[Surgical quality registries: large room for improvement if they should be used for analyses of life style risk factors and the effect of preoperative initiatives on postoperative complications].
Surgical quality registries: large room for improvement if they should be used for analyses of life style risk factors and the effect of preoperative initiatives on postoperative complications Tobacco, alcohol, malnutrition, overweight and physical inactivity increase postoperative morbidity. Preoperative intervention has been shown to improve the outcome significantly. The aim was to investigate if these lifestyle risk factors were reported in the Swedish national surgical quality registries together with preoperative interventions and postoperative complications. Altogether, 44 registers reporting on surgical procedures were identified. Preoperative documentation existed in about half of the registries, but relevant health promoting intervention was not documented. Postoperative complications were reported with varying degrees. No registry had complete reporting of preoperative lifestyle risk factors, related intervention and postoperative complications. For most registries, there is a large room for improvement if they should be used for analyses of risk factors and the effect of implementation of preoperative initiatives on postoperative complications.


Clinical evaluation of two adult oxygenator systems in terms of mortality and major adverse events.
The primary aim of this study was to examine the effects of two oxygenator systems on major adverse events and mortality. A total of 181 consecutive patients undergoing coronary artery bypass grafting in our clinic were retrospectively analyzed. The patients were divided into two groups according to the oxygenator used: Group M, in which a Medtronic Affinity (Medtronic Operational Headquarters, Minneapolis, MN, USA) oxygenator was used, and Group S, in which a Sorin Inspire (Sorin Group Italia, Mirandola, Italy) oxygenator was used. Group S consisted of 89 patients, whereas Group M included 92 patients. No statistically significant differences were found between the two groups in terms of age (p = .112), weight (p = .465), body surface area (p = .956), or gender (p = .484). There was no statistically significant difference in hemorrhage on the first or second postoperative day (p = .318 and p = .455, respectively). No statistically significant differences were observed in terms of red blood cell (p = .468), fresh frozen plasma (p = .116), or platelet concentrate transfusion (p = .212). Infections, wound complications, and delayed sternal closure were significantly more common in Group M (p = .006, p = .023, and p = .019, respectively). Extracorporeal membrane oxygenators and intra-aortic balloon pumps were required significantly more frequently in Group S (p = .025 and p = .013, respectively). Major adverse events occurred in 16 (18%) patients in Group S and 14 (15.2%) patients in Group M (p = .382). Mortality was observed in six (6.7%) patients in Group S and three (3.3%) patients in Group M (p = .232). No statistically significant difference was found between the two groups in terms of length of hospital stay (p = .451). The clinical outcomes of the two oxygenator systems, including mortality, major adverse events, hemorrhage, erythrocyte and platelet transfusions, and length of hospital stay, were similar.


How crowding affects letter confusion.
Acuity for letter recognition is known to be worse when multiple letters are presented with narrow interletter spacings than with wide spacings. How would interletter spacing affect the kind of errors made by human subjects? Five-letter strings that were randomly drawn from the 26 uppercase letters of the English alphabet were presented foveally to the subjects. The interletter spacings were 1.0 and 0.1 letter height. Letter confusion matrices were constructed from the data collected using these spacing conditions. Narrow- and wide-spacing letter strings produced different letter confusion matrices. Aside from the letter confusions that were shared by both wide- and narrow-spacing strings, narrow-spacing strings produced more random confusions and a set of unique letter confusions, which was not observed under the wide-spacing condition. Increased random guessing and lateral interactions between features of neighboring letters can account for most of the acuity deterioration observed under the narrow-spacing condition.


Induction of hepatocyte proliferation by retinoic acid.
Retinoids have been shown to exert an anticarcinogenic effect through suppression of the cell cycle, induction of apoptosis and/or differentiation. In rat liver, in particular, retinoic acid has been shown to inhibit regeneration after partial hepatectomy, most probably through repression of the expression of c-fos and c-jun. Surprisingly enough, in spite of the proposed therapeutic effects of all-trans retinoic acid (tRA) no data are available on its effect on normal adult liver. Here, we show that tRA administration in the diet (150 mg/kg) increased DNA synthesis in mouse liver, at 1 and 2 weeks, with a return to control values at 4 weeks (labelling index was 16.5, 8.3 and 3.3%, respectively, versus control values of 1.4, 1.3 and 2.5%). Increase in mitotic index paralleled that of bromodeoxyuridine incorporation. Kinetic studies showed that entry into S phase began between 24 and 48 h, with a peak between 96 and 120 h. Histological observation of the liver and biochemical evaluation of the levels of serum glutamate-pyruvate transaminases did not reveal any evidence of cell death demonstrating that increased DNA synthesis was not due to tRA-induced liver damage and regeneration, but rather the consequence of a direct mitogenic effect. In addition, analysis of total hepatic DNA content after a 7-day treatment showed a significant increase in tRA-fed mice compared with controls (21.11 mg/100 g body wt in tRA-fed mice versus 15.67 mg/100 g body wt of controls). Hepatocyte proliferation in tRA-fed mice was associated with increased hepatic levels of cyclin D1, E and A, and enhanced expression of the member of pRb family, p107. In conclusion, the results showed that tRA induces hepatocyte proliferation in the absence of cell death, similarly to other ligands of steroid/thyroid hormone nuclear receptor superfamily. The mitogenic effect of tRA cautions about its possible use for antitumoral purposes in liver carcinogenesis.


Immunohistochemical characterization of the inflammatory infiltrate in placental Chagas' disease: a qualitative and quantitative analysis.
Chagas' disease, a systemic illness endemic to some regions of South America, is caused by the protozoan Trypanosoma cruzi. Transplacental infection may occur during any phase and cause fetal death. This study is the first to characterize the inflammatory cells in chagasic villitis by immunohistochemistry. Paraffin sections of 8 placentas with villitis by T. cruzi (4 live births and 4 stillbirths), as well as 8 control placentas without inflammation, were stained with hematoxylin and eosin, monoclonal antibodies for CD45RO, CD20, CD45RO/OPD4, CD8, HNKI, CD15, MAC387, and CD68 proteins, and a polyclonal antibody for S-100 protein. Quantification of positive cells was performed in 3 different high-power fields. In all cases of chagasic villitis, the inflammatory infiltrate was composed mainly of CD68+ macrophages, T lymphocytes, and a few natural killer cells. Among T cells, CD8+ cells outnumbered CD4+ cells in all placentas (CD4+:CD8+ ratios ranged from 0.04 to 0.38). B cells were absent or rare. In stillbirths, villitis was diffuse and severe with numerous T. cruzi, while in live births it was focal with few parasites. Other features that characterized villitis in stillbirths were 1) frequent trophoblastic necrosis, 2) presence of MAC387+ macrophages and CD15+ granulocytes attached to the sites of trophoblastic necrosis, 3) low CD4+: CD8+ ratios in most cases, 4) increased numbers of S-100 positive cells in the villous stroma. In conclusion, CD68+ macrophages and CD8+ T lymphocytes were the major cell population in villitis caused by T. cruzi. However, the pattern of inflammatory reaction differed between stillbirths and live births and was probably related to the number of parasites in the placental villi.


miRNA-370 acts as a tumor suppressor via the downregulation of PIM1 in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a primary malignancy of liver. Nowadays HCC is one of the most common and aggressive malignancies worldwide. This study shows the aberrant up-regulation or down-regulation of miR-370correlates with the development and prognosis of different human malignancies including HCC. The HCC cell lines were used as model cell lines and the anti-tumor effect of miR-370 in vitro were examined. The level of miR-370 in HCC cells was determined by qRT-PCR and restored in GC cells by using miR-370 mimic. Moreover, the target gene of miR-370 was then identified. The expression of miR-370 in HCC cell lines was significantly lower than that in the other human liver cells. The miR-370 acted as a tumor suppressor in HCC. Moreover, it showed that miR-370 exerted anti-tumor effect by targeting PIM1 directly, a serine/threonine-specific kinase involved in the development and progression of HCC. miR-370 acted as the tumor suppressor in HCC and was a potential therapeutic target for HCC treatment.


Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production.
The antimalarial agent artesunate (ART) activates programmed cell death (PCD) in cancer cells in a manner dependent on the presence of iron and the generation of reactive oxygen species. In malaria parasites, ART cytotoxicity originates from interactions with heme-derived iron within the food vacuole. The analogous digestive compartment of mammalian cells, the lysosome, similarly contains high levels of redox-active iron and in response to specific stimuli can initiate mitochondrial apoptosis. We thus investigated the role of lysosomes in ART-induced PCD and determined that in MCF-7 breast cancer cells ART activates lysosome-dependent mitochondrial outer membrane permeabilization. ART impacted endolysosomal and autophagosomal compartments, inhibiting autophagosome turnover and causing perinuclear clustering of autophagosomes, early and late endosomes, and lysosomes. Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced death, thus identifying lysosomal iron as the lethal source of reactive oxygen species upstream of mitochondrial outer membrane permeabilization. Moreover, lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling. ART killing did not involve activation of the BH3-only protein, Bid, yet ART enhanced TNF-mediated Bid cleavage. We additionally demonstrated the lysosomal PCD pathway in T47D and MDA-MB-231 breast cancer cells. Importantly, non-tumorigenic MCF-10A cells resisted ART-induced PCD. Together, our data suggest that ART triggers PCD via engagement of distinct, interconnected PCD pathways, with hierarchical signaling from lysosomes to mitochondria, suggesting a potential clinical use of ART for targeting lysosomes in cancer treatment.


A fractional order approach to modeling and simulations of the novel COVID-19.
The novel coronavirus (SARS-CoV-2), or COVID-19, has emerged and spread at fast speed globally; the disease has become an unprecedented threat to public health worldwide. It is one of the greatest public health challenges in modern times, with no proven cure or vaccine. In this paper, our focus is on a fractional order approach to modeling and simulations of the novel COVID-19. We introduce a fractional type susceptible-exposed-infected-recovered (SEIR) model to gain insight into the ongoing pandemic. Our proposed model incorporates transmission rate, testing rates, and transition rate (from asymptomatic to symptomatic population groups) for a holistic study of the coronavirus disease. The impacts of these parameters on the dynamics of the solution profiles for the disease are simulated and discussed in detail. Furthermore, across all the different parameters, the effects of the fractional order derivative are also simulated and discussed in detail. Various simulations carried out enable us gain deep insights into the dynamics of the spread of COVID-19. The simulation results confirm that fractional calculus is an appropriate tool in modeling the spread of a complex infectious disease such as the novel COVID-19. In the absence of vaccine and treatment, our analysis strongly supports the significance reduction in the transmission rate as a valuable strategy to curb the spread of the virus. Our results suggest that tracing and moving testing up has an important benefit. It reduces the number of infected individuals in the general public and thereby reduces the spread of the pandemic. Once the infected individuals are identified and isolated, the interaction between susceptible and infected individuals diminishes and transmission reduces. Furthermore, aggressive testing is also highly recommended.


Coronary Computed Tomography Angiography: Enhancing Risk Stratification and Diagnosis of Cardiovascular Disease in Women.
There are numerous gender- and sex-based differences that contribute to the increased morbidity and mortality related to atherosclerotic cardiovascular disease (ASCVD) in women. Early detection of risk and targeted management of atherosclerotic disease is fundamental to reduce ASCVD risk and improve outcomes in women. In this review, we examine the utility of cardiac computed tomography (CT) and coronary CT angiography (CTA) in three ASCVD scenarios including coronary artery calcium scoring for risk stratification in asymptomatic women, and coronary CTA for diagnosis and prognosis of stable ischemic heart disease and acute chest pain. The risks of radiation exposure and the potential applications of novel technologies in women are explored. CTA provides the capabilities of early recognition and management of nonobstructive coronary artery disease (CAD). Recent advancements in plaque composition and morphology further enhance the prognostic yield from coronary CTA. Innovations in stress perfusion and computational fluid dynamics allow for evaluation of physiological measures of ischemia. In addition, developments in artificial intelligence (AI) may also help unlock a deeper understanding of atherosclerosis and risk in women. Coronary CTA is an accurate and useful modality for early detection and management of ASCVD in women. Novel technologies hold great promise for furthering our understanding of sex-specific pathophysiology and potential improvement in clinical management and outcomes.


Urology in pre-civil war Charleston.
With a history spanning more than 3 centuries, Charleston, South Carolina was one of the initial locations of urological teaching in the southern United States. The Medical University of South Carolina was chartered in 1823 and is the oldest medical school in the South. We reviewed the historical archives of the Waring Library of the Medical University of South Carolina, specifically the history of urological practice in the city, including doctoral dissertations from medical school students regarding the teaching and practice of urology in pre-Civil War Charleston, to better understand the early development of the specialty. We reviewed graduate medical student dissertations from the historical archives of the Medical University of South Carolina from 1824 to 1860. In addition, we accessed and reviewed the records of the Medical Society of South Carolina, The Charleston Medical Journal and Review, and The American Urological Association Centennial History 1902 to 2002 volumes 1 and 2. These historical documents and dissertations review in depth various medical conditions, diagnoses and treatments in pre-Civil War Charleston. Topics such as urolithiasis, urethral stricture, stone composition and hydrocele are a few of the areas considered. Review of these documents fosters insight into the evolving diagnosis and treatment of several urological conditions. Some treatments such as the use of tobacco for urinary retention have fallen out of favor, while others such as the surgical repair of vesicovaginal fistula are still practiced. The history of urology in pre-Civil War Charleston and at the Medical University of South Carolina demonstrates an advanced understanding of urological diseases and the technology designed to treat them with a distinctly European influence.


Development of a Data Collection Instrument for Violent Patient Encounters against Healthcare Workers.
Healthcare and social workers have the highest incidence of workplace violence of any industry. Assaults toward healthcare workers account for nearly half of all nonfatal injuries from occupational violence. Our goal was to develop and evaluate an instrument for prospective collection of data relevant to emergency department (ED) violence against healthcare workers. Participants at a high-volume tertiary care center were shown 11 vignettes portraying verbal and physical assaults and responded to a survey developed by the research team and piloted by ED personnel addressing the type and severity of violence portrayed. Demographic and employment groups were compared using the independent-samples Mann-Whitney U Test. There were 193 participants (91 male). We found few statistical differences when comparing occupational and gender groups. Males assigned higher severity scores to acts of verbal violence versus females (mean M,F=3.08, 2.70; p<0.001). While not achieving statistical significance, subgroup analysis revealed that attending physicians rated acts of verbal violence higher than resident physicians, and nurses assigned higher severity scores to acts of sexual, verbal, and physical violence versus their physician counterparts. This survey instrument is the first tool shown to be accurate and reliable in characterizing acts of violence in the ED across all demographic and employment groups using filmed vignettes of violent acts. Gender and occupation of ED workers does not appear to play a significant role in perception of severity workplace violence.


Virus-lymphocyte interactions. II. Expression of viral sequences during the course of persistent lymphocytic choriomeningitis virus infection and their localization to the L3T4 lymphocyte subset.
Viruses that cause in vivo persistent infections need to selectively compromise the host's immunologic surveillance machinery in order to survive. To understand the molecular basis of how this is accomplished we have analyzed persistent virus infection by lymphocytic choriomeningitis in its normal host, the mouse. Earlier we noted by infectious center analysis that five in 10(4) lymphocytes carried by persistently infected mice contained infectious materials throughout the course of infection. A previous publication extended these results, in BALB mice by showing that the L3T4+ lymphocyte subset in lymph nodes and spleens was predominantly involved. Using cDNA labeled probes to the viral genome and in situ hybridization we report that 1 to 2% of circulating lymphocytes from several mouse strains contain viral RNA sequences for the three viral structural genes. By FACS analysis, the Thy-1.2+, L3T4+ subset primarily harbors virus while viral sequences are usually not detected in the Lyt-2+ subset as early as 6 days after initiating infection in newborns and throughout the course of the persistence. These findings suggest that incomplete, presumably defective, virus is generated in a subset of Th lymphocytes during persistent infection and that during this time infection of cytotoxic T cell subsets is minimal.


Peripheral glia have a pivotal role in the initial response to axon degeneration of peripheral sensory neurons in zebrafish.
Axon degeneration is a feature of many peripheral neuropathies. Understanding the organismal response to this degeneration may aid in identifying new therapeutic targets for treatment. Using a transgenic zebrafish line expressing a bacterial nitroreductase (Ntr)/mCherry fusion protein in the peripheral sensory neurons of the V, VII, IX, and X cranial nerves, we were able to induce and visualize the pathology of axon degeneration in vivo. Exposure of 4 days post fertilization Ntr larvae to the prodrug metronidazole (Met), which Ntr metabolizes into cytotoxic metabolites, resulted in dose-dependent cell death and axon degeneration. This was limited to the Ntr-expressing sensory neurons, as neighboring glia and motor axons were unaffected. Cell death was rapid, becoming apparent 3-4 hours after Met treatment, and was followed by phagocytosis of soma and axon debris by cells within the nerves and ganglia beginning at 4-5 hours of exposure. Although neutrophils appear to be activated in response to the degenerating neurons, they did not accumulate at the sites of degeneration. In contrast, macrophages were found to be attracted to the sites of the degenerating axons, where they phagocytosed debris. We demonstrated that peripheral glia are critical for both the phagocytosis and inflammatory response to degenerating neurons: mutants that lack all peripheral glia (foxD3-/-; Ntr) exhibit a much reduced reaction to axonal degeneration, resulting in a dramatic decrease in the clearance of debris, and impaired macrophage recruitment. Overall, these results show that this zebrafish model of peripheral sensory axon degeneration exhibits many aspects common to peripheral neuropathies and that peripheral glia play an important role in the initial response to this process.


Novel selective inhibitors of the zinc plasmodial aminopeptidase PfA-M1 as potential antimalarial agents.
Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward neutral aminopeptidase (APN-CD13), a related protease in mammals. Structure-activity relationships in these series are described. Further optimization of the best inhibitor yielded a nanomolar, selective inhibitor of PfA-M1. This inhibitor displays good physicochemical and pharmacokinetic properties and a promising antimalarial activity.


[Sodium excretion in children with lithogenic disorders].
The causes of nephrolithisis are multifactorial and have not yet been enough investigated [1]. Hypercalciuria is the most common cause of metabolic nephrolithiasis [2-4]. Close relationship between urinary calcium and urinary sodium has been a subject of reported observations in the past, showing that high urinary sodium is associated with high urinary calcium [5-7]. Hyperoxaluria, hyperuricosuria and cystinuria are also metabolic disorders that can lead to nephrolithiasis. Recent studies have indicated that urinary elimination of cystine is influenced by urinary sodium excretion. Based on these observations it has been hypothesised that patients with high urinary sodium excretion are at high risk of urinary stone disease. The purpose of the study was to investigate sodium excretion in a 24-hour urine and first morning urine collected from children with lithogenic metabolic abnormalities (hypercalciuria, hyperoxaluria, hyperuricosuria, cystinuria), both with nephrolithiasis and without it, in order to determine its significance in urinary calculi formation. Urinary sodium excretion was investigated in 2 groups of children: patients with lithogenic metabolic abnormalities, but without urinary stone disease (L group) and patients with nephrolithiasis (C group). Both groups were divided into 2 subgroups: patients with hypercalciuria and without it. There were 22 patients in group L (mean age 11.97 +/- 4.13 years), of whom 17 formed a hypercalciuric subgroup and 5 formed a non-hypercalciuric subgroup (3 patients with hyperuricosuria and 2 patients with hyperoxaluria). Group C consisted of 21 patients with nephrolithiasis (mean age 12.67 +/- 3.44 years), of whom 6 formed a hypercalciuric subgroup and 15 formed a non-hypercalciuric group (2 patients with cystinuria and 13 patients without lithogenic metabolic abnormalities). Control group consisted of 42 healthy age-matched children. All subjects had a normal renal function. A detailed history and clinical examination were done, and ultrasonography was performed in all patients. A 24-hour urine, first morning urine and serum specimen were analysed for sodium, potassium, calcium, uric acid, urea and creatinine. Fractional excretion of sodium, as well as urinary sodium to creatinin ratio and urinary sodium to potassium ratio, were calculated from the findings. Sodium and potassium levels were determined by flame photometry, calcium was measured by atomic absorption technique (Beckman Atomic Spectrophotometer, Synchron CX-5 model, USA), uric acid by carbonate method and creatinine by Jaffe technique. Cystine and dibasic amino acids were quantified by ion chromatography. Urinary oxalate excretion was determined by enzyme spectrophotometry. Hypercalciuria was defined by 24-hour calcium excretion greater than 3.5 mg/kg per day and/or calcium to creatinine ratio greater than 0.20 [8]. Uric acid excretion was expressed as uric acid excretion factored for glomerular filtration, according to Stapleton's and Nash's formula [9]. Normal values were lower than 0.57 mg/dl of glomerular filtration rate in 24-hour samples. Mean values were statistically analyzed by Pearson's linear correlation and analysis of variance (ANOVA). Urinary sodium concentration values including urinary sodium to potassium ratios, are shown in Table 1. We found that urinary sodium excretion was significantly increased in patients of both L and C groups when compared with controls (p < 0.05). Further analysis of the subgroups showed that urinary sodium excretion was significantly higher only in patients with hypercalciuria of both L and C groups in comparison to controls (p < 0.05) (Table 2). A significant positive correlation was found between 24-hour urinary sodium to creatinine ratio and urinary calcium to creatinine ratio (r = 0.31; p < 0.001) (Graph 1), as well as between urinary sodium to potassium ratio in 24-hour and first morning urine (r = 0.69; p < 0.001) (Graph 2). (A


Measuring stigma in children receiving mental health treatment: Validation of the Paediatric Self-Stigmatization Scale (PaedS).
Research on the impact of stigma associated with mental illness in children is scarce. Considering the known negative effects of stigma associated with mental illness in adults, it is crucial to explore the stigma experienced by children who access mental health treatment. However, no scale measuring self-stigmatization in younger children is available to date. This study aimed to develop and validate such a scale, the Paediatric Self-Stigmatization Scale (PaedS). A total of 156 children (119 receiving outpatient and 37 receiving inpatient treatment), aged 8-12 years, completed the PaedS, the Self-Perception Profile for Children and the Pediatric Quality of Life Inventory (PedsQL - Child Report, ages 8-12). In addition, parents completed the PedsQL (Parent Report for Children, ages 8-12), the Strengths and Difficulties Questionnaire (SDQ) and a modified subscale of the PaedS measuring the children's rejection by others due to their mental health difficulties. A confirmatory factor analysis showed that a four-factor structure, comprising Societal Devaluation, Personal Rejection, Self-Stigma and Secrecy scales, had excellent fit to the data (CFI=0.95; TLI=0.95; RMSEA=0.05). Child-reported PaedS scores were positively correlated with parental-reported PaedS scores and negatively with PedsQL, the SDQ, and 5 out of 6 subscales of the Self-Perception Profile for Children, suggesting adequate convergent validity (all P-values<0.05). The PaedS is a valid instrument, which is hoped to advance the understanding of self-stigmatization in children with mental health difficulties and contribute to its prevention.


Detection and diversity of pathogenic Vibrio from Fiji.
Here we investigate the diversity of pathogenic Vibrio species in marine environments close to Suva, Fiji. We use four distinct yet complementary analyses - biochemical testing, phylogenetic analyses, metagenomic analyses and molecular typing - to provide some preliminary insights into the diversity of vibrios in this region. Taken together our analyses confirmed the presence of nine Vibrio species, including three of the most important disease-causing vibrios (i.e. V. cholerae, V. parahaemolyticus and V. vulnificus), in Fijian marine environments. Furthermore, since toxigenic V. parahaemolyticus are present on fish for consumption we suggest these bacteria represent a potential public health risk. Our results from Illumina short read sequencing are encouraging in the context of microbial profiling and biomonitoring. They suggest this approach may offer an efficient and cost-effective method for studying the dynamics of microbial diversity in marine environments over time.


Comparison of iohexol and lactulose-mannitol tests as markers of disease activity in patients with inflammatory bowel disease.
Increased intestinal permeability has been proposed as one aetiological factor for inflammatory bowel diseases (IBD). We have previously found that intestinal permeability of a water-soluble contrast medium, iohexol, correlates with disease activity. The objective was to compare the iohexol test with the lactulose-mannitol ratio, which is a more extensively studied permeability marker, in patients with active IBD. Urinary excretion of iohexol was compared to the lactulose-mannitol ratio in 22 patients with an exacerbation of IBD and in 10 healthy controls. Median intestinal absorption of iohexol was 0.64% (range 0.13-3.8%) in the 22 patients and 0.3% (range 0.15-0.54%) in the controls (p = 0.016), whereas the median lactulose-mannitol ratio was 0.037 (range 0.01-0.260) in patients and 0.03 (range 0.004-0.063) in controls (N.S.). Correlation between urinary excretion of iohexol and lactulose-mannitol ratio was positive (R = +0.41, p = 0.018). The urinary excretion of iohexol correlated positively with endoscopic disease activity (R = +0.74, p < 0.001) and the modified Harvey-Bradshaw index (R = +0.44, p = 0.04). The lactulose-mannitol ratio correlated positively with endoscopic disease activity (R = +0.44, p = 0.05), but correlations with clinical index or c-reactive protein were poor. In conclusion, the iohexol test is a superior activity marker compared to the lactulose-mannitol ratio which probably reflects, instead, some pathogenic property of IBD.


Cellular mechanism of inhibition of osteoclastic resorption of bone and calcified cartilage by long-term pamidronate administration in ovariectomized mature rats.
We examined the effects of long-term bisphosphonate (BP, pamidronate) administration at a therapeutic dose (1.5 mg/kg/day) on the distribution, structure, and vacuolar-type H(+)-ATPase expression of osteoclasts, and the resulting trabecular bone volume and structure in ovariectomized (OVX) mature rats. Six-month-old female rats were allocated to sham-operated control, untreated-OVX, and BP-administered OVX groups. Postoperatively, BP was administered intraperitoneally once a day to OVX rats for up to 30 days. On postoperative days 14, 30, and 60, all of the rats were killed and the distal metaphyseal area of the dissected humeri was examined. Quantitative backscattered-electron image analysis revealed that the trabecular bone volume/unit medullary area in untreated OVX rats was significantly (P < 0.05) lower than that in sham-operated controls at 30 and 60 days postoperation. BP administration significantly (P < 0.05) increased trabecular bone volume at 14, 30, and 60 days postoperation in BP-administered OVX rats compared to both sham-operated and untreated OVX rats. Compared to untreated OVX rats, the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts along the bone trabeculae in BP-administered OVX rats was not significantly decreased on days 14 and 30, but was significantly decreased on day 60. Ultrastructurally, BP administration caused the disappearance of both the ruffled border (RB) and the clear zone (CZ) structures, and decreased the expression of vacuolar-type H(+)-ATPase in most osteoclasts, but did not significantly induce apoptosis of osteoclasts detected by the terminal dUTP nick end-labeling (TUNEL) method. Our results suggest that long-term BP administration significantly reduces bone and calcified cartilage resorption through impairment of the structure and bone-resorbing function of osteoclasts, and thereby effectively maintains trabecular bone volume and structure in ovariectomy-induced acute estrogen deficiency in mature rats.


Elevated Plasma Angiopoietinlike Protein 5 (ANGPTL5) Is More Positively Associated with Glucose Metabolism Disorders in Patients with Metabolic Syndrome.
BACKGROUND Angiopoietinlike protein 5 (ANGPTL5) is an adipocytokine and has an important role in metabolic processes including lipid metabolism, obesity, and type 2 diabetes mellitus. On the basis of these roles, the present study aimed to investigate the level and role of plasma ANGPTL5 in metabolic syndrome (MS) patients. MATERIAL AND METHODS A total of 139 participants was enrolled in this study; 69 of them were diagnosed with MS. Plasma ANGPTL5 levels were measured by enzyme-linked immunosorbent assay. Sex, age, and other laboratory tests were compared statistically. Correlations between ANGPTL5 and biochemical parameters such as lipid levels and insulin resistance were all evaluated statistically. RESULTS In patients with MS, plasma ANGPTL5 levels were higher than in those without MS (P<0.05). Moreover, after adjusting for the glucose profiles, positive correlations were found between plasma ANGPTL5 levels and body mass index (BMI), waist circumference, and waist-hip ratio (WHR); a weak negative correlation was found between ANGPTL5 concentration and high-density lipoprotein cholesterol. After controlling the lipid profiles, positive correlations were found between ANGPTL5 concentration and BMI, WHR, fasting plasma glucose, fasting insulin, glycated hemoglobin, and homeostatic model assessment (HOMA) of insulin resistance; a negative correlation was found between plasma ANGPTL5 concentration and HOMA of ß-cell function. The area under the curve was approximately 0.912 in receiver operating characteristic curve analysis. CONCLUSIONS The findings in the present study showed that plasma ANGPTL5 was more positively correlated with glucose metabolism disorders than with lipid metabolism disorders in patients with MS, which suggested that ANGPTL5 might serve as a potential and useful clinical predictor of MS.


Estimation of aqueous distributional spaces in the dual perfused rat liver.
1. The aim of this study was to estimate the aqueous distributional spaces of the liver as a function of the route of input: portal vein (PV) versus hepatic artery (HA). 2. Studies were performed in the situ single (PV) and dual (PV-HA) perfused rat liver (n = 6-10) using Krebs bicarbonate buffer at constant PV (12 ml min-1) and HA (3 ml min-1) flow rates. An impulse input-output response technique was employed, varying the route of input, using non-labelled erythrocytes (intravascular marker), 125I-albumin and [14C]sucrose (extracellular markers), and [14C]urea and 3H2O (total water markers) as the reference indicators. 3. Distributional spaces were estimated using two different methods, namely standard and specific. The standard method was applied to hepatic outflow data obtained from the single PV perfused liver. The specific method was used when operating in the dual perfused mode to provide an estimate of the excess space perfused solely by the HA input. Specific spaces, interstitial and intracellular volumes, were estimated by difference. 4. The results were evaluated by means of visual inspection of the outflow profiles and comparison of the distributional spaces. Different hepatic effluent profiles obtained as a function of the route of input indicated that these two inputs did not completely mix within the liver. Estimates of the distributional spaces supported this observation, and further suggested that the arterial input perfuses 9-12 % more hepatic tissue than the venous input. 5. The knowledge obtained from the existence of a specific arterial space can be extended to help make predictions about the fate of an eliminated compound following arterial administration. Any difference between the HA and PV in terms of hepatic recovery could be attributed to this excess space and its enzyme density.


Effects of interviewer familiarity and supportiveness on children's recall across repeated interviews.
Child witnesses often describe their experiences across multiple interviews. It is unknown whether talking with a familiar interviewer increases disclosures, however, or whether any benefits of a familiar interviewer could be achieved by ensuring that interviewers (regardless of familiarity) behave in socially supportive ways. This study tested the effects of interviewer familiarity and social support on children's reports of an adult's transgressions. We predicted that familiarity and supportiveness would increase transgression reports at a second interview and that children who spoke with familiar, supportive interviewers would disclose the most transgressions. Children (N = 160, 5 to 9 years) participated in a science event involving 6 transgressions. Across 2 interviews, they spoke with the same trained university student interviewer or different interviewers, and these interviewers engaged in supportive or neutral behaviors. Interviews were coded for overall information reported, number of transgressions, and confabulations. There were no effects of support in the first interview or on total details reported in either interview. Children reported more transgressions to supportive than neutral interviewers in the second interview (IRR = 1.19), even during open-ended prompting (IRR = 1.26), and they omitted fewer transgressions that had been reported in the first interview (IRR = 0.69). Confabulations were infrequent. There were no condition differences in the total number of confabulations reported across interviews, but these errors occurred more often in the second interview in the supportive condition. Interviewer support may play a greater role than familiarity in facilitating children's testimony. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Encoding specificity in plant calcium signalling: hot-spotting the ups and downs and waves.
Calcium ions function as intracellular second messengers in regulating a plethora of cellular processes from acclimative stress responses to survival and programmed cell death. The generation of specificity in Ca2+ signals is dependent on influx and efflux from the extracellular milieu, cytosol and intracellular organelles. One aspect of plant Ca2+ signalling that is currently attracting a great deal of interest is how 'Ca2+-signatures', specific spatio-temporal changes in cytosolic-free Ca2+, encode the necessary information to bring about this range of physiological responses. Here, current information is reviewed on how Ca2+-signatures are generated in plant cells and how stimulus-specific information can be encoded in the form of Ca2+-signatures.


A quantitative test for superoxide radicals produced in biological systems.
The preparation and properties of a partially succinoylated cytochrome c, suited for the detection of superoxide anion radicals in liver microsomes, is reported. By succinoylation of 45% of the primary amino groups of horse heart cytochrome c the activity towards solubilized NADPH--cytochrome P-450 reductase was diminished by 99% compared with native cytochrome c. The capacities of cytochrome b5 and cytochrome c oxidase to reduce the succinoylated ferricytochrome c and oxidize succinoylated ferrocytochrome c respectively were decreased to a similar extent. However, the bimolecular rate constant for the reduction of the partially succinoylated ferricytochrome c by O2-. was estimated to be one-tenth of the value for the reaction of O2-. with native ferricytochrome c a pH 7.7. On this basis the quantification of O2-. generated by NADPH-supplemented liver microsomes became possible. The initial rates of succinoylated ferricytochrome c reduction determined at various finite concentrations of the cytochrome c derivative can be extrapolated to obtain true rates of O2-. generation in a homogeneous system. The problems encountered in the quantitative determination of O2-. produced in biological membranes, e.g. microsomes, are discussed.


Pulsatile Cortisol Feedback on ACTH Secretion Is Mediated by the Glucocorticoid Receptor and Modulated by Gender.
Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu. The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output (by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively. The study was conducted at the Mayo Center for Translational Science Activities. Healthy middle-aged men (n = 16) and women (n = 25) participated in the study. This was a randomized, prospective, double-blind, placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured. Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women. Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.


O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia.
The development of resistance to chemotherapy is a major cause of relapse in acute lymphoblastic leukemia (ALL). Though several mechanisms associated with drug resistance have been studied in detail, the role of carbohydrate modification remains unexplored. Here, we investigated the contribution of 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) to survival and drug resistance development in ALL cells. A strong induction of 9-O-acetylated Neu5Ac including 9-O-acetyl GD3 was detected in ALL cells that developed resistance against vincristine or nilotinib, drugs with distinct cytotoxic mechanisms. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to such drugs. Moreover, removal of intracellular and cell surface-resident 9-O-acetyl Neu5Ac by lentiviral transduction of the esterase was lethal to ALL cells in vitro even in the presence of stromal protection. Interestingly, expression of the esterase in normal fibroblasts or endothelial cells had no effect on their survival. Transplanted mice induced for expression of the O-acetylesterase in the ALL cells exhibited a reduction of leukemia to minimal cell numbers and significantly increased survival. This demonstrates that Neu5Ac 9-O-acetylation is essential for survival of these cells and suggests that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells.


The tuning-fork model of human social cognition: a critique.
The tuning-fork model of human social cognition, based on the discovery of mirror neurons (MNs) in the ventral premotor cortex of monkeys, involves the four following assumptions: (1) mirroring processes are processes of resonance or simulation. (2) They can be motor or non-motor. (3) Processes of motor mirroring (or action-mirroring), exemplified by the activity of MNs, constitute instances of third-person mindreading, whereby an observer represents the agent's intention. (4) Non-motor mirroring processes enable humans to represent others' emotions. After questioning all four assumptions, I point out that MNs in an observer's brain could not synchronically resonate with MNs in an agent's brain unless they discharged in a single brain in two distinct tasks at different times. Finally, I sketch a conceptualist alternative to the resonance model according to which a brain mechanism active in both the execution and the perception of e.g., the act of grasping is the neural basis of the concept of e.g., grasping.


Low value of second-look endoscopy for detecting residual colorectal cancer after endoscopic removal.
Endoscopic resection is often feasible for submucosal invasive colorectal cancers (T1 CRCs) and usually judged as complete. If histology casts doubt on the radicality of resection margins, adjuvant surgical resection is advised, although residual intramural cancer is found in only 5% to 15% of patients. We assessed the sensitivity of biopsy specimens from the resection area for residual intramural cancer as a potential tool to estimate the preoperative risk of residual intramural cancer in patients without risk factors for lymph node metastasis (LNM). In this multicenter prospective cohort study, patients with complete endoscopic resection of T1 CRC, scheduled for adjuvant resection due to pathologically unclear resection margins, but absent risk factors for LNM, were asked to consent to second-look endoscopy with biopsies. The results were compared with the pathology results of the surgical resection specimen (criterion standard). One hundred three patients were included. In total, 85% of resected lesions were unexpectedly malignant, and 45% were removed using a piecemeal resection technique. Sixty-four adjuvant surgical resections and 39 local full-thickness resections were performed. Residual intramural cancer was found in 7 patients (6.8%). Two of these patients had cancer in second-look biopsy specimens, resulting in a sensitivity of 28% (95% confidence interval, <58%). The preoperative risk of residual intramural cancer in the case of negative biopsy specimens was not significantly reduced (P = .61). The sensitivity of second-look endoscopy with biopsies for residual intramural cancer after endoscopic resection of CRC is low. Therefore, it should not be used in the decision whether or not to perform adjuvant resection. (Clinical trial registration number: NCT02328664.).


Cyclic Force Applied to FAs Induces Actin Recruitment Depending on the Dynamic Loading Pattern.
Mechanical forces acting on focal adhesions (FAs) are believed to be an important determinant for cytoskeletal reorganization. However, the effect of the temporal pattern of forces on cellular responses has not been elucidated. In the present study, we examined the responses of FAs to locally-applied cyclic forces. Magnetic micro beads coated with fibronectin were attached to the apical surface of endothelial cells and continuous or cyclic forces at frequencies of 0.1-10 Hz with duty cycles of 0-100% were applied to the beads using a newly developed electromagnetic tweezer. A significant increase in actin recruitment around the beads was observed when cyclic forces at 1-2 Hz and 25-50% duty cycles were applied. This tendency disappeared upon modification of myosin activity. These results indicate that the sensitivity to temporal patterns of forces is detemined by the viscoelastic properes of FAs and depends on myosin activity.


Sensitivity and specificity of immunological methods for the detection of anti-topoisomerase I (Scl70) autoantibodies: results of a multicenter study. The Italian Society of Laboratory Medicine Study Group on the Diagnosis of Autoimmune diseases.
The ability of immunometric methods to identify anti-topoisomerase I (Scl70) antibodies is controversial. We wished to quantify the performance of the currently available commercial systems for the assay of anti-topoisomerase I antibodies in a large multicenter study. Fifty Italian clinical laboratories analyzed 36 serum samples: 27 from individuals with scleroderma/systemic sclerosis, and 9 from a control group. The scleroderma/systemic sclerosis samples were positive in our laboratories by both ELISA and immunoblot (IB), and the control samples were negative. The laboratories used 42 immunoenzymatic (ELISA), 21 IB, 3 counterimmunoelectrophoresis, and 2 dot-blot methods, produced by 23 different manufacturers. We obtained 2389 results. The ELISA methods showed 99.2% specificity and 97.2% sensitivity for detection of anti-Scl70 antibodies. For IB methods, specificity was 97.6% and sensitivity was 96.1%. The Western-blot method had poor analytical specificity (27% false positives for anti-extractable nuclear antigen antibodies other than anti-Scl70). Excluding Western blots, commercial ELISA and IB reagents as used in clinical laboratories have a sensitivity and a specificity >95% for determination of anti-Scl70 antibodies.


[Changes in markers of systemic inflammatory response and functional state of the vascular wall in patients with early syphilis].
The purpose of the study was to assess the functional state of endothelium and vascular stiffness using biochemical parameters and non-invasive instrumental methods of examination before and after specific treatment of patients with early forms of syphilis. A total of 51 patients with early syphilis were examined, 30 healthy individuals served as controls. Blood C-reactive protein, fibrinogen, and sialic acid levels were measured. Rigidity index was estimated using a Pulse Trace photopletizmograph (Micro Medical, England). Patients with early forms of syphilis had markedly increased concentrations of CRP, fibrinogen, sialic acids (markers of inflammation) and the ridgidity index both before and after specific therapy.


Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II).
This article reports on patient-reported sexual dysfunction and micturition symptoms following a randomized trial of laparoscopic and open surgery for rectal cancer. Patients in the COLOR II randomized trial, comparing laparoscopic and open surgery for rectal cancer, completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR38 questionnaire before surgery, and after 4 weeks, 6, 12 and 24 months. Adjusted mean differences on a 100-point scale were calculated using changes from baseline value at the various time points in the domains of sexual functioning, sexual enjoyment, male and female sexual problems, and micturition symptoms. Of 617 randomized patients, 385 completed this phase of the trial. Their mean age was 67·1 years. Surgery caused an anticipated reduction in genitourinary function after 4 weeks, with no significant differences between laparoscopic and open approaches. An improvement in sexual dysfunction was seen in the first year, but some male sexual problems persisted. Before operation 64·5 per cent of men in the laparoscopic group and 55·6 per cent in the open group reported some degree of erectile dysfunction. This increased to 81·1 and 80·5 per cent respectively 4 weeks after surgery, and 76·3 versus 75·5 per cent at 12 months, with no significant differences between groups. Micturition symptoms were less affected than sexual function and gradually improved to preoperative levels by 6 months. Adjusting for confounders, including radiotherapy, did not change these results. Sexual dysfunction is common in patients with rectal cancer, and treatment (including surgery) increases the proportion of patients affected. A laparoscopic approach does not change this. NCT00297791 (http://www.clinicaltrials.gov).


Impact of Climate Variability and Abundance of Mosquitoes on Dengue Transmission in Central Vietnam.
Dengue fever is an important arboviral disease in many countries. Its incidence has increased during the last decade in central Vietnam. Most dengue studies in Vietnam focused on the northern area (Hanoi) and southern regions but not on central Vietnam. Dengue transmission dynamics and relevant environmental risk factors in central Vietnam are not understood. This study aimed to evaluate spatiotemporal patterns of dengue fever in central Vietnam and effects of climatic factors and abundance of mosquitoes on its transmission. Dengue and mosquito surveillance data were obtained from the Department of Vector Control and Border Quarantine at Nha Trang Pasteur Institute. Geographic Information System and satellite remote sensing techniques were used to perform spatiotemporal analyses and to develop climate models using generalized additive models. During 2005-2018, 230,458 dengue cases were reported in central Vietnam. Da Nang and Khanh Hoa were two major hotspots in the study area. The final models indicated the important role of Indian Ocean Dipole, multivariate El Niño-Southern Oscillation index, and vector index in dengue transmission in both regions. Regional climatic variables and mosquito population may drive dengue transmission in central Vietnam. These findings provide important information for developing an early dengue warning system in central Vietnam.


Butterfly edge effects are predicted by a simple model in a complex landscape.
Edge responses have been studied for decades and form a critical component of our understanding of how organisms respond to landscape structure and habitat fragmentation. Until recently, however, the lack of a general, conceptual framework has made it difficult to make sense of the patterns and variability reported in the edge literature. We present a test of an edge effects model which predicts that organisms should avoid edges with less-preferred habitat, show increased abundance near edges with preferred habitat or habitat containing complementary resources, and show no response to edges with similar-quality habitat that offers only supplementary resources. We tested the predictions of this model against observations of the edge responses of 15 butterfly species at 12 different edge types within a complex, desert riparian landscape. Observations matched model predictions more than would be expected by chance for the 211 species/edge combinations tested over 3 years of study. In cases where positive or negative edge responses were predicted, observed responses matched those predictions 70% of the time. While the model tends to underpredict neutral results, it was rare that an observed edge response contradicted that predicted by the model. This study also supported the two primary ecological mechanisms underlying the model, although not equally. We detected a positive relationship between habitat preferences and the slope of the observed edge response, suggesting that this basic life history trait underlies edge effects and influences their magnitude. Empirical evidence also suggested the presence of complementary resources underlies positive edge responses, but only when completely confined to the adjacent habitat. This multi-species test of a general edge effects model at multiple edge types shows that resource-based mechanisms can explain many edge responses and that a modest knowledge of life history attributes and resource availability is sufficient for predicting and understanding many edge responses in complex landscapes.


Genome size and karyotype length in some interstitial polychaete species of the genus Ophryotrocha (Dorvilleidae).
Interstitial polychaetes of the genus Ophryotrocha are very small, progenetic, and morphologically very similar. These worms have been widely used in evolutionary biology and sexuality studies. To have a better insight into the karyological evolution of this genus, we measured the total karyotypic length and the 2C nuclear DNA content of the nine best-known species of this genus. No interspecific differences were observed in karyotypic lengths, apart from that of O. gracilis, which was significantly greater than the karyotypic length of five of the nine species. The genome size (i.e., 1C DNA content calculated from 2C DNA content) in eight of the nine species is about 0.4 pg, irrespective of the chromosome number. A group of four gonochoric and morphologically indistinguishable species, with 2n = 6 metacentric chromosomes, appears to be heterogeneous with regard to its DNA content, because one of the species, O. macrovifera, has a genome twice the size of that of the other three species. A hermaphroditic species, O. hartmanni, has a genome three times that size. No correlation has been observed between genome size and body size, egg cell diameter, or time interval from egg fertilization to sexual maturity. The basic genome size of 0.4 pg is among the lowest recorded in invertebrates. Hypotheses about selective pressures that maintain such a low amount of nuclear DNA in this genus are discussed.


Clinical laboratories are laboratories for re-engineering.
The concept of re-engineering rests on computer coordination of information. As a management tool, it has been tested and found to be ambiguous. At best it sharpens laboratory objectives, but at worst it fragments skills and threatens the community attitudes needed for teamwork. Experience with its most fruitful components has long been a part of laboratory management.


Influence of a Bacillus sp. on physiological activities of two arbuscular mycorrhizal fungi and on plant responses to PEG-induced drought stress.
The effects of bacterial inoculation (Bacillus sp.) on the development and physiology of the symbiosis between lettuce and the arbuscular mycorrhizal (AM) fungi Glomus mosseae (Nicol. and Gerd.) Gerd. and Trappe and Glomus intraradices (Schenck and Smith) were investigated. Plant growth, mineral nutrition and gas-exchange values in response to bacterial inoculation after PEG-induced drought stress were also evaluated. In AM plants, inoculation with Bacillus sp. enhanced fungal development and metabolism, measured as succinate dehydrogenase (SDH) and alkaline phosphatase (ALP) activities, more than plant growth. Under non-stressed conditions, G. intraradices colonization increased all plant physiological values to a higher extent when in dual inoculation with the bacterium. Under stress conditions, the bacterium had an important stimulatory effect on G. intraradices development. Under such conditions, the effects of the bacterium on photosynthetic rate, water use efficiency (WUE) and stomatal conductance of lettuce plants differed with the fungus species. Plant-gas exchange was enhanced in G. intraradices- and reduced in G. mosseae-colonized plants when co-inoculated with Bacillus sp. Thus, the effects of each fungus on plant physiology were modulated by the bacterium. Stress was detrimental, particularly in G. intraradices-colonized plants without the bacterium, reducing intra and extraradical mycelium growth and vitality (SDH), as well as plant-gas exchange. Nevertheless, Bacillus sp. inoculation improved all these plant and fungal parameters to the same level as in non-stressed plants. The highest amount of alive and active AM mycelium for both fungi was obtained after co-inoculation with Bacillus sp. These results suggest that selected free-living bacteria and AM fungi should be co-inoculated to optimize the formation and functioning of the AM symbiosis in both normal and adverse environments.


Topically applied fluocinonide in an adhesive base in the treatment of oral vesiculoerosive diseases.
Patients with oral vesiculoerosive diseases frequently require corticosteroid treatment to induce healing and reduce pain. Because of the adverse effects associated with systemic use, topical application of 0.05% fluocinonide in an adhesive base was investigated. The study group was comprised of 89 patients with erythema multiforme, lichen planus, benign mucous membrane pemphigoid, or pemphigus. In the double-blind phase involving 15 patients, seven responded completely and eight partially to the topical ointment. In the open study that included 74 patients, 35 had complete disappearance of signs and symptoms, while 39 experienced partial benefit. There were no adverse side effects. All 89 patients were observed for three to 35 months and each patient's condition continued to respond to the treatment when its use was required.


Methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a derivative of glycyrrhetinic acid, functions as a potent angiogenesis inhibitor.
Methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a triterpenoid acid derived synthetically from glycyrrhetinic acid, has been characterized as a peroxisome proliferator-activated receptor γ agonist with a broad range of receptor-dependent and -independent anticancer activities. Although CDODA-Me decreases the expression of some angiogenic genes in cancer cells, the direct effects of this compound on angiogenesis have not been defined. In this study, we have extensively investigated the activities of CDODA-Me in multiple angiogenesis assays. Our results showed that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and lamellipodium and capillary-like structure formation of human umbilical endothelial cells (HUVECs) in a concentration-dependent manner. Moreover, CDODA-Me abrogated VEGF-induced sprouting of microvessels from rat aortic rings ex vivo and inhibited the generation of new vasculature in the Matrigel plugs in vivo, where CDODA-Me significantly decreased the number of infiltrating von Willebrand factor-positive endothelial cells. To understand the molecular basis of this antiangiogenic activity, we examined the signaling pathways in CDODA-Me-treated HUVECs. Our results showed that CDODA-Me significantly suppressed the activation of VEGF receptor 2 (VEGFR2) and interfered with the mammalian target of rapamycin (mTOR) signaling, including mTOR kinase and its downstream ribosomal S6 kinase (S6K), but had little effect on the activities of extracellular signal-regulated protein kinase and AKT. Taken together, CDODA-Me blocks several key steps of angiogenesis by inhibiting VEGF/VEGFR2 and mTOR/S6K signaling pathways, making the compound a promising agent for the treatment of cancer and angiogenesis-related pathologies.


Distribution of colorectal neoplasms. A left to right shift of polyps and cancer.
A 20-year retrospective review was made of all patients undergoing operative procedures for both adenocarcinoma and benign polyps of the colorectum at the two teaching hospitals of the University of South Carolina. A total of 1,112 patients with adenocarcinoma and 429 patients with benign polypoid disease were identified. Classification of each adenocarcinoma according to location showed a 12 per cent increase in the number of right-sided lesions and a 44 per cent decrease in rectosigmoid lesions when compared with historical series. Despite this proximal shift, the rate of association of benign adenomatous polyps contained in cancer resections (13 per cent) is similar to previous series. Furthermore, evaluation of benign adenomatous polyps showed a similar increase of proximal colonic lesions and a decrease of rectosigmoid adenomas. The results of this retrospective study support the concept that adenocarcinoma is occurring with increasing frequency in the right colon. Despite this left to right shift, a constant association of benign polyps within cancer resections was found, supporting the concept of a polyp-cancer sequence. This study identified a similar shift in benign adenomatous polyps alone, supporting the concept that benign neoplasias are premalignant and are probably responsible for the increased incidence of proximally located colonic adenocarcinomas.


Meta-analysis of the effects of flaxseed interventions on blood lipids.
Several clinical trials have investigated the effects of flaxseed and flaxseed-derived products (flaxseed oil or lignans) on blood lipids; however, the findings have been inconsistent. We aimed to identify and quantify the effectiveness of flaxseed and its derivatives on blood lipid profiles. A comprehensive literature search was performed on the basis of English reports of randomized controlled trials of flaxseed or its derivatives on lipid profiles in adults, which were published from January 1990 to October 2008. Attempts also were made to access unpublished data. Study quality was assessed by using the Jadad score, and a meta-analysis was conducted. Twenty-eight studies were included. Flaxseed interventions reduced total and LDL cholesterol by 0.10 mmol/L (95% CI: -0.20, 0.00 mmol/L) and 0.08 mmol/L (95% CI: -0.16, 0.00 mmol/L), respectively; significant reductions were observed with whole flaxseed (-0.21 and -0.16 mmol/L, respectively) and lignan (-0.28 and -0.16 mmol/L, respectively) supplements but not with flaxseed oil. The cholesterol-lowering effects were more apparent in females (particularly postmenopausal women), individuals with high initial cholesterol concentrations, and studies with higher Jadad scores. No significant changes were found in the concentrations of HDL cholesterol and triglycerides. Flaxseed significantly reduced circulating total and LDL-cholesterol concentrations, but the changes were dependent on the type of intervention, sex, and initial lipid profiles of the subjects. Further studies are needed to determine the efficiency of flaxseed on lipid profiles in men and premenopausal women and to explore its potential benefits on other cardiometabolic risk factors and prevention of cardiovascular disease.


Microfluidic sensing devices employing in situ-formed liquid crystal thin film for detection of biochemical interactions.
Although biochemical sensing using liquid crystals (LC) has been demonstrated, relatively little attention has been paid towards the fabrication of in situ-formed LC sensing devices. Herein, we demonstrate a highly reproducible method to create uniform LC thin film on treated substrates, as needed, for LC sensing. We use shear forces generated by the laminar flow of aqueous liquid within a microfluidic channel to create LC thin films stabilized within microfabricated structures. The orientational response of the LC thin films to targeted analytes in aqueous phases was transduced and amplified by the optical birefringence of the LC thin films. The biochemical sensing capability of our sensing devices was demonstrated through experiments employing two chemical systems: dodecyl trimethylammonium bromide (DTAB) dissolved in an aqueous solution, and the hydrolysis of phospholipids by the enzyme phospholipase A(2) (PLA(2)).


[Immediate type allergies due to metal compounds: platinum salts].
Immediate type allergies due to metal compounds containing chromium, nickel, cobalt and platinum are rare. However, allergies to platinum salts represent a major health hazard in few precious metal refineries and catalyst productions. Sensitization can be shown with a highly specific and sensitive skin prick test. A dose-response relationship has clearly been established by prospective longitudinal studies, however the definition of a valid threshold limit is difficult due to the high variability of exposure. Smoking is a predicting factor, whereas atopy is not. Prognosis depends on the duration of symptomatic exposure in high exposure areas. Secondary prevention (medical surveillance) is effective in the prevention of persistent symptoms and bronchial hyperresponsiveness.


Phenylalanine flux, oxidation, and conversion to tyrosine in humans studied with L-[1-13C]phenylalanine.
Phenylalanine metabolism was determined in 41 studies of adult males (n = 10) consuming an energy-sufficient diet and receiving graded levels of dietary phenylalanine and excess tyrosine (40 mg.kg-1.day-1). After a dietary adaptation period to either 4.2 or 14.0 mg.kg-1.day-1 of phenylalanine; flux, plasma concentration, oxidation, and conversion to tyrosine were measured at test phenylalanine intakes of 5, 7, 10, 14, 21, 28, or 60 mg.kg-1.day-1. Oxidation was low and constant (1.3 mumol.kg-1.h-1) at intakes at or below 10 mg.kg-1.day-1 and increased linearly above this level. Conversion to tyrosine was minimal (2.1%) at these intakes. Breakpoint analysis showed the phenylalanine requirement with excess tyrosine to be 9.1 mg.kg-1.day-1. Plasma phenylalanine concentrations confirmed this estimate of requirement. Prior adaptation did not significantly affect overall flux, plasma concentration, or oxidation nor did it affect the requirement estimate. With the assumption that tyrosine can supply two-thirds of the aromatic amino acid requirement, these data suggest that the aromatic amino acid requirement should be 30 mg.kg-1.day-1 and the World Health Organization recommendation of 14 mg.kg-1.day-1 is an underestimate.


Detection of Gray Mold Leaf Infections Prior to Visual Symptom Appearance Using a Five-Band Multispectral Sensor.
Fungal leaf diseases cause economically important damage to crop plants. Protective treatments help producers to secure good quality crops. In contrast, curative treatments based on visually detectable symptoms are often riskier and less effective because diseased crop plants may develop disease symptoms too late for curative treatments. Therefore, early disease detection prior symptom development would allow an earlier, and therefore more effective, curative management of fungal diseases. Using a five-lens multispectral imager, spectral reflectance of green, blue, red, near infrared (NIR, 840 nm), and rededge (RE, 720 nm) was recorded in time-course experiments of detached tomato leaves inoculated with the fungus Botrytis cinerea and mock infection solution. Linear regression models demonstrate NIR and RE as the two most informative spectral data sets to differentiate pathogen- and mock-inoculated leaf regions of interest (ROI). Under controlled laboratory conditions, bands collecting NIR and RE irradiance showed a lower reflectance intensity of infected tomato leaf tissue when compared with mock-inoculated leaves. Blue and red channels collected higher intensity values in pathogen- than in mock-inoculated ROIs. The reflectance intensities of the green band were not distinguishable between pathogen- and mock infected ROIs. Predictions of linear regressions indicated that gray mold leaf infections could be identified at the earliest at 9 h post infection (hpi) in the most informative bands NIR and RE. Re-analysis of the imagery taken with NIR and RE band allowed to classify infected tissue.


Evidence of Conjoint Activation of the Anterior Insular and Cingulate Cortices during Effortful Tasks.
The ability to perform effortful tasks is a topic that has received considerable interest in the research of higher functions of the human brain. Neuroimaging studies show that the anterior insular and the anterior cingulate cortices are involved in a multitude of cognitive tasks that require mental effort. In this study, we investigated brain responses to effort using cognitive tasks with task-difficulty modulations and functional magnetic resonance imaging (fMRI). We hypothesized that effortful performance involves modulation of activation in the anterior insular and the anterior cingulate cortices, and that the modulation correlates with individual performance levels. Healthy participants performed tasks probing verbal working memory capacity using the reading span task, and visual perception speed using the inspection time task. In the fMRI analysis, we focused on identifying effort-related brain activation. The results showed that working memory and inspection time performances were directly related. The bilateral anterior insular and anterior cingulate cortices showed significantly increased activation during each task with common portions that were active across both tasks. We observed increased brain activation in the right anterior insula and the anterior cingulate cortex in participants with low working memory performance. In line with the reported results, we suggest that activation in the anterior insular and cingulate cortices is consistent with the neural efficiency hypothesis (Neubauer).


Opioids, sleep, and sleep-disordered breathing.
Opioid medications are increasingly used to treat chronic pain. Opioid-associated respiratory depression, and their potential to cause nocturnal apneas, is increasingly recognized as a major contributor to nocturnal hypoxemia and sleep-disordered breathing. Given the widespread use of opioids, understanding their mechanism of action and their potential to cause adverse effects particularly during sleep is critical. This article reviews the salient features of the physiologic control of respiration and sleep, and the role opioids play in altering that regulation. Additionally, we summarize the evidence regarding the association between opioid use and sleep-disordered breathing and explore treatment modalities for opioid-associated nocturnal respiratory depression and apneas.


Development of a coffee bean certified reference material (KRISS CRM 108-10-023) for elemental analysis.
The development of a novel coffee bean matrix certified reference material (CRM) for elemental analysis is described. The CRM was prepared by processing green coffee beans into a dry homogeneous powder. Mass fractions of elements in the CRM were measured using double isotope dilution inductively coupled plasma mass spectrometry (double ID-ICP-MS), and measurement results for eight elements (Mg, Ca, Fe, Cu, Zn, Cd, Hg, and Pb) of sufficient quality were certified. The mass fraction range was from 0.09476 mg/kg (Cd) to 1908 mg/kg (Mg), with relative expanded uncertainty range of 0.66% (Cd) to 12% (Pb). Measurement results of two elements (Cr and Ni) with insufficient quality were provided for information only. During characterization, an effective approach for the measurement of isotopic abundances and molar masses of elements with high natural isotopic variations for double ID-ICP-MS was developed and applied. The CRM developed in the present study is expected to be a useful measurement standard for assuring the quality of measurement procedures for coffee beans or related materials.


Cytological and pharmacological observations on the release of histamine by mast cells.
Experimental solutions known to affect mast cells or to cause liberation of histamine from the tissue were introduced into the peritoneal cavity of rats. Samples of the peritoneal fluid were withdrawn at intervals afterward and assayed for histamine and the condition of the mast cells was subsequently ascertained by microscopic examination of stained spreads of the mesenteries. Intraperitoneal injection of distilled water caused osmotic disruption of the mast cells and the appearance of an appreciable amount of histamine in the peritoneal fluid. Injection of Tyrode solution alone was not particularly damaging to the mast cells and little or no histamine was released. Injection of Tyrode solution containing compound 48/80 resulted in extensive release of granules from mast cells and the appearance of large amounts of histamine in the fluid. Solution of 48/80 failed however to cause histamine release when injected into rats whose subserosal mast cells had previously been destroyed. A series of increasing doses of compound 48/80 had a graded morphological effect upon mast cells and resulted in a graded increase in the amount of histamine that appeared in the peritoneal fluid. It is unlikely therefore that this compound acts by simply lysing the plasma membrane. It is concluded that mast cells in the rat are extraordinarily rich in histamine which is liberated under conditions which cause mast cells to release their granules. The histamine set free by the potent histamine liberator, compound 48/80, appears to come principally from the tissue mast cells.


Rotator cuff strength following open subscapularis tendon repair.
The purpose of this study was to evaluate supraspinatus and subscapularis strength following repair of either isolated or anterosuperior subscapularis tears associated with a supraspinatus tear. Open subscapularis repairs were done in 24 patients, 12 isolated and 12 anterosuperior. At an average follow-up of 40 months, UCLA, ASES, and Constant scores were recorded. Subscapularis and supraspinatus strengths were tested using a spring gauge. Ultrasound scanning was performed in 20 patients. Average scores were 27 UCLA, 77 ASES and 90 relative Constant. Subscapularis strength was 92% of the non-operated shoulder. Supraspinatus strength was 90%. Statistical analysis showed a significant decrease in supraspinatus strength in the anterosuperior group. No other significant differences were noted. Ultrasound scanning showed an intact subscapularis tendon in all. Full thickness supraspinatus tears were found in 5 and partial thickness in 1. Not the subscapularis, but the supraspinatus determines the outcome of anterosuperior repairs, with more re-tears and decreased strength.


Trait emotional suppression is associated with increased activation of the rostral anterior cingulate cortex in response to masked angry faces.
Emotional suppression (ES) is a critical component of the ability to self-regulate emotion. However, people who chronically use ES as a primary strategy often experience heightened anxiety or depression. Although functional neuroimaging studies have extensively mapped the brain regions involving in emotional regulation, the neural substrates of ES as a trait construct remain relatively unexplored. Using a validated backward masked facial affect paradigm, we examined the association between ES and functional brain responses to masked angry, fearful, and happy faces. Healthy adults underwent functional MRI and completed the Courtauld Emotional Control Scale as a measure of ES. Correlations between self-reported ES and brain responses to the facial affect stimuli (affective>neutral) were evaluated within the brain regions involved in emotional processing, including the amygdala, insula, anterior cingulate cortex, medial prefrontal cortex, and orbitofrontal cortex. In response to angry faces, higher trait tendency to suppress anger and anxiety was significantly correlated with increased activation within the rostral anterior cingulate cortex, whereas no correlation was observed for masked happy or fearful faces. This finding suggests that the rostral anterior cingulate cortex contributes to the unconscious suppression of emotional responses to angry facial affect and may play a role in the mediating anatomy of trait ES.


Nature of copper(II)-lanthanide(III) magnetic interactions and generation of a large magnetic moment with magnetic anisotropy of 3d-4f cyclic cylindrical tetranuclear complexes [CuIILLnIII(hfac)2]2, (H3L = 1-(2-hydroxybenzamido)-2-(2-hydroxy-3-methoxybenzylideneamino)ethane and Hhfac = hexafluoroacetylacetone, LnIII = Eu, Gd, Tb, Dy).
A cyclic cylindrical 3d-4f tetranuclear structure, in which the 3d and 4f magnetic ions are arrayed alternately, has been found to be a suitable molecular design to produce a large magnetic moment and large magnetic anisotropy. Complexes 3-10 with the chemical formula [MLLn(hfac)2]2 ((MII, LnIII) = (Cu, Eu) (3), (Cu, Gd) (4), (Cu, Tb) (5), (Cu, Dy) (6), (Ni, Eu) (7), (Ni, Gd) (8), (Ni, Tb) (9), (Ni, Dy) (10)) have been synthesized, where H3L = 1-(2-hydroxybenzamido)-2-(2-hydroxy-3-methoxybenzylideneamino)ethane and Hhfac = hexafluoroacetylacetone. The powder X-ray diffractions and FAB-mass spectra demonstrated that these complexes assume a similar tetranuclear structure. The crystal structures of 4 and 5 showed that each complex has a cyclic cylindrical tetranuclear CuII2LnIII2 structure, in which the CuII complex functions as a "bridging ligand-complex" to two adjacent LnIII ions. The temperature-dependent magnetic susceptibilities from 2 to 300 K and the field-dependent magnetizations at 2 K from 0 to 5 T have been measured for four pairs of CuII2LnIII2 and NiII2LnIII2, in which compound NiII2LnIII2 containing diamagnetic NiII ion was used as the reference complex to evaluate the CuII-LnIII magnetic interaction. Comparison of the magnetic properties of the CuII2LnIII2 complex with those of the corresponding NiII2LnIII2 complex showed that the magnetic interaction between CuII and EuIII ions is weakly ferromagnetic and that between CuII and either of GdIII, TbIII, and DyIII ions is ferromagnetic. Complex CuII2GdIII2, 4, has an S = 8 spin ground state, due to the ferromagnetic spin coupling between SGd = 7/2 and SCu = 1/2 with coupling constants of J1 = +3.1 cm-1 and J2 = +1.2 cm-1. The magnetic measurements showed that compounds 5 and 6, CuII2LnIII2 (LnIII = Tb, Dy), exhibit large magnetic moments and large magnetic anisotropy due to the LnIII ion.


PEDL+: protein-centered relation extraction from PubMed at your fingertip.
Relation extraction (RE) from large text collections is an important tool for database curation, pathway reconstruction, or functional omics data analysis. In practice, RE often is part of a complex data analysis pipeline requiring specific adaptations like restricting the types of relations or the set of proteins to be considered. However, current systems are either non-programmable web sites or research code with fixed functionality. We present PEDL+, a user-friendly tool for extracting protein-protein and protein-chemical associations from PubMed articles. PEDL+ combines state-of-the-art NLP technology with adaptable ranking and filtering options and can easily be integrated into analysis pipelines. We evaluated PEDL+ in two pathway curation projects and found that 59% to 80% of its extractions were helpful. PEDL+ is freely available at https://github.com/leonweber/pedl.


Hyperimmunoglobulinaemia, T-cell deficiency and plasmacytosis in RFM mice with host versus graft disease induced by the perinatal inoculations (T6XRFM)F1 spleen cells.
Host versus graft (HVG) syndrome may be induced in parental strain mice by perinatal inoculations of F1 hybrid spleen cells. The principal manifestations of the disease include thrombocytopaenia, intravascular fibrin deposits, intestinal haemorrhage, hepatic infarcts, lymphosplenomegaly and renal disease. Immune complexes have been shown to be the cause of the renal lesions, and have been implicated as the triggers for disseminated intravascular coagulation. In the present studies of RFM mice perinatally inoculated with (T6 x RFM)F1 spleen cells (RFM/(T6 x RFM)F1 mice), quantitative determinations of serum immunoglobulins (Ig) revealed marked elevations of IgG1, IgG2, IgA and IgM. Electrophoretic analyses revealed the polyclonal pattern which typically follows chronic antigenic stimulation. However, IgG1 levels which reached 29 to 72 times control values suggested disruption of homeostatic mechanisms which control circulating Ig levels. Because antibody responses to histocompatibility antigens were present only occasionally, and then in low titre, it seemed unlikely these antigens were the principal causes of hypergammaglobulinaemia and plasmacytosis. Morphological studies indicated that the elevated levels of Ig seen in end-stage HVG syndrome correlated well with marked plasmacytosis, the third morphological finding in a sequence that included the precocious development of germinal centres and subsequent depletion of thymic-dependent (T) lymphocytes. The fact that spleen cells from RFM/(T6 x RFM)F1 mice were severely impaired in their capacity to cause graft versus host disease in related (T6 x RFM)F1 and unrelated C3H mice provided strong evidence that the HVG reaction resulted in T-cell depletion, rather than specific immunoincompetence.


Effects of alprazolam and bromazepam on visual search and verbal recognition memory in humans: a study with event-related brain potentials.
The effects of two benzodiazepines (alprazolam and bromazepam) on performance and event-related brain potentials (ERPs) in visual search and verbal recognition memory paradigms were tested in a placebo-controlled double-blind paradigm employing 12 young healthy subjects. Both drugs exerted similar effects on performance and electrophysiological measures. Reaction times and hit rates were adversely affected in both paradigms. The ERP pattern in the visual search experiment suggested an impairment in selective attention (reduction of N1 component) and of automatic feature registration (posterior N2 reduction). In the world recognition experiment a dramatic reduction of the N400 component was seen under benzodiazepines. This is interpreted as reflecting an impaired ability to perform context integration processes.


Comparison of Primary and Secondary Anterior Septal Reconstruction: A Cohort Study.
This article compares outcomes in patients presenting for either primary or secondary (revision) anterior septal reconstruction (ASR) to treat caudal septal deviation. Patients undergoing ASR by senior author (S. P. M.) between January 1, 2012 and September 1, 2017, with both preoperative and postoperative Nasal Obstruction Symptom Evaluation (NOSE) scores documented in the chart were included. Data were compared between patients undergoing primary and secondary ASR by univariable and multivariable logistic regression. A total of 199 patients were included in this study; 128 (64%) underwent primary ASR and 71 (36%) underwent secondary ASR. After multivariable analysis, a greater ratio of females and autologous rib graft harvest in the secondary compared with primary ASR, and decreased odds of inferior turbinate reduction in the secondary group was found. There was no significant difference in NOSE scores between the primary and secondary group, and there were very few complications or revision surgeries. While outcomes are similar between primary and secondary (revision) ASR to treat caudal septal deviation, there was a significantly higher rate of autologous rib harvest, highlighting the importance of addressing deviations of the caudal septum at the primary procedure to reduce morbidity related to rib graft harvest and revision surgery.


Gene-environment interplay between parent-child relationship problems and externalizing disorders in adolescence and young adulthood.
Previous studies have shown that genetic risk for externalizing (EXT) disorders is greater in the context of adverse family environments during adolescence, but it is unclear whether these effects are long lasting. The current study evaluated developmental changes in gene-environment interplay in the concurrent and prospective associations between parent-child relationship problems and EXT at ages 18 and 25 years. The sample included 1382 twin pairs (48% male) from the Minnesota Twin Family Study, participating in assessments at ages 18 years (mean = 17.8, s.d. = 0.69 years) and 25 years (mean = 25.0, s.d. = 0.90 years). Perceptions of parent-child relationship problems were assessed using questionnaires. Structured interviews were used to assess symptoms of adult antisocial behavior and nicotine, alcohol and illicit drug dependence. We detected a gene-environment interaction at age 18 years, such that the genetic influence on EXT was greater in the context of more parent-child relationship problems. This moderation effect was not present at age 25 years, nor did parent-relationship problems at age 18 years moderate genetic influence on EXT at age 25 years. Rather, common genetic influences accounted for this longitudinal association. Gene-environment interaction evident in the relationship between adolescent parent-child relationship problems and EXT is both proximal and developmentally limited. Common genetic influence, rather than a gene-environment interaction, accounts for the long-term association between parent-child relationship problems at age 18 years and EXT at age 25 years. These results are consistent with a relatively pervasive importance of gene-environmental correlation in the transition from late adolescence to young adulthood.


Inhibition of ref-1 stimulates the production of reactive oxygen species and induces differentiation in adult cardiac stem cells.
Redox effector protein-1 (Ref-1) plays an essential role in DNA repair and redox regulation of several transcription factors. In the present study, we examined the role of Ref-1 in maintaining the redox status and survivability of adult cardiac stem cells challenged with a subtoxic level of H2O2 under inhibition of Ref-1 by RNA interference. Treatment of cardiac stem cells with a low concentration of H2O2 induced Ref-1-mediated survival signaling through phosphorylation of Akt. However, Ref-1 inhibition followed by H2O2 treatment extensively induced the level of intracellular reactive oxygen species (ROS) through activation of the components of NADPH oxidase, like p22( phox ), p47( phox ), and Nox4. Cardiac differentiation markers (Nkx2.5, MEF2C, and GATA4), and cell death by apoptosis were significantly elevated in Ref-1 siRNA followed by H2O2-treated stem cells. Further, inhibition of Ref-1 increased the level of p53 but decreased the phosphorylation of Akt, a molecule involved in survival signaling. Treatment with ROS scavenger N-acetyl-L-cysteine attenuated Ref-1 siRNA-mediated activation of NADPH oxidase and cardiac differentiation. Taken together, these results indicate that Ref-1 plays an important role in maintaining the redox status of cardiac stem cells and protects them from oxidative injury-mediated cell death and differentiation.


Effects of insulin-like growth factor-1 on random pattern skin flap survival in rats.
To investigate the effects of pharmacological delay with insulin-like growth factor-1 (IGF-1) on skin flap survival. Thirty Sprague-Dawley rats were submitted to dorsal skin flap (3x9 cm). Seven days before the surgery, the animals were subdivided into three groups of 10 rats. In group 1 (controls), no injection was done. Seven days before the elevation, saline had been injected to the marked skin flap area in group 2 (sham group), and group 3 (experimental group) underwent a pharmacological delay with subcutaneous IGF-1 injections. On the seventh postoperative day, flap area was analyzed for survival. Tissue samples were obtained for histological and biochemical evaluations. Survival rates were 43.55 ± 16%, 21.40 ± 8%, and 43.12 ± 14% in groups 1, 2, and 3, respectively. Differences between group 2 and other groups were statistically significant. No significant difference was detected between all three groups for tissue or plasma vascular endothelial growth factor (VEGF) levels. There was no significant histological difference between groups. Although a single injection of insulin-like growth factor-1 (IGF-1) did not significantly increase flap survival, its wound healing features are still encouraging and further meticulously planned studies, especially with repeated applications or controlled-release methods, and combinations with binding protein are required.


Mono-L-aspartyl chlorin e6 (NPe6) and hematoporphyrin derivative (HpD) in photodynamic therapy administered to a human cholangiocarcinoma model.
Despite their relatively localized nature, the therapy for surgically unresectable cholangiocarcinomas has been largely unsuccessful. Photodynamic therapy is a promising technique for both curative and palliative treatment of this malignancy. The effectiveness of a potential new photosensitizer, mono-l-aspartyl chlorin e6 (NPe6), was compared with that of a traditional drug, hematoporphyrin derivative (HpD), in photodynamic therapy administered to a human cholangiocarcinoma model. An established cholangiocarcinoma cell line was inoculated subcutaneously in the left back of male nude mice age 8 weeks. After a predetermined tumor size was reached, the mice were randomly assigned to either a control group or an experimental group. Experimental tumor-bearing mice received either HpD (5 mg/kg or 10 mg/kg) or NPe6 (2 mg/kg, 5 mg/kg, or 8 mg/kg) followed by photoradiation. HpD and NPe6 were administered intraperitoneally at 24 and 2 hours, respectively, prior to light exposure. Photoradiation was conducted using a xenon-mercury arc lamp with a 405-650 nm filter at a light flux of 80 J/cm2. Tumor response was assessed by serial tumor volume measurements. Control mice showed an estimated mean tumor volume doubling rate of 9.0 days. Triaxial tumor measurements correlated well with autopsy measurements (correlation coefficient = 0.9). Overall differences in tumor volume reduction were detected (P < 0.001) among the three groups: HpD, NPe6, and controls (photoradiation only, HpD only, or NPe6 only). The degree of tumor volume reduction was superior for dosages of NPe6 compared with all dosages of HpD (P < 0.05). Although a dose effect was detected (P < 0.05) for HpD and separately for NPe6, a consistent dose-response relationship was not observed for either. Inhibition of tumor regrowth was better for NPe6 compared with HpD. The depth of tissue injury was significantly increased (P < 0.05), by 67%, for 5-8 mg/kg of NPe6 compared with 5-10 mg/kg of HpD. The duration of cutaneous photosensitization was also decreased for NPe6 compared with HpD. Photodynamic therapy with HpD or NPe6 was effective inducing tumor regression in the cholangiocarcinoma model in this study. At the dosages studied, NPe6 appeared to induce greater tumor regression than HpD, with decreased tumor regrowth and duration of cutaneous photosensitization.


Nanoengineered drug releasing aluminium wire implants: a model study for localized bone therapy.
A needle puncture approach using nanoengineered aluminium (Al) wires as drug-releasing implants is explored for localized drug delivery in bone using an ex vivo bone reactor. The wire implants were prepared by electrochemical anodization with the formation of a thin nanoporous alumina (NPA) layer on their surface and pore diameters of 30-35 nm and pore lengths of 10-60 μm. An in vitro drug release study of a model drug from the implants, prepared with different thicknesses of NPA layers (pore lengths), showed a considerable influence on drug release characteristics. The results confirmed that by controlling the pore length it is possible to tune the drug releasing performance of the implants and achieve a sustained release for an extended period. The biocompatibility study of the implants evaluated using human osteoblast cell culture showed strong growth of cells, their spreading and their adhesion to the implant surface. The drug loaded wire implants inserted inside bone by a needle puncture approach are evaluated for ex vivo drug release inside bone using a bone reactor (Zetos). The results demonstrated consistent and slow drug release from implants and distribution inside bone monitored in situ using a live imaging technique. The cross-sectional study of inserted wire implants after an extended period of release confirmed stable and unchanged NPA morphology. Histology of bone in contact with implants indicates the presence of viable osteocytes along the inserted area indicating that this method is a reliable approach and NPA wire implants are harmless devices. Overall, this study demonstrates that needle guided implantation of nanoengineered and drug loaded porous wires could be used as a new drug releasing implants for localized bone therapy and treatment of bone disease such as bacterial infection, healing, and potentially bone cancer.


A crystal structure of a collaborative RNA regulatory complex reveals mechanisms to refine target specificity.
In the Caenorhabditis elegans germline, fem-3 Binding Factor (FBF) partners with LST-1 to maintain stem cells. A crystal structure of an FBF-2/LST-1/RNA complex revealed that FBF-2 recognizes a short RNA motif different from the characteristic 9-nt FBF binding element, and compact motif recognition coincided with curvature changes in the FBF-2 scaffold. Previously, we engineered FBF-2 to favor recognition of shorter RNA motifs without curvature change (Bhat et al., 2019). In vitro selection of RNAs bound by FBF-2 suggested sequence specificity in the central region of the compact element. This bias, reflected in the crystal structure, was validated in RNA-binding assays. FBF-2 has the intrinsic ability to bind to this shorter motif. LST-1 weakens FBF-2 binding affinity for short and long motifs, which may increase target selectivity. Our findings highlight the role of FBF scaffold flexibility in RNA recognition and suggest a new mechanism by which protein partners refine target site selection.


Frequency of brain injury in a forensic psychiatric population.
Over the last years, a growing number of studies involving individual patients and/or populations have demonstrated that Traumatic Brain Injuries (TBI) determine innumerable psychiatric symptoms, including significant alterations which may influence diagnoses, prognosis and treatment, not to mention clear psychosocial implications (both legal and those related to social security). The objectives of this study were 1) to detect the existence of TBI in a forensic psychiatric population before the occurrence of the wrongs; 2) To verify whether or not those injuries had been identified by the experts at the psychiatric institution. 3,323 records of patients examined by forensic experts at the Forensic Psychiatric Institute Dr. Maurício Cardoso in Porto Alegre were analyzed; the records covered the period between 1995 and 1999. in the studied population, there were 133 cases of TBI prior to the wrongs, 39 of which were mild, and 94, moderate or severe. Out of the total number of TBI cases found, 111 cases were not taken into account, many of them having motoric, cognitive, psychic and sensori perception alterations. the significant number of patients that had had TBI before having committed a wrong - a fact that had not been considered by the experts (neurologists and psychiatrists) at the institution - is a strong indicator of how little attention is paid to the consequences of these injuries. Considering the relevance of the psychosocial aspects, new studies should be conducted in psychiatric populations to increase the knowledge about the consequences of these injuries.