share the responsibility for the improvement of reporting safety data.


The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy.
There is an urgent need for new and advanced approaches to modeling the pathological mechanisms of complex human neurological disorders. This is underscored by the decline in pharmaceutical research and development efficiency resulting in a relative decrease in new drug launches in the last several decades. Induced pluripotent stem cells represent a new tool to overcome many of the shortcomings of conventional methods, enabling live human neural cell modeling of complex conditions relating to aberrant neurodevelopment, such as schizophrenia, epilepsy and autism as well as age-associated neurodegeneration. This review considers the current status of induced pluripotent stem cell-based modeling of neurological disorders, canvassing proven and putative advantages, current constraints, and future prospects of next-generation culture systems for biomedical research and translation.


[Retrospective analysis of the fluorograms of patients with primary lung cancer].
Poor recognition of early stages of primary lung cancer during fluoroscopic examinations made the authors revise and analyse the archival fluorographs in 60 lung cancer patients, and compare them with the previous conclusions made by roentgenologists. In 23 patients previous fluorographs made during the period from 4 months to 5 years and a half already revealed the changes at the site of the detected cancer, which were interpreted as residual phenomena of pulmonary tuberculosis, postpneumonia pneumosclerosis or unrecognized cases (6) due to poorly manifested changes. Some recommendations are given how to select persons for a dispensary supervision, it is advocated that practising radiologists should examine retrospectively archival fluorographs to study early pulmonary cancer. Also, the problem of identifying malignancy in small forms of the pathology, revealed roentgenologically, is awaiting its solution by research workers of all specialties.


Minimalist linkers suitable for irreversible inhibitors in simultaneous proteome profiling, live-cell imaging and drug screening.
Activity-based protein profiling (ABPP) and bioimaging have been powerful approaches for in situ drug screening and target identification. However, these approaches are still hindered by the preparation of high-quality probes. To address this challenge, we developed a series of novel minimalist linkers for irreversible inhibitors by incorporation of various bioorthogonal handles into an α,β-unsaturated amide, a common moiety of many irreversible inhibitors. The linker-containing probes have been demonstrated to be suitable for simultaneous protein labelling, live cell imaging and drug screening.


Effect of plantar fasciotomy on stability of arch of foot.
Five anatomic specimen feet were studied at three different loading levels to determine the three-dimensional position of the individual bones constituting the arch. Bone displacements were compared before and after plantar fasciotomy. Bone displacements changed to a greater extent with higher loads. With a 222-N load the greatest difference in position in dorsiflexion after fasciotomy occurred at the talar to tibial joint, followed by the metatarsal relative to navicular and navicular to talar joints. The greatest difference in displacement in eversion was at the metatarsal relative to navicular, followed by the navicular to talar and calcaneal to talar joints. The greatest difference in displacement in abduction was at the navicular to talar and then the calcaneal to talar joints. The observed displacement of all joints, with changes about all three axes, was consistent with the finding of flattening of the arch in previous reports on plantar fasciotomy. Thus, these data suggest that sectioning of the fascia, which sometimes is performed for fasciitis, may have an effect on the mechanical behavior of the arch.


Augmented oxidative stress increases 8-oxoguanine preferentially in the transcriptionally active genomic regions.
8-Oxoguanine (8-oxoG) is the most common DNA base modification in the mammalian genome, associated with oxidative stress. Here we analysed the alterations in the distribution of 8-oxoG across the entire murine genome, before and after an elevation of oxidative stress by the use of ferric nitrilotriacetate (Fe-NTA) as an oxidative stress inducer in the renal proximal tubules. We isolated DNA fragments containing 8-oxoGs with immunoprecipitation from the murine genome, and amplified them by PCR for a distribution analysis with microarray-based comparative genomic hybridisation. The distribution profiles revealed that frequencies of 8-oxoG fluctuated with a cycle of 1-10 Mb along the chromosomes and the amplitude of the fluctuation was reduced after Fe-NTA administration. The distributions of 8-oxoG along the entire genome in the control and oxidatively stressed conditions were negatively correlated with that of gene density but positively correlated with that of Lamin B1 interaction, which corresponds to lamina-associated domains. These results on the murine genome were consistent with those on the rat genome we previously reported. We further discovered a negative correlation between the distributions of 8-oxoG and transcriptional activity along the genome. Finally, a comparison of the distributions before and after Fe-NTA administration suggested that 8-oxoGs are generated in response to the augmented oxidative stress preferentially in the transcriptionally active genomic regions, where 8-oxoGs have been less accumulated in the control condition.


Insights into the mechanism of Escherichia coli methionine aminopeptidase from the structural analysis of reaction products and phosphorus-based transition-state analogues.
In an effort to differentiate between alternative mechanistic schemes that have been postulated for Escherichia coli methionine aminopeptidase (eMetAP), the modes of binding of a series of products and phosphorus-based transition-state analogues were determined by X-ray crystallography. Methionine phosphonate, norleucine phosphonate, and methionine phosphinate bind with the N-terminal group interacting with Co2 and with the respective phosphorus oxygens binding between the metals, interacting in a bifurcated manner with Co1 and His178 and hydrogen bonded to His79. In contrast, the reaction product methionine and its analogue trifluoromethionine lose interactions with Co1 and His79. The interactions with the transition-state analogues are, in general, very similar to those seen previously for the complex of the enzyme with a bestatin-based inhibitor. The mode of interaction of His79 is, however, different. In the case of the bestatin-based inhibitor, His79 interacts with atoms in the peptide bond between the P(1)' and P(2)' residues. In the present transition-state analogues, however, the histidine moves 1.2 A toward the metal center and hydrogen bonds with the atom that corresponds to the nitrogen of the scissile peptide bond (i.e., between the P(1) and P(1)' residues). These observations tend to support one of the mechanistic schemes for eMetAP considered before, although with a revision in the role played by His79. The results also suggest parallels between the mechanism of action of methionine aminopeptidase and other "pita-bread" enzymes including aminopeptidase P and creatinase.


[Comparative anti-hypertensive effectiveness and tolerance of drugs in patients with mild and moderate arterial hypertension].
120 patients with mild and moderate arterial hypertension were treated outpatiently for 6 weeks with dilren (group 1), norvask (group 2), invoril (group 3) and caposide (group 4). Each group consisted of 30 patients. The drugs were given in doses: 300 mg/day, 5-10 mg/day, 10-20 mg/day and 1 tablet a day (50 mg capoten + 25 mg hydrochlortiaside), respectively. Arterial pressure was measured by patients in the morning and in the evening. A complete hypotensive response (AP < 140/90 mm Hg) to dilren was achieved in 25(83.3) patients, norvask in 22(73.3%), invoril in 18(60%), caposide in 13(43.3%) patients. The other 45(37.5%) patients responded partially. Side effects occurred in 31(25.8%) of 120 patients. In caposide, norvask, invoril and dilren treatment they were recorded in 9(30.3%), 8(26.7%), 8(26.7%) and 6(20%) patients, respectively. 11 patients withdrew because of side effects. Thus, dilren (300 mg/day), norvask (5-10 mg/day) and invoril (10-20 mg/day) are effective and safe in mild and moderate arterial hypertension. Caposide (1 tablet a day) failed to provide an adequate fall in arterial pressure throughout 24 hours.


Nicotinamide Riboside Alleviates Corneal and Somatic Hypersensitivity Induced by Paclitaxel in Male Rats.
Patients receiving chemotherapy may experience ocular discomfort and dry eye-like symptoms; the latter may be neuropathic in nature. This study assessed corneal and somatic hypersensitivity in male rats treated with paclitaxel and whether it was relieved by nicotinamide riboside (NR). Corneal sensitivity to tactile and chemical stimulation, basal tear production, and sensitivity of the hindpaw to tactile and cool stimuli were assessed before and after paclitaxel in the absence and presence of sustained treatment with 500 mg/kg per os NR. Corneal nerve density and hindpaw intraepidermal nerve fiber (IENF) density were also examined. Paclitaxel-treated rats developed corneal hypersensitivity to tactile stimuli, enhanced sensitivity to capsaicin but not hyperosmolar saline, and increased basal tear production. Corneal nerve density visualized with anti-β-tubulin or calcitonin gene-related peptide (CGRP) was unaffected. Paclitaxel induced tactile and cool hypersensitivity of the hindpaw and a loss of nonpeptidergic hindpaw IENFs visualized with anti-protein gene product (PGP) 9.5 and CGRP. NR reversed tactile hypersensitivity of the cornea without suppressing tear production or chemosensitivity; it did not alter corneal afferent density. NR also reversed tactile and cool hypersensitivity of the hindpaw without reversing the loss of hindpaw IENFs. These findings suggest that paclitaxel may be a good translational model for chemotherapy-induced ocular discomfort and that NR may be useful for its relief. The ability of NR to relieve somatic tactile hypersensitivity independent of changes in sensory nerve innervation suggests that reversal of terminal arbor degeneration is not critical to the actions of NR.


The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling.
Wnt signalling is involved in cellular homeostasis and development. Dysregulation of the Wnt signalling pathway has been linked to colorectal cancer. The orphan nuclear receptor TR3 plays important roles in proliferation and apoptosis. In this study, we investigated how TR3 suppresses intestinal tumorigenesis by regulating Wnt signalling. Intestinal polyps were quantified in Apc(min/+), Apc(min/+)/TR3(-/-) and Apc(min/+)/villin-TR3 mice. Wnt signalling activity was evaluated by assessing β-galactosidase activity in a BAT-Gal reporter strain. The TR3 agonist cytosporone B was used to evaluate the role of TR3 in intestinal tumorigenesis. Crosstalk between TR3 and β-catenin/TCF4 was analysed by molecular methods in colorectal cancer cells. The phosphorylation of TR3 by glycogen synthase kinase (GSK) 3β and the correlation between GSK3β activity and TR3 phosphorylation were evaluated in clinical samples and colorectal cancer cells. TR3 was found to significantly suppress Wnt signalling activity and the proliferation of intestinal epithelial cells. Apc(min/+)/TR3(-/-) mice developed more intestinal polyps than Apc(min/+)/TR3(+/+) mice, whereas either transgenic overexpression of TR3 in the intestine or treatment with cytosporone B in Apc(min/+) mice significantly decreased intestinal tumour number. Mechanistically, TR3 disrupted the association of β-catenin and TCF4 on chromatin and facilitated the recruitment of transcriptional co-repressors to the promoters of Wnt signalling target genes. However, TR3 was phosphorylated by GSK3β in most clinical colorectal cancers, which attenuated the inhibitory activity of TR3 towards Wnt signalling. TR3 is a negative regulator of Wnt signalling and thus significantly suppresses intestinal tumorigenesis in Apc(min/+) mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3β in clinical colorectal cancers.


[Pharmaceutical care and attention suspended: compromise-formations between pharmacy and psychoanalysis [corrected]].
This paper presents an interdisciplinary overview of the rational use of medicine from a metapsychological standpoint. The need to reinstate the activity of the pharmaceutical professionals vis-à-vis their patients through pharmaceutical care demands the intervention of new know-how that can ensure a revitalization of this human relationship. In this sense, by means of a compilation of passages from the works of Freud, some of the most important metapsychological concepts were presented: psychic apparatus, evenly hovering attention and commitment formations. These concepts were then presented as an applicable theoretical tool for qualitative analysis in pharmaceutical care, though especially for participant observation. Thus, the main objective was to provide new tools for the pharmacists in terms of listening and receptivity, which can enhance their professional routine regarding the relationship with their patients, as well as in the gathering and interpretation of qualitative data concerning human issues involving pharmaceutical care.


Towards a model for understanding the development of post-traumatic stress and general distress in mental health nurses.
In their daily work, mental health nurses (MHN) are often exposed to stressful events, including patient-perpetrated aggression and violence. Personal safety and health concerns, as well as concern for the physical and psychological well-being of patients, dominate; these concerns have a profound impact on nurses. This cross-sectional study explored and compared the psychological well-being of 196 hospital-based MHN (97 forensic and 99 mainstream registered psychiatric nurses or psychiatric state enrolled nurses). The aim was to examine exposure to inpatient aggression and work stress, and identify factors contributing to the development of post-traumatic stress reactions and general distress. Multiple regression analyses indicated that working in a mainstream setting is associated with increased work stress; however, mainstream and forensic nurses experienced similar psychological well-being. As a group, 14-17% of mainstream and forensic nurses met the diagnostic criteria for post-traumatic stress disorder, and 36% scored above the threshold for psychiatric caseness. A tentative model of post-traumatic stress and general distress in nurses was developed, illustrating the impact of aggression and stress on well-being. The present study affirms that mental health nursing is a challenging and stressful occupation. Implications for organizations, managers, and individual nurses are discussed.


Accuracy of estimated phylogenetic trees from molecular data. I. Distantly related species.
The accuracies and efficiencies of four different methods for constructing phylogenetic trees from molecular data were examined by using computer simulation. The methods examined are UPGMA, Fitch and Margoliash's (1967) (F/M) method, Farris' (1972) method, and the modified Farris method (Tateno, Nei, and Tajima, this paper). In the computer simulation, eight OTUs (32 OTUs in one case) were assumed to evolve according to a given model tree, and the evolutionary change of a sequence of 300 nucleotides was followed. The nucleotide substitution in this sequence was assumed to occur following the Poisson distribution, negative binomial distribution or a model of temporally varying rate. Estimates of nucleotide substitutions (genetic distances) were then computed for all pairs of the nucleotide sequences that were generated at the end of the evolution considered, and from these estimates a phylogenetic tree was reconstructed and compared with the true model tree. The results of this comparison indicate that when the coefficient of variation of branch length is large the Farris and modified Farris methods tend to be better than UPGMA and the F/M method for obtaining a good topology. For estimating the number of nucleotide substitutions for each branch of the tree, however, the modified Farris method shows a better performance than the Farris method. When the coefficient of variation of branch length is small, however, UPGMA shows the best performance among the four methods examined. Nevertheless, any tree-making method is likely to make errors in obtaining the correct topology with a high probability, unless all branch lengths of the true tree are sufficiently long. It is also shown that the agreement between patristic and observed genetic distances is not a good indicator of the goodness of the tree obtained.


Arabidopsis ABCG28 is required for the apical accumulation of reactive oxygen species in growing pollen tubes.
Tip-focused accumulation of reactive oxygen species (ROS) is tightly associated with pollen tube growth and is thus critical for fertilization. However, it is unclear how tip-growing cells establish such specific ROS localization. Polyamines have been proposed to function in tip growth as precursors of the ROS, hydrogen peroxide. The ABC transporter AtABCG28 may regulate ROS status, as it contains multiple cysteine residues, a characteristic of proteins involved in ROS homeostasis. In this study, we found that AtABCG28 was specifically expressed in the mature pollen grains and pollen tubes. AtABCG28 was localized to secretory vesicles inside the pollen tube that moved toward and fused with the plasma membrane of the pollen tube tip. Knocking out AtABCG28 resulted in defective pollen tube growth, failure to localize polyamine and ROS to the growing pollen tube tip, and complete male sterility, whereas ectopic expression of this gene in root hair could recover ROS accumulation at the tip and improved the growth under high-pH conditions, which normally prevent ROS accumulation and tip growth. Together, these data suggest that AtABCG28 is critical for localizing polyamine and ROS at the growing tip. In addition, this function of AtABCG28 is likely to protect the pollen tube from the cytotoxicity of polyamine and contribute to the delivery of polyamine to the growing tip for incorporation into the expanding cell wall.


"I Do Not Trust Health Information Shared by My Parents": Credibility Judgement of Health (Mis)information on Social Media in China.
The surge of health misinformation on social media poses a threat to public health. This qualitative study reports how users process health misinformation from the dominant strong-tie social media, WeChat, in China. We conducted ten on-site focus groups involving 76 adult participants. Drawing on the apomediation theory and the dual processing model of credibility assessment, we found the heuristic approach to processing health information was the dominant route of engagement. We identified four categories of credibility assessment cues, including (1) expertise, authority, and commercial intent of original sources, (2) expertise of apomediaries (i.e. social media information sharers) and generational bias, (3) clickbait and sensational content versus objective scientific style, and (4) disconfirmation versus confirmation bias. We highlight that apomediaries are playing an increasingly important role in informing credibility judgment. Specifically, younger adults have formed a generational bias of deeming older apomediaries as cues of lower credibility.


Activation of TLR3 in keratinocytes increases expression of genes involved in formation of the epidermis, lipid accumulation, and epidermal organelles.
Injury to the skin, and the subsequent release of noncoding double-stranded RNA (dsRNA) from necrotic keratinocytes, has been identified as an endogenous activator of Toll-like receptor 3 (TLR3). As changes in keratinocyte growth and differentiation follow injury, we hypothesized that TLR3 might trigger some elements of the barrier repair program in keratinocytes. dsRNA was observed to induce TLR3-dependent increases in human keratinocyte mRNA abundance for ABCA12 (ATP-binding cassette, sub-family A, member 12), glucocerebrosidase, acid sphingomyelinase, and transglutaminase 1. Additionally, treatment with dsRNA resulted in increases in sphingomyelin and morphologic changes including increased epidermal lipid staining by Oil Red O and TLR3-dependent increases in lamellar bodies and keratohyalin granules. These observations show that dsRNA can stimulate some events in keratinocytes that are important for skin barrier repair and maintenance.


Relative resistance of fresh isolates of melanoma to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.
In previous studies, we have shown that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could induce varying degrees of apoptosis in approximately two-thirds of human melanoma lines. In the present study, we have examined the sensitivity of fresh isolates and early passages of melanoma cells to TRAIL-induced apoptosis from eight patients. We found that fresh isolates were relatively resistant to TRAIL-induced apoptosis and that this appeared to be associated with low TRAIL death receptor (TRAIL-R) expression. TRAIL-R expression was also undetectable in tissue sections from the same melanoma. We attempted to create a model for these findings by generation of TRAIL-resistant melanoma lines from TRAIL-sensitive lines grown for prolonged periods in TRAIL. The resulting TRAIL-resistant melanoma cell lines had low TRAIL-R expression, and sensitivity to TRAIL was increased rapidly by pretreatment with proteasome inhibitors known to inhibit activation of nuclear factor-kappaB. However, the latter treatment had no significant effect on the sensitivity of fresh isolates to TRAIL. The levels of the inhibitors of apoptosis, Flice-like inhibitory protein and Bcl-2, also did not relate to resistance to TRAIL-induced apoptosis. These results suggest that down-regulation of TRAIL-R on melanoma cells may be the primary determinant of resistance of fresh isolates to TRAIL, and the basis for this requires further investigation.


Effects of adding a virtual reality environment to different modes of treadmill walking.
Differences in gait between overground and treadmill walking are suggested to result from imposed treadmill speed and lack of visual flow. To counteract this effect, feedback-controlled treadmills that allow the subject to control the belt speed along with an immersive virtual reality (VR) have recently been developed. We studied the effect of adding a VR during both fixed speed (FS) and self-paced (SP) treadmill walking. Nineteen subjects walked on a dual-belt instrumented treadmill with a simple endless road projected on a 180° circular screen. A main effect of VR was found for hip flexion offset, peak hip extension, peak knee extension moment, knee flexion moment gain and ankle power during push off. A consistent interaction effect between VR and treadmill mode was found for 12 out of 30 parameters, although the differences were small and did not exceed 50% of the within subject stride variance. At FS, the VR seemed to slightly improve the walking pattern towards overground walking, with for example a 6.5mm increase in stride length. At SP, gait became slightly more cautious by adding a VR, with a 9.1mm decrease in stride length. Irrespective of treadmill mode, subjects rated walking with the VR as more similar to overground walking. In the context of clinical gait analysis, the effects of VR are too small to be relevant and are outweighed by the gains of adding a VR, such as a more stimulating experience and possibility of augmenting it by real-time feedback.


"Intrinsic" Anion Exchange Polymers through the Dissociation of Strong Basic Groups: PPO with Grafted Bicyclic Guanidines.
We synthesized anion exchange polymers by a reaction of chloromethylated poly(2,6-dimethyl-1,4-phenylene)oxide (PPO) with strongly basic 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). TBD contains secondary and tertiary amine groups in the guanidine portion. To favor the functionalization with the secondary amine, TBD was activated with butyl lithium. The yield of amine formation via the reaction of the benzyl chloride moiety with TBD was 85%. Furthermore, we prepared polymers with quaternary ammonium groups by the reaction of PPO-TBD with CH3I. The synthesis pathways and ionomer structure were investigated by NMR spectroscopy. The thermal decomposition of both ionomers, studied by thermogravimetry, started above 200 °C, corresponding to the loss of the basic group. The ion exchange capacities, water uptake and volumetric swelling are also reported. The "intrinsic" anion conductivity of PPO-TBD due to the dissociation of grafted TBD was in the order of 1 mS/cm (Cl form). The quaternized ionomer (PPO-TBD-Me) showed an even larger ionic conductivity, above 10 mS/cm at 80 °C in fully humidified conditions.


Detection error influences both temporal seroprevalence predictions and risk factors associations in wildlife disease models.
Understanding the prevalence of pathogens in invasive species is essential to guide efforts to prevent transmission to agricultural animals, wildlife, and humans. Pathogen prevalence can be difficult to estimate for wild species due to imperfect sampling and testing (pathogens may not be detected in infected individuals and erroneously detected in individuals that are not infected). The invasive wild pig (Sus scrofa, also referred to as wild boar and feral swine) is one of the most widespread hosts of domestic animal and human pathogens in North America.We developed hierarchical Bayesian models that account for imperfect detection to estimate the seroprevalence of five pathogens (porcine reproductive and respiratory syndrome virus, pseudorabies virus, Influenza A virus in swine, Hepatitis E virus, and Brucella spp.) in wild pigs in the United States using a dataset of over 50,000 samples across nine years. To assess the effect of incorporating detection error in models, we also evaluated models that ignored detection error. Both sets of models included effects of demographic parameters on seroprevalence. We compared our predictions of seroprevalence to 40 published studies, only one of which accounted for imperfect detection.We found a range of seroprevalence among the pathogens with a high seroprevalence of pseudorabies virus, indicating significant risk to livestock and wildlife. Demographics had mostly weak effects, indicating that other variables may have greater effects in predicting seroprevalence.Models that ignored detection error led to different predictions of seroprevalence as well as different inferences on the effects of demographic parameters.Our results highlight the importance of incorporating detection error in models of seroprevalence and demonstrate that ignoring such error may lead to erroneous conclusions about the risk associated with pathogen transmission. When using opportunistic sampling data to model seroprevalence and evaluate risk factors, detection error should be included.


Transducin and the inhibitory nucleotide regulatory protein inhibit the stimulatory nucleotide regulatory protein mediated stimulation of adenylate cyclase in phospholipid vesicle systems.
The adenylate cyclase coupled inhibitory nucleotide regulatory protein (Ni) and the bovine retinal nucleotide regulatory protein transducin (T) appear to share some common functional properties since their GTPase activity is stimulated to similar extents by the retinal photoreceptor rhodopsin. In the present work, we sought to assess whether these functional similarities might extend to their interaction with adenylate cyclase. This necessitated the development of reconstitution systems in which guanine nucleotide regulatory protein mediated inhibition of adenylate cyclase activity could be demonstrated and characterized in a lipid milieu. In the absence of the pure human erythrocyte stimulatory nucleotide regulatory protein (Ns), the insertion into phospholipid vesicles of either pure Ni from human erythrocytes or pure bovine T with the resolved catalytic moiety of bovine caudate adenylate cyclase (C) does not establish GppNHp inhibition of either Mg2+- or forskolin-stimulated adenylate cyclase. However, the coinsertion into lipid vesicles of either Ni or T with Ns and resolved C results in an inhibition of Ns(GppNHp) stimulatable C activity. As is the case in intact membranes, the reconstituted inhibition of the Ns-stimulated C activity extends into the steady-state phase of time courses of activity. This inhibition is highly sensitive to the MgCl2 concentration. At 2 mM MgCl2, the inhibition is greater than 80% while at 50 mM MgCl2 it is only approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)


Automated Identification of Relevant Frontier Orbitals for Chemical Compounds and Processes.
Quantum-chemical multi-configurational methods are required for a proper description of static electron correlation, a phenomenon inherent to the electronic structure of molecules with multiple (near-)degenerate frontier orbitals. Here, we review how a property of these frontier orbitals, namely the entanglement entropy is related to static electron correlation. A subset of orbitals, the so-called active orbital space is an essential ingredient for all multi-configurational methods. We proposed an automated selection of this active orbital space, that would otherwise be a tedious and error prone manual procedure, based on entanglement measures. Here, we extend this scheme to demonstrate its capability for the selection of consistent active spaces for several excited states and along reaction coordinates.


Natural Antimicrobial Edible Coatings for Microbial Safety and Food Quality Enhancement.
Natural antimicrobial agents have been investigated as alternatives to synthetic ones for ensuring food safety and quality. However, the practical use of these preservatives in the food industry is limited due to their negative impact on the odor and taste of food products, as well as the early loss of functionality due to their rapid diffusion and interaction with food components. The incorporation of natural antimicrobial agents into edible coatings has been investigated to control diffusion of active compounds and maintain their concentrations at a critical level on a food surface. Recently, nanoencapsulating and multilayered/nanolaminate delivery systems have emerged as promising tools to enhance the functionality of edible coatings. This review highlights the potential use of polymeric edible coatings for the incorporation of natural antimicrobial agents and the improvement of their controlled release in food systems. The methods used to assess the antimicrobial activity of encapsulated natural antimicrobial agents and the most recent findings regarding the application of nanoencapsulating and multilayered/nanolaminate delivery systems in food products are also discussed.


Mapping the spatial distribution of charge carriers in LaAlO3/SrTiO3 heterostructures.
At the interface between complex insulating oxides, novel phases with interesting properties may occur, such as the metallic state reported in the LaAlO(3)/SrTiO(3) system . Although this state has been predicted and reported to be confined at the interface, some studies indicate a much broader spatial extension, thereby questioning its origin. Here, we provide for the first time a direct determination of the carrier density profile of this system through resistance profile mappings collected in cross-section LaAlO(3)/SrTiO(3) samples with a conducting-tip atomic force microscope (CT-AFM). We find that, depending on specific growth protocols, the spatial extension of the high-mobility electron gas can be varied from hundreds of micrometres into SrTiO(3) to a few nanometres next to the LaAlO(3)/SrTiO(3) interface. Our results emphasize the potential of CT-AFM as a novel tool to characterize complex oxide interfaces and provide us with a definitive and conclusive way to reconcile the body of experimental data in this system.


An evaluation of Guttaflow and gutta-percha in the filling of lateral grooves and depressions.
The purpose of this study was to compare the flow of GuttaFlow (Coltène/Whaledent Inc, Cuyahoga Falls, OH) and gutta-percha into lateral grooves and depressions in the apical 7 mm of the root canal system. A maxillary canine was used to fabricate a split-tooth model with depressions and lateral grooves placed in the canal walls at 1 mm, 3 mm, 5 mm, and 7 mm from the working length. The model was obturated with GuttaFlow or gutta-percha and Roth's 801 sealer (Roth International, Chicago, IL). Obturations with gutta-percha were performed by using warm vertical compaction with the System B plugger (Analytic Endodontics, Orange, CA) advanced to 5 mm, 4 mm, or 3 mm from the working length. All obturations with GuttaFlow showed extrusion of material beyond the apex. GuttaFlow completely obturated the grooves and depressions at all levels from the working length, and, at the 1-mm level, GuttaFlow flowed significantly better into grooves. GuttaFlow flowed better than gutta-percha into depressions at the 1-mm level when the System B plugger was inserted to 5 mm and 4 mm from the working length, but no significant differences were seen when the System B plugger was inserted to 3 mm from the working length. Gutta-percha flowed significantly better into grooves and depressions at the 1-mm level when the System B plugger was inserted 3 mm from the working length compared with 5 mm and 4 mm from working length.


Effect of industrial effluent on the morphological parameters and chlorophyll content of green gram (Phaseolus aureus Roxb).
A pot culture experiment was conducted to study the effect of biomass power plant effluent on seed germination, seedling growth and chlorophyll content of green gram (variety LGG 460) have been estimated at different effluent concentrations and time intervals. The effluent is alkaline in nature (pH 8.5), odorless, and comprises of heavy metals such as Cr (0.071 mg l(-1)), Cu (0.014 mg l(-1)), Mn (0.036mg l(-1)), Fe (0.05 mg l(-1)), Co (0.31 mg l(-1)), Ni (0.041 mg l(-1)), Cd (0.028 mg l(-1)), Pb (0.108 mg l(-1)) and Zn (6.73 mg l(-1)). The germination percentage of seed, seedling growth and chlorophyll content showed a gradual decline with increase in effluent concentration. It has been observed that at 25% effluent concentration, there is growth in the root length (3.50 cm seedling(-1)), an increase in shoot length (23.90 cm seedling(-1)) and total chlorophyll content (4.467 mg g(-1) fresh weight) up to 20 days. After 20 day there is decline in all the parameters observed. However at higher concentrations of the effluent, toxic effects were observed from 20th day. This suggests that the effluent can be used safely for green gram cultivation, only after proper treatment and dilution.


Optimal antiarrhythmic drug therapy for electrical storm.
Electrical storm, defined as 3 or more separate episodes of ventricular tachycardia or ventricular fibrillation within 24 hours, carries significant morbidity and mortality. These unstable ventricular arrhythmias have been described with a variety of conditions including ischemic heart disease, structural heart disease, and genetic conditions. While implantable cardioverter defibrillator implantation and ablation may be indicated and required, antiarrhythmic medication remains an important adjunctive therapy for these persons.


Detection of new HIV infections in a multicentre HIV antiretroviral pre-exposure prophylaxis trial.
Monthly specimens collected from FEM-PrEP-a Phase III trial [1] were investigated for the detection of acute HIV (AHI) infection. To evaluate the efficiency of the study-specific HIV algorithm in detecting AHI, and the performance of each of the serological and molecular tests used in diagnosing new infections, and their contribution to narrowing the window period. A total of 83 pre-seroconversion specimens from 61 seroconverters from the FEM-PrEP trial were further analyzed in a sub-study. During the trial, HIV seroconversion was diagnosed on site using a testing algorithm with simple/rapid tests (SRTs) and confirmed with a gold standard testing algorithm (see short communication: Fig. 1). The infection date was determined more accurately by the use of standard ELISAs and Nucleic Acid Amplification Tests (NAAT) in a look-back procedure. For this sub-study, the international central laboratory repeated the study algorithm using SRTs. A total of 83 pre-seroconversions specimens from 61 seroconverters were analyzed in a look-back procedure. RNA was detected in 35/61 seroconverters at the visit before the seroconversion visit as determined at the study sites. Four seroconversion dates were inaccurate at one study site as the international central laboratory detected the HIV infection one visit earlier using the same test algorithm. Using the gold standard, an additional seroconversion was detected at an earlier visit. The combined antigen/antibody and the single antigen test had a higher sensitivity compared to the SRTs in detecting acute infections. In the FEM-PrEP trial, the international central laboratory detected a small number of seroconversions one month earlier than the study sites using the same study algorithm. Standard tests are still the most sensitive tests in detecting pre-seroconversion or acute HIV infection, but they are costly, time consuming and not recommended for use on-site in a clinical trial.