Finite Element Analysis of the Effect of Talar Osteochondral Defects of Different Depths on Ankle Joint Stability.
BACKGROUND Talus cartilage injury leads to changes in biomechanics of the ankle joint and ultimately affects ankle joint function, but which talus cartilage defects require surgery is still uncertain. This research used a finite element method to simulate the effect of different depth of talus cartilage defects on the stress and stability of the ankle joint in a certain area. MATERIAL AND METHODS A three-dimensional finite element model with different depths of osteochondral defects was created to simulate and calculate joint stress and displacement of the articular surface of the distal tibia and the proximal talus while the ankle joint was in the push-off, midstance, and heel-strike phases. RESULTS The equivalent stress of the proximal talus did not change significantly at a defect depth of 1 mm, whereas the equivalent stress of the upper talus increased significantly at a defect depth of ≥3 mm or more, reaching a maximum value at a defect depth of 10 mm. The equivalent stress of the tibial cartilage and the equivalent stress and displacement in the corresponding forces in the midstance phase and heel-strike phase were significantly different from those in the normal group, but the difference in stress in each defect group was not obvious. CONCLUSIONS The effect of cartilage defects of the talus on biomechanics of the ankle is clear, especially in the midstance and push-off phases. When the defect reaches the subchondral bone (at a depth of 3 mm), the most obvious change in ankle joint stability occurs, and it does not increase linearly with the increase in depth of the defect.


Corticosteroid-induced osteoporosis prevention: longitudinal practice patterns in The Netherlands 2001-2005.
We investigated prevention trends and predictors for osteoporosis prevention in long term corticosteroid users. The use of bisphosphonates increased from 2001 to 2005. Longer duration of corticosteroid use and DMARD use were predictors for receiving prevention. Females appear reasonably well treated; however, men require more attention. Previous studies have shown that long-term corticosteroid users are undertreated for osteoporosis prevention. Our aim was to identify prevention trends in long-term corticosteroid users from 2001-2005 in The Netherlands and to identify predictors for bisphosphonate prophylaxis. Pharmacy dispensing data were used from 9 community pharmacies. All oral corticosteroid doses were converted to "prednisolone equivalents". We then identified long-term (> or =90 days) corticosteroid episodes, which required bisphosphonate prophylaxis as per 2002 Dutch guidelines; Multivariate logistic regression was used to identify predictors for receiving prevention. We identified 615 different corticosteroid patients requiring prophylaxis. From 2001-2005 the use of bisphosphonates increased from 38% to 54% (p = 0.001). In 2005 females were prescribed more bisphosphonates than males (61% vs. 39%; p = 0.002), or any treatment (72% vs. 45%; p < 0.001). Multivariate analysis showed that longer duration of corticosteroid use and disease-modifying anti-rheumatic drug (DMARD) use were independent predictors of bisphosphonate use. Use of respiratory medication was a negative predictor of bisphosphonate use. There has been a significant increase in osteoporosis prophylaxis in a population at high risk for osteoporosis/fractures. In particular, females appear reasonably well treated; however, men are still not receiving prevention to the same degree as women.


Shengmai injection, a traditional chinese patent medicine, for intradialytic hypotension: a systematic review and meta-analysis.
Intradialytic hypotension (IDH) is a global public health problem. A rising number of IDH sufferers resort to Chinese patent medicine, Shengmai Injection (SMI) in China. The objectives of present study are to assess the effectiveness and safety of SMI as an adjunct therapy for IDH. A systematic search of 6 medical databases was performed up to December 2011. Randomized trials involving SMI adjuvant therapy versus conventional therapy were identified. RevMan 5.0 was used for data analysis. Ten randomized clinical trials with 437 participants were identified. Methodological quality was considered inadequate in all trials. Compared with conventional therapy, SMI adjunct therapy showed significant effects in improving the clinic effective rate (P < 0.01), decreasing the incidence of IDH episode (P < 0.01), decreasing the frequency of nursing interventions (P < 0.01), and increasing diastolic blood pressure (P < 0.01). There was no statistical significance in the improvement of mean arterial pressure (P = 0.22) and systolic blood pressure (P = 0.08) between two groups. Four studies had mentioned adverse events, but no serious adverse effects were reported in any of the included trials. In conclusion, SMI adjunct therapy appears to be potentially effective in treatment of IDH and is generally safe. However, further rigorous designed trials are needed.


Gender-Based Violence Interventions in Low- and Middle-Income Countries: A Systematic Review of Interventions at Structural, Community, Interpersonal, Individual, and Multiple Levels.
Gender-based violence (GBV) disproportionately impacts women and girls in low- and middle-income countries (LMIC). This review described the characteristics of structural, community, interpersonal, individual, and multilevel GBV interventions in LMIC and examined components of interventions implemented at different socio-ecological levels. We conducted a systematic search of peer-reviewed literature on GBV intervention evaluation studies in LMIC using the following databases: PubMed, CINAHL, Embase, Cochrane, Academic Search Ultimate, PsycInfo, and Web of Science. The search resulted in 3,256 articles, with 60 articles meeting the eligibility criteria. Thirty-eight articles reported positive GBV outcomes with significant differences between intervention and control arms on at least one GBV outcome. Very few interventions were found to be stand-alone GBV interventions. The key components of interventions effective in addressing victimization and perpetration across levels were education or psychoeducation, psychotherapy, skills development, gender transformative activities, community engagement, focus on men and/or partners, and health promotion activities such as HIV or STI prevention. Most interventions were multilevel, with positive outcomes for victimization. Fewer evidence-based interventions existed for addressing perpetration. There is need for additional research using rigorous methods to establish an evidence base for effective interventions in under-researched regions in LMIC as well as for interventions that address perpetration of GBV.


Endothelial-Specific Overexpression of Histone Deacetylase 2 Protects Mice against Endothelial Dysfunction and Atherosclerosis.
We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in protecting endothelial cells from oxidized low-density lipoprotein (OxLDL)-induced injury. In this study, we examined the effects of endothelial-specific HDAC2 overexpression on endothelial-dependent vasorelaxation and atherogenesis in vivo. Endothelial-specific HDAC2-overexpressing transgenic mice (HDAC2-Tg) were generated under control of the Tie2 promoter. An atherosclerosis model was produced by injecting HDAC2-Tg and wild-type (WT) mice with adeno-associated virus encoding a PCSK9 gain-of-function mutant under control of a liver-specific promoter and feeding them a high-fat diet for 12 weeks. Aortic stiffness in vivo was determined by measuring pulse wave velocity. Wire myography was used to measure endothelium dependent (acetylcholine) and independent (sodium nitroprusside) relaxation in isolated mice aortas. Atherosclerotic plaque burden in aortas was determined by Oil Red O staining and protein expression was determined by western blotting. At baseline, HDAC2-Tg mice had normal mean arterial blood pressure (MAP) and body weight, but pulse wave velocity (PWV), an inverse measure of vascular health and stiffness, was decreased, suggesting that their vessels were more compliant. Moreover, basal nitric oxide production was enhanced in the vessels of HDAC2-Tg mice as compared to that in WT controls, although no significant differences in acetylcholine (endothelial component)- or sodium nitroprusside (non-endothelial component)-mediated relaxation were observed. However, after exposure to OxLDL, aortas from HDAC2-Tg mice exhibited greater acetylcholine-induced relaxation than did those from WT mice. Thus, endothelial-specific vasodilator production was enhanced despite oxidative injury. Atherosclerosis induction in WT mice led to a significant increase in PWV, but in HDAC2-Tg mice, PWV and MAP remained unchanged. Further, aortic rings from HDAC2-Tg exhibited better endothelial-dependent vascular relaxation than did those from WT mice, but not when treated with nitric oxide synthase inhibitor L-NAME. Finally, plaque burden, determined by Oil red O staining, was significantly increased in WT, but not HDAC2-Tg mice, subjected to the atherogenic model. Deletion of endothelial HDAC2 led to impaired endothelial cell-dependent vascular relaxation and increased PWV, compared with those in littermate controls. HDAC2 protects against endothelial dysfunction and atherogenesis induced by oxidized lipids. Hence, overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis. HDAC2-Tg mice provide an opportunity to determine the role of endothelial HDAC2 in vascular endothelial homeostasis.


Template-Free Nanostructured Fluorine-Doped Tin Oxide Scaffolds for Photoelectrochemical Water Splitting.
The synthesis and characterization of highly stable and conductive F:SnO2 (FTO) nanopyramid arrays are investigated, and their use as scaffolds for water splitting is demonstrated. Current densities during the oxygen evolution reaction with a NiFeOx catalyst at 2 V vs reversible hydrogen electrode were increased 5-fold when substituting commercial FTO (TEC 15) by nanostructured FTO scaffolds. In addition, thin α-Fe2O3 films (∼50 nm thick) were employed as a proof of concept to show the effect of our nanostructured scaffolds during photoelectrochemical water splitting. Double-layer capacitance measurements showed a drastic increase of the relative electrochemically active surface area for the nanostructured samples, in agreement with the observed photocurrent enhancement, whereas UV-vis spectroscopy indicates full absorption of visible light at wavelengths below 600 nm.


Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth.
Translation initiation in eukaryotes is a rate-limiting step in protein synthesis. It is a complicated process that involves many eukaryotic initiation factors (eIFs). Altering the expression level or the function of eIFs may influence the synthesis of some proteins and consequently cause abnormal cell growth and malignant transformation. P170, the largest putative subunit of eIF3, has been found elevated in human breast, cervical, esophageal, and lung cancers, suggesting that p170 may have a potential role in malignant transformation and/or cell growth control. Our recent studies suggested that p170 is likely a translational regulator and it may mediate the effect of mimosine on the translation of a subset mRNAs. Mimosine, a plant nonprotein amino acid, inhibits mammalian DNA synthesis, an essential event of cell growth. The rate-limiting step in DNA synthesis is the conversion of the ribonucleotides to their corresponding deoxyribonucleotides catalysed by ribonucleotide reductase of which the activity is regulated by the level of its M2 subunit. It has been reported that inhibiting the activity of M2 also inhibits cell growth. To understand the relationship between protein and DNA synthesis and between p170 and cell growth control, we investigated in this study whether p170 regulates the synthesis of M2 and, thus, cell growth. We found that altering the expression level of p170 changes the synthesis rate of both M2 and DNA. Decreasing p170 expression in human lung cancer cell line H1299 and breast cancer cell line MCF7 significantly reversed their malignant growth phenotype. However, the overall [35S]methionine incorporation following dramatic decrease in p170 expression was only approximately 25% less than the control cells. These observations, together with our previous findings, suggest that p170 may regulate the translation of a subset mRNAs and its elevated expression level may be important for cancer cell growth and for maintaining their malignant phenotype.


Pubic arch detection in transrectal ultrasound guided prostate cancer therapy.
New biopsy techniques, increased life expectancy, and prostate-specific antigen (PSA) screening have contributed to an increase in the reported incidence of prostate cancer. Among several treatment options available to the patients, transperineal prostate brachytherapy has emerged as a medically successful, cost-effective outpatient procedure for treating localized prostate cancer. Transperineal prostate brachytherapy employs transrectal ultrasound (TRUS) as the primary imaging modality to accurately preplan and subsequently execute the placement of radioactive seeds into the prostate. Under TRUS guidance, a needle (preloaded with radioactive seeds) is inserted through a template guide, through the perineum and into a predetermined prostate target. The pubic arch, formed by the central union of pelvic bones, is a potential barrier to the passage of these needles in the prostate. A critical aspect, therefore, in the planning and execution of the brachytherapy procedure is the accurate assessment of pubic arch interference (PAI) in relation to the prostate. Traditionally, the evaluation of PAI has involved computed tomography correlate scanning or crude subjective evaluations. In this paper, we describe a new method of assessing PAI by detecting the pubic arch via image processing on the TRUS images. The PAI detection (PAID) algorithm first uses a technique known as sticks to selectively enhance the contrast of linear features in ultrasound images. Next, the enhanced image is thresholded via percentile thresholding. Finally, we fit a parabola (a model for the pubic arch) recursively to the thresholded image. Our evaluation result from 15 cases indicates that the algorithm can successfully detect the pubic arch with 90% accuracy. Based on this study, we believe that detecting the pubic arch and assessing PAI can be done practically and more accurately in the clinical setting using TRUS rather than the current available methods.


Childhood Thyroid Function Reference Ranges and Determinants: A Literature Overview and a Prospective Cohort Study.
Reported cutoffs for childhood thyrotropin (TSH) and free thyroxine (fT4) reference ranges vary widely, and knowledge on the determinants of childhood thyroid function is sparse. This study aimed to summarize the existing studies on thyroid function reference ranges in children. Furthermore, the objective was to investigate the determinants of childhood TSH and fT4 concentration in a population based-prospective cohort. First, to identify studies on childhood thyroid reference ranges, The National Library of Medicine's PubMed, Embase, Ovid Medline, Web of Science, and Google Scholar databases were systematically searched. Second, in a non-selected sample of 4273 children (median age 6.0 years, range 4.9-9.1 years) from the cohort, the associations of age, sex, anthropometric characteristics, ethnicity, maternal education, and time and season at venipuncture were studied with TSH and fT4 concentrations. The study also investigated to what extent between-individual variations in the determinants of TSH and fT4 could influence the calculation of reference ranges. Published reference ranges for TSH and fT4 differ per age range and within age ranges (cutoffs low TSH: 0.13 to >1 mIU/L; high TSH: 2.36 to >10 mIU/L; low fT4: 7.0 to >10 pmol/L; high fT4: 15.5 to >30 pmol/L). In the present cohort, weight, sex, and ethnicity were determinants of TSH (p ≤ 0.03) and fT4 concentrations (p ≤ 0.01), and height and time at venipuncture were determinants of TSH only (p < 0.0001). The between-individual variation depending on clinical determinants for TSH ranged between 0.64 and 0.96 mIU/L (total population 0.87 mIU/L) for the lower limit and 4.30 and 5.62 mIU/L (total population 5.20 mIU/L) for the upper limit, whereas for fT4, the lower limit ranged between 13.6 and 14.2 pmol/L (total population 13.8 pmol/L) and the upper limit ranged between 20.2 and 23.0 pmol/L (total population 20.8 pmol/L). Considerable differences exist in the reported reference ranges for childhood TSH and fT4 across and within age ranges and assays. The present cohort shows only a minimal association between TSH and fT4, suggesting that the hypothalamus-pituitary-thyroid axis remains unaffected by thyroid interfering factors. Various determinants of TSH and fT4 in children were identified, which accounted for a considerable variation of reference range cutoffs.


Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle.
The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARdelta, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARdelta has also been verified in humans. In addition, it has become clear that the action of PPARdelta is not restricted to skeletal muscle. Indeed, PPARdelta has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARdelta in the reversal of any tendency toward the development of insulin resistance.


[A study on the level of antibody against measles through maternal-fetal transfer and the immuno-response to measles vaccine among 4 to 7 month olds].
A total number of 143 infants at the age of 4 to 7 months from Yantai city-Shandong was selected for the study of antibody level against measles by maternal-fetal transfer and immuno-response to measles vaccine in October of 1993. The results showed that the negative rates of maternal-fetal antibody among infants of 4, 5, 6 and 7 month olds were 75.00%, 81.25%, 94.87% and 90.1%, respectively. The positive rates and geometric mean titers (GMTs) for immuno-response to measles vaccine were 92.86%, 84.38%, 97.44%, 100.00% and 55.17, 42.41, 69.95, 71.46, respectively. There were significant lower immune response to measles vaccine in infants who had high titer ( > 1:2) than those who had low titer ( <or= 1:2) of maternal-fetal antibody (chi 2 = 88.38, P < 0.001). In order to decrease the number of measles cases under 1 year old (especially under 9 month-old), the author suggested that the primary immunization for measles vaccine should be started at 6 month olds.


Reverse malingering-staying on the job at any cost.
Reverse malingering in the workplace is not as common as malingering. Despite their injuries, some workers will stay at work for various reasons regardless of the potential for further injury. Employers must be aware of reverse malingering and should consider alternative work assignments that will satisfy themselves and employees. [Workplace Health Saf 2013;61(7):297-298.].


Shotgun transcriptome, spatial omics, and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactions.
In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin-angiotensin-aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.


Prevalence and correlates of depressive symptoms in secondary school children in Dhaka city, Bangladesh.
Objectives: Depression is a leading contributor to the global burden of disease, and often starts at a young age. Depression in young people can increase the risk of unhealthy lifestyle behaviour and can lead to substantial disability, social problems, poor health, and suicide. Other research has examined depressive symptoms among adult populations in Bangladesh, but little is known about other age groups. The aim of this study was to assess the prevalence and socio-demographic correlates of depressive symptoms among secondary school children of Dhaka city, Bangladesh.Design: A self-completed questionnaire was administered to 898 students from eight secondary schools of Dhaka, the capital City of Bangladesh. Of the respondents, 755 (372 males, 383 females; average age 14.26 years; SD 1.15) completed the 10-item Center for Epidemiological Studies Depression Scale (CESD-10). A score of 10 or more was used to indicate depressive symptoms. Parents completed a separate questionnaire to provide individual and household/family-level data. Generalized Estimating Equations (GEE) was used to assess sociodemographic and lifestyle factors associated with adolescent depressive symptoms.Results: Among the responding adolescents, 25% reported depressive symptoms with prevalence more common among females than males (30% vs. 19%). Factors significantly associated with symptoms of depression included being female, aged 15-16 years, self-perception of non-normal weight, feeling unsafe at school, sleep disturbance, low life satisfaction, high intake of sugary drinks, and regularly skipping breakfast.Conclusion: Depressive symptoms are prevalent among secondary school children in urban Bangladesh. Interventions for adolescents with depressive symptoms could focus on lifestyle practices such as weight management, personal safety, sleep hygiene and healthy eating.


A prospective randomized comparison of sublingual and oral misoprostol when combined with mifepristone for medical abortion at 12-20 weeks gestation.
Sublingual misoprostol has been shown to be effective in medical abortion. A prospective double-blinded placebo-controlled trial was done to compare the efficacy and side-effects of sublingual to oral misoprostol when used with mifepristone for medical abortion from 12 to 20 weeks gestation. A total of 120 women at 12-20 weeks of gestation were randomized to receive 200 mg oral mifepristone followed by either sublingual or oral misoprostol 400 mg every 3 h for a maximum of five doses 36-48 h later. The course of misoprostol was repeated if the woman did not abort within 24 h. There was no significant difference (P = 0.43) in the success rate at 24 h [relative risk = 1.075; 95% confidence interval (CI): 0.94-1.19]. Abortion occurred in 91.4% in the sublingual group (95% CI: 81.0-96.7%) as compared to 85.0% (95% CI: 73.7-92.1%) in the oral group. The median induction-to-abortion interval was significantly shorter (P = 0.009) in the sublingual group (5.5 h) as compared to the oral group (7.5 h). The incidence of fever was higher in the sublingual group (P < 0.0001). The incidences of other side-effects were similar. Sublingual misoprostol, when combined with mifepristone, is effective for medical abortion in the second trimester. The induction-to-abortion interval is shorter when sublingual misoprostol is used when compared to oral misoprostol.


Effect of the converting-enzyme inhibitor SQ 14 225 (captopril) in early one-kidney, one-clip hypertension in the rat.
1. Arterial plasma renin activity was significantly elevated in rats with one-kidney, one-clip hypertension of less than 3 weeks duration. 2. Intraperitoneal injection of the angiotensin-converting enzyme inhibitor SQ 14 225 (captopril) caused a dose-related decrease in systolic blood pressure in hypertensive rats. The lowest dose of captopril used (3.5 mg/kg) inhibited conversion of exogenous angiotensin I and maximally potentiated the depressor response to bradykinin, but failed to restore blood pressure to that of the normotensive controls. 3. Removal of the solitary clipped kidney also did not restore blood pressure to normal. Injection of captopril (3.5 mg/kg) 24 h after nephrectomy, when no circulating renin activity was detectable, lowered blood pressure further in hypertensive but not in similarly nephrectomized controls. 4. These results indicate that raised blood pressure in early one-kidney, one-clip hypertension in the rat cannot be entirely attributed to the renin-angiotensin system, even when plasma renin activity is significantly increased. 5. This study has also confirmed a hypotensive action of captopril in anephric rats when plasma renin activity is undetectable.


Greater effect of adiposity than physical activity or lean mass on physical function in community-dwelling older adults.
Adiposity, lean mass, and physical activity (PA) are known to influence physical function in older adults, although the independent influences are not completely characterized. Older adults (N = 156, M age = 68.9 ± 6.7 yr, 85 men) were assessed for body composition via dual-energy X-ray absorptiometry, PA by accelerometer, and physical function via timed up-and-go (UP&GO), 30-s chair stand, 6-min walk (6-min WALK), and Star-Excursion Balance Test. In the absence of percentage-body-fat by PA interactions (p > .05), main effects existed such that a higher percentage body fat was associated with poorer performance in UP&GO, 30-s chair stand, and 6-min WALK (p < .05). No significant main effects were found for PA and functional performance. Adiposity explains 4.6-11.4% in physical functional variance (p < .05). Preventing increases in adiposity with age may help older adults maintain functional independence.


Reclassification of Trichlorobacter thiogenes as Geobacter thiogenes comb. nov.
Reclassification of the species Trichlorobacter thiogenes as Geobacter thiogenes comb. nov. is proposed on the basis of physiological traits and phylogenetic position. Characteristics additional to those provided in the original description revealed that the type strain (strain K1(T)=ATCC BAA-34(T)=JCM 14045(T)) has the ability to use Fe(III) as an electron acceptor for acetate oxidation and has an electron donor and acceptor profile typical of a Geobacter species, contains abundant c-type cytochromes, and has a temperature optimum of 30 degrees C and a pH optimum near pH 7.0; traits typical of members of the genus Geobacter. Phylogenetic analysis of nifD, recA, gyrB, rpoB, fusA and 16S rRNA genes further indicated that T. thiogenes falls within the Geobacter cluster of the family Geobacteraceae. Based on extensive phylogenetic evidence and the fact that T. thiogenes has the hallmark physiological characteristics of a Geobacter species, Trichlorobacter thiogenes should be reclassified as a member of the genus Geobacter.


Natural products discovery needs improved taxonomic and geographic information.
Covering: up to 2016Marine and terrestrial organisms yield a remarkable chemical diversity and are important sources for discovery of new chemical products. In order to maximize the bioprospecting efficiency of natural products (NP), taxonomy, geography and biodiversity are starting to be used to draw conclusions on which taxonomic groups and/or regions may be of interest for future research. However, accurate taxonomic information and sampling location of source organisms have often been overlooked. Although these issues were already reported a few decades ago and improvements have been made, such outstanding problems are still recurrent in recent peer-reviewed literature. Here, we focus on the importance of taxonomic and geographic identification of source material and illustrate how taxonomic and geographic data of source organisms continues to be poorly handled. It is our opinion that this issue needs to be discussed within the NP community with the ultimate goal of improving publication standards and guaranteeing the scientific principle of research reproducibility. Moreover, by doing so, it will be possible to take advantage of information available in the literature to develop cross-disciplinary meta-analyses that may help to advance the state of the art of NP research and future bioprospecting endeavours.


Preoperative and postoperative response to inhaled nitric oxide.
The preoperative dose response to inhaled nitric oxide (NO) was compared with the need for and response to NO after cardiac surgery in patients with congenital heart defect and secondary pulmonary hypertension. In a preoperative vasodilator test with inhaled NO 20, 40 and 80 ppm and oxygen, mean pulmonary artery pressure (PAP) was at least 40 mmHg and/or the pulmonary vascular resistance index (PVRI) 4 Wood units. Preoperatively, NO 40 ppm and FiO2 0.9 reduced systolic pulmonary/systemic arterial pressure (PAPs/SAPs) from 0.89 (SD 0.10) to 0.80 (0.18) and pulmonary/systemic vascular resistance (PVR/SVR) from 0.26 (0.13) to 0.13 (0.08). Haemodynamic assessment was repeated in 11 patients postoperatively. NO treatment was started if PAPs/SAPs rose to 0.8 or the pulmonary oximetry fell below 40%. Postoperatively, eight of 11 patients, including 6 patients with Down's syndrome, needed NO. PAPs/SAPs decreased more than preoperatively: 48.5% vs 11.2, p = 0.0045. Pulmonary oximetry increased by 15.7%, p = 0.02. The degree of preoperative response to NO did not differ between the patients with postoperative pulmonary hypertension and the other children. Patients with early pulmonary hypertensive crisis (first 24 h; n = 6) had a higher PVRI (7.6 vs 4.4 Um2; p = 0.003) and PVR/SVR (0.34 VS 0.17; p = 0.02) preoperatively. Two patients died in pulmonary hypertensive crisis.


Smart Error Sum Based on Hybrid Two-Trace Two-Dimensional (2T2D) Correlation Analysis.
Based on hybrid 2D correlation analysis, we recently derived and introduced a "smart error sum," a sophisticated loss function that can be used for solving nonlinear inverse problems like the determination of optical constants and oscillator parameters from a series of optical spectra in the infrared spectral region. The advantage of the smart error sum compared to the conventional sum of squared errors lies in its ability to marginalize multiplicative systematic errors such as, for example, reflectance values above unity in transflection spectra. This is enabled by a transformation, which allows fits to not exclusively focus on forcing fit spectra to agree with experimental spectra at every wavenumber point by all means, but also to take correlations such as spectral similarities and their changes with certain perturbations into account. In this work, we extend our approach to accommodate the treatment of individual spectra, instead of only series, based on hybrid two-trace two-dimensional (2T2D) correlation analysis. We evaluate and prove the value of our approach by individually analyzing experimental transflection spectra of polymethyl methacrylate (PMMA) layers on gold substrates. The comparison of the results with those obtained by the original smart error sum based on the whole set of spectra as well as those resulting from conventional fitting of series and individual spectra (using the conventional sum of squared errors) confirms the validity and soundness of the 2T2D smart error sum.


Morphological analysis of selective destruction of pancreatic beta-cells by cytotoxic T lymphocytes in NOD mice.
Interactions of pancreatic islets and islet-associated mononuclear cells (IAMCs) from the nonobese diabetic (NOD) mouse were morphologically investigated. To obtain IAMCs, pancreatic islets isolated from adult NOD mice were cultured for 7 days with interleukin 2. Noted by light microscopy, interactions between IAMCs and freshly isolated islets from young NOD mice began 30 min after the initiation of the coculture, and 6 h later, normal cellular array of the islets was lost. By electron microscopy, most IAMCs had low nucleus-cytoplasm ratio, the nucleus was notched and exhibited condensed chromatin along the nuclear membrane, and well-developed Golgi complexes and several mitochondria were distributed in the cytoplasm. These IAMCs adhered to beta-cells, but not to alpha- or delta-cells, with their pseudopods and caused cytolysis of beta-cells. Immunohistochemical study with antibodies specific for pancreatic hormones demonstrated that only cells reacting with anti-insulin antibody were selectively lost as the incubation time proceeded. Electron immunohistochemistry by immunogold technique showed that effector cells in IAMCs reacted with anti-CD8 (Lyt-2) antibody, but not anti-CD4 (L3T4) or anti-asialogangliosideM1 antibody. In addition, the concentration of pancreatic hormones in the culture medium, used as a marker of cytolysis, also demonstrated that insulin was significantly increased after 6 h of culture, whereas glucagon and somatostatin were not. These results suggest that CD8+ cytotoxic T lymphocytes are involved in the selective destruction of pancreatic beta-cells in the NOD mouse.


ovadExploring alternative strategies for Staphylococcus aureus Nasal decolonization: Insights from Preclinical Studies.
Nasal decolonization of Staphylococcus aureus with the antibiotic mupirocin is a common clinical practice before complex surgical procedures, to prevent hospital acquired infections. However, widespread use of mupirocin has led to the development of resistant S. aureus strains and there is a limited scope for developing new antibiotics for S. aureus nasal decolonization. It is therefore necessary to develop alternative and non-antibiotic nasal decolonization methods. In this review, we broadly discussed the effectiveness of different non-antibiotic antimicrobial agents that are currently not in clinical practice, but are experimentally proved to be efficacious in promoting S. aureus nasal decolonization. These include lytic bacteriophages, bacteriolytic enzymes, tea tree oil, apple vinegar and antimicrobial peptides. We have also discussed the possibility of using photodynamic therapy for S. aureus nasal decolonization. This article highlights the importance of further large scale clinical studies for selecting the most suitable and alternative nasal decolonizing agent.


One-stage ultrasonographically guided hepatectomy for multiple bilobar colorectal metastases: a feasible and effective alternative to the 2-stage approach.
Two-stage hepatectomy with or without portal vein embolization allows treatment of multiple bilobar metastases, thereby expanding operative indications for these patients. Two operations are needed, however, and some patients are not able to complete the treatment strategy because of disease progression. Using experience gained from our policy of ultrasonographically guided resection, we explored the safety and effectiveness of 1-stage operative procedures in patients otherwise recommended for the 2-stage approach. A total of 29 patients with multiple (>or=4) bilobar colorectal liver metastases (CLM) were selected from 100 consecutive patients submitted to surgical resection. The total number of preoperative CLM was 163 (median, 5; range, 2-20). The operative strategy was based on tumor-vessel relationships at intraoperative ultrasonography (IOUS) and on findings at color Doppler IOUS. There was no in-hospital mortality. Tumor removal was feasible with 1-stage operative procedures in all but 3 patients who underwent laparotomy. The overall morbidity rate was 23% (6/26); none of the patients required reoperation. Major morbidity occurred in 1 patient (4%). Blood transfusions were administered in 4 patients (15%). After a mean follow-up of 17 months (median, 14; range, 6-54), 3 patients had died from systemic recurrence, 12 patients were alive without disease, and 11 were alive with disease. No local recurrences were observed at the resection margin. IOUS-guided resection based on strict criteria allows a 1-stage operative treatment in selected patients with multiple bilobar CLM. This strategy decreases the need for a two-stage hepatectomy, thereby avoiding the disadvantages of a 2-stage approach.


Response of the spleen of Balb/c and p53-transgenic mice to low doses of carcinogen and to polyclonal antibodies generated against the soluble 53 kDa protein.
We have previously reported that p53-transgenic mice are highly sensitive to low doses of a carcinogen and to vaccination with soluble 53 kDa antibodies, compared to normal mice. The splenic manifestation of this strain dependent hypersensitivity was investigated immunohistochemically and morphometrically. The spleen was obtained from Balb/c and human p53 promoter-CAT transgenic mice. Mice had either been treated with the carcinogen dimethylhydrazine (DMH), vaccinated before DMH treatment with polyclonal IgG generated against the soluble 53 kDa protein, or left untreated. Significant differences in the splenic structures were found between the strains compared, including the area occupied by the white and red pulps, the periarterial lymphoid sheath (PALS) and the marginal zone, and in the number of lymphoblasts and lymphocytes. Exposure to DMH stimulated the immune response, but in transgenic mice the number of B and T lymphocytes and especially helper T lymphocytes was significantly lower than in Balb/c mice. Vaccination followed by DMH injections did not improve the insufficiency of the immune response in transgenic mice. In transgenic mice, the number of B lymphocytes in follicles was almost half and the total number of cells in PALS and the number of T lymphocytes were only 71% and 60% respectively in BALB/c mice. In the marginal zone, macrophages proliferated as lymphocytes decreased. Insufficiency of the immune system after exposure to a carcinogen is more pronounced in transgenic mice, and is mainly related to the B-cell system. It may stem from defects in B lymphocytes or from inherent differences in their maturation and regulation. The increase in the number of macrophages, dendritic cells and neutrophils illustrates the compensatory processes that can remedy this developing immune insufficiency.


Concomitant secretion of Y-MSH with ACTH and beta-endorphin in humans.
Using a specific radioimmunoassay for gamma-melanotropin (gamma-MSH), one of the predicted fragments in the amino-terminal portion of the adrenocorticotropin(ACTH)-beta-lipotropin (beta-LPH) precursor, gamma-MSH-like immunoreactivity (gamma-MSH-LI) was detected in human plasma from 4 of 5 patients with Addison's disease and 2 of 3 patients with Nelson's syndrome. None of the normal subjects or patients with Cushing's disease showed detectable concentrations (more than 150 pg/ml) of gamma-MSH-LI. gamma-MSH-LI was secreted concomitantly with ACTH-like immunoreactivity (ACTH-LI) and beta-endorphin-like immunoreactivity (beta-endorphin-LI) in response to insulin-induced hypoglycemia and the administration of lysine-vasopressin. Conversely, intravenous injection of cortisol lowered plasma concentrations of gamma-MSH-LI concomitantly with those of ACTH-LI and beta-endorphin-LI. Gel chromatographic studies of the plasma extracts showed a single peak of gamma-MSH-LI near the elution position of human beta-LPH. These results suggest that gamma-MSH-LI in human plasma is present as a big form and that this big gamma-MSH is secreted concomitantly with ACTH and beta-endorphin.


Neuropeptides and central nervous system injury. Clinical implications.
It has been proposed that endogenous opioids play a pathophysiologic role in the secondary injury that follows spinal trauma, brain trauma, and cerebral ischemia. Opiate antagonists, at high doses, have been found to improve outcome in various experimental models of central nervous system injury. Thyrotropin-releasing hormone, which appears to act in part as a functional antagonist of opioid systems, has proved effective in the treatment of experimental spinal cord and brain trauma. The literature relating to these developments is reviewed, with emphasis on the potential clinical application of these classes of substances.


Enuresis prevalence and accompanying factors in schoolchildren: a questionnaire study from southeast Anatolia.
The aims of this study were to establish the prevalence of enuresis, to determine accompanying factors, and to identify common methods in the management of enuresis in Turkish children aged between 6 and 11 years living in eastern Anatolia. The parents of 3,527 schoolchildren aged between 6 and 11 years completed a self-administered questionnaire. The questionnaire asked about sociodemographic data, enuresis data, physical or psychological disorders, and family stressors. Descriptive statistics and chi2 test were used for data analysis. The response rate was 88%. The overall prevalence of reported enuresis was 12.96%, and the prevalence of marked enuresis (at least weekly) was 9.8%. Enuresis was notably more common in boys (male:female ratio 1.6), and the prevalence rates decreased by age without gender bias. Of all enuretic children, 21% had also daytime bed-wetting. The rate of a positive family history was 42% for siblings only and 66% for the other family members. Significantly more of the dry children woke up spontaneously at night to void as compared with the enuretic children (p < 0.001). The parental concern level was not high, and only 15% of the children visited a physician for the management of enuresis. Low socioeconomic status, unfavorable perinatal or postnatal history, and unsatisfactory familial characteristics were significantly more frequent in the enuretic group (p < 0.05). The enuretic children had also higher rates of poor school performance and poor social adaptation as compared with nonenuretic children (p < 0.001). These results suggest that the prevalence of enuresis in eastern Anatolia is similar to that reported from western Anatolia and from most other countries. Turkish families did not report a high-level concern about enuresis, and the problem was managed primarily within the family.


Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome.
This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.


Iliac crest autogenous bone grafting: donor site complications.
Autogenous bone grafting is often done in orthopaedic surgery for a variety of conditions. The iliac crest is currently the most common donor site for obtaining autogenous bone graft. We searched the literature to summarize reported complications related to the donation of autogenous bone from the iliac crest. Our review revealed reports of arterial injury, ureteral injury, herniation, chronic pain, nerve injury, infection, fracture, pelvic instability, cosmetic defects, hematoma, and tumor transplantation. Currently, autogenous bone grafting is a necessary part of the treatment of various orthopaedic conditions. Obtaining bone from the iliac crest can be associated with significant morbidity. As bone grafting technology emerges, the known complications of the current standard should be weighed against the risk of alternate therapies.


What do Sunni Muslims think about religiously forbidden reproductive options?
This study explored the attitudes of Sunni Muslims towards religiously forbidden reproductive options: gamete donation, sex selection, surrogacy, and adoption. A total of 824 married Sunni Muslim people read 12 hypothetical vignettes depicting five types of assisted reproductive technologies: (i) sperm donation; (ii) egg donation, (iii) surrogacy; (iv) sex selection of a male foetus; and (v) and sex selection of a female foetus. They also related to the option of adopting a baby. Each vignette was presented twice: once depicting a relatively younger couple and once again describing a relatively older couple. The respondents were asked to state the level of their objection or acceptance for each of the twelve vignettes. In accord with the Islamic ruling, respondents reported objections to sex selection, egg and sperm donation, and surrogacy. However, they expressed a moderate level of acceptance of adoption of a baby. The greatest objection was directed at sperm donation, followed by objection to egg donation. Our study shows that the Sunni Muslims do not support the provision of fertility care for reproductive options that clearly contravene Islamic religious ruling. The findings may help fertility experts understand the cultural and religious complexities in treating Sunni Muslim couples.


Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene.
Baller-Gerold syndrome (BGS) is a rare autosomal recessive condition with radial aplasia/hypoplasia and craniosynostosis (OMIM 218600). Of >20 cases reported so far, a few appear atypical and have been reassigned to other nosologic entities, including Fanconi anaemia, Roberts SC phocomelia, and Pfeiffer syndromes after demonstration of corresponding cytogenetic or molecular abnormalities. Clinical overlap between BGS, Rothmund-Thomson syndrome (RTS), and RAPADILINO syndrome is noticeable. Because patients with RAPADILINO syndrome and a subset of patients with RTS have RECQL4 mutations, we reassessed two previously reported BGS families and found causal mutations in RECQL4 in both. In the first family, four affected offspring had craniosynostosis and radial defect and one of them developed poikiloderma. In this family, compound heterozygosity for a R1021W missense mutation and a g.2886delT frameshift mutation of exon 9 was found. In the second family, the affected male had craniosynostosis, radial ray defect, poikiloderma, and short stature. He had a homozygous splice site mutation (IVS17-2A>C). In both families, the affected offspring had craniosynostosis, radial defects, and growth retardation, and two developed poikiloderma. Our results confirm that BGS in a subgroup of patients is due to RECQL4 mutations and could be integrated into a clinical spectrum that encompasses RTS and RAPADILINO syndrome.


[Current epidemiology of carcinoma of the esophagus and cardia in Germany].
In the past 20-30 years the incidence of adenocarcinoma (AC) of the esophagus and the cardia has risen in western countries, while that of squamous cell carcinoma (SC) of the esophagus has largely stayed constant. Current data in the epidemiology of these cancers in Germany were analysed. The data of the epidemiological cancer register of the Saarland (Old State of former West Germany) and the combined registers of the New States of Germany (former East Germany) and Berlin were collected. Because of the excellent registration procedures, data from the Saarland and the New States, Mecklenburg-Pommern, Brandenburg and Saxony were selected for this study. The incidence was calculated and corrected for age in relation to the world population. The incidence of esophageal AC among males in the Saarland rose from 0.22 per 100 000 population to 1.17 between 1986 to 1997, an increase of 432%, while in Brandenburg, Mecklenburg-Vorpommern and Saxomy it rose, between 1977 and 1998, from 0.23 to 0.8 i.e. by 248%. Esophageal SC incidence remained largely constant in both cancer registers since 1986. In 1998 it was 3.31 in the three New States of Germany and 5.05 in the Saarland. In females the incidence was markedly lower. In 1996-1998 fewer than 10% of cases of esophageal cancer were in UICC stage 1 (T 1 N 0 M 0, early carcinoma). Correspondingly the 5-year survival of all patients with esophageal carcinoma in the Saarland was less than 10% in 1971-1995. AC of the cardia also increased. In the three New States of Germany the incidence among males rose from 1.27 in 1977 to 2.18 in 1998, in females from 0.4 to 0.58. During the same period malignant tumors of the entire stomach, including the cardia, decreased in males from 29.5 to 17.1, in females from 14.3 to 9.2. In Germany, during the past 15-20 years, the incidence of esophageal AC and presumably also of AC of the cardia has increased. But the incidence of squamous cell carcinoma of the esophagus has remained largely constant. The proportion of early carcinoma and the 5-year survival with esophageal carcinoma remains under 10%.


Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.
To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin. Multicentre randomised placebo controlled trial. Outpatient clinics of three non-academic hospitals in the Netherlands. 390 patients with type 2 diabetes receiving treatment with insulin. 850 mg metformin or placebo three times a day for 4.3 years. Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at 4, 17, 30, 43, and 52 months. Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of -19% (95% confidence interval -24% to -14%; P<0.001) and in folate concentration of -5% (95% CI -10% to -0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI -1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 micromol/l (95% CI 18.8 to 30.0 micromol/l), compared with a mean homocysteine level of 18.1 micromol/l (95% CI 16.7 to 19.6 micromol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 micromol/l (95% CI 14.3 to 15.5 micromol/l; P<0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (>220 pmol/l). Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered. Trial registration Clinicaltrials.gov NCT00375388.


Functional characterization of multiple PAS domain-containing diguanylate cyclases in Synechocystis sp. PCC 6803.
Bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a second messenger known to control a variety of bacterial processes. The model cyanobacterium, Synechocystis sp. PCC 6803, has a score of genes encoding putative enzymes for c-di-GMP synthesis and degradation. However, most of them have not been functionally characterized. Here, we chose four genes in Synechocystis (dgcA-dgcD), which encode proteins with a GGDEF, diguanylate cyclase (DGC) catalytic domain and multiple Per-ARNT-Sim (PAS) conserved regulatory motifs, for detailed analysis. Purified DgcA, DgcB and DgcC were able to catalyze synthesis of c-di-GMP from two GTPs in vitro. DgcA had the highest activity, compared with DgcB and DgcC. DgcD did not show detectable activity. DgcA activity was specific for GTP and stimulated by the divalent cations, magnesium or manganese. Full activity of DgcA required the presence of the multiple PAS domains, probably because of their role in protein dimerization or stability. Synechocystis mutants carrying single deletions of dgcA-dgcD were not affected in their growth rate or biofilm production during salt stress, suggesting that there was functional redundancy in vivo. In contrast, overexpression of dgcA resulted in increased biofilm formation in the absence of salt stress. In this study, we characterize the enzymatic and physiological function of DgcA-DgcD, and propose that the PAS domains in DgcA function in maintaining the enzyme in its active form.


[The application of laser beam welding of biological tissues for the purpose of ossiculoplasty].
The objective of the present work was to estimate the functional outcome of ossiculoplasty in the patients presenting with chronic suppurative otitis media and treated by means of laser beam welding of biological tissues. In order to obtain a good functional result of tympanoplasty including ossiculoplasty, it is necessary to conserve the elements of the sound-conducting system in the positions to which they were set during surgery. We reached this goal by fixing individual elements of the chain of the auditory ossicles by means of the laser beam welding of biological tissues with the use of platelet-rich plasma as a solder alloy. The audiometric examination of the patients within 1, 3, and 12 months after surgery showed that this technique improves the functional outcome of the treatment of the patients with chronic suppurative otitis media using prostheses for the substitution of the auditory ossicles.


Altitudinal flower size variation correlates with local pollinator size in a bumblebee-pollinated herb, Prunella vulgaris L. (Lamiaceae).
The influence of locally different species interactions on trait evolution is a focus of recent evolutionary studies. However, few studies have demonstrated that geographically different pollinator-mediated selection influences geographic variation in floral traits, especially across a narrow geographic range. Here, we hypothesized that floral size variation in the Japanese herb Prunella vulgaris L. (Lamiaceae) is affected by geographically different pollinator sizes reflecting different pollinator assemblages. To evaluate this hypothesis, we posed two questions. (1) Is there a positive correlation between floral length and the proboscis length of pollinators (bumblebees) across altitude in a mountain range? (2) Does the flower-pollinator size match influence female and male plant fitness? We found geographic variation in the assemblage of pollinators of P. vulgaris along an altitudinal gradient, and, as a consequence, the mean pollinator proboscis length also changed altitudinally. The floral corolla length of P. vulgaris also varied along an altitudinal gradient, and this variation strongly correlated with the local pollinator size but did not correlate with altitude itself. Furthermore, we found that the size match between the floral corolla length and bee proboscis length affected female and male plant fitness and the optimal size match (associated with peak fitness) was similar for the female and male fitness. Collectively, these results suggest that pollinator-mediated selection influences spatial variation in the size of P. vulgaris flowers at a fine spatial scale.


Forearm compartment syndrome as a result of eosinophilic fasciitis: case report.
Eosinophilic fasciitis is an uncommon scleroderma-like connective tissue disease, usually characterized by symmetrical and painful swelling and induration of the skin and thickened fascia infiltrated with lymphocytes and eosinophils. A middle-aged woman with follicular lymphoma being treated with chemotherapy presented with acute onset atraumatic forearm swelling and severe pain. The history, physical examination, and pressure measurements were consistent with compartment syndrome. Intraoperative biopsy of the forearm fascia confirmed eosinophilic fasciitis.


Hox gene misexpression and cell-specific lesions reveal functionality of homeotically transformed neurons.
Hox genes are critical for establishing the segmental pattern of the vertebrate hindbrain. Changes in their expression can alter neural organization of hindbrain segments and may be a mechanism for brain evolution. To test the hypothesis that neurons induced through changes in Hox gene expression can integrate into functional neural circuits, we examined the roles of ectopic Mauthner cells (M-cells) in the escape response of larval zebrafish. The activity of the paired Mauthner cells in rhombomere 4 (r4) has been shown to be critical for generating a high-performance startle behavior in response to stimulation of the tail (Liu and Fetcho, 1999). Previous studies have found that misexpression of particular Hox genes causes ectopic M-cells to be generated in r2 in addition to the r4 cells (Alexandre et al., 1996; McClintock et al., 2001). With calcium imaging, we found that the homeotically transformed neurons respond to startle stimuli. To determine the roles of ectopic and endogenous M-cells in the behavior, we lesioned the r2, r4, or both M-cells with cell-specific laser lesion and examined the effect on startle performance. Lesion of the normal M-cells did not decrease escape performance when the ectopic cells were present. These results indicate that the homeotically transformed Mauthner cells are fully functional in the escape circuit and are functionally redundant with normal M-cells. We suggest that such functional redundancy between neurons may provide a substrate for evolution of neural circuits.


Effects of copolypeptides on amyloid fibrillation of hen egg-white lysozyme.
The fibrillation of hen egg-white lysozyme (HEWL) in the absence and presence of simple, unstructured D,L-lysine-co-glycine (D,L-Lys-co-gly) and D,L-lysine-co-L-phenylalanine (D,L-Lys-co-Phe) copolypeptides was studied by using a variety of analytical techniques. The attenuating and decelerating effects on fibrillation are significantly dependent on the polypeptide concentration and the composition ratios in the polypeptide chain. Interestingly, D,L-Lys-co-gly and D,L-Lys-co-Phe copolypeptides with the same composition ratio have comparable attenuating effects on fibrillation. The copolypeptide with highest molar fraction of glycine residue exhibits the strongest suppression of HEWL fibrillation. The copolypeptide has the highest hydrophobic interacting capacity due to the more molar ratio of apolar monomer in the polymer backbone. The major driving forces for the association of HEWL and copolypeptides are likely to be hydrogen bonding and hydrophobic interactions, and these interactions reduce the concentration of free protein in solution available to proceed to fibrillation, leading to the increase of lag time and attenuation of fibrillation. The results of this work may contribute to the understanding of the molecular factors affecting amyloid fibrillation and the molecular mechanism(s) of the interactions between the unstructured polypeptides and the amyloid proteins.


Polymorphism of the HLA class II loci in Siberian populations.
The populations that colonized Siberia diverged from one another in the Paleolithic and evolved in isolation until today. These populations are therefore a rich source of information about the conditions under which the initial divergence of modern humans occurred. In the present study we used the HLA system, first, to investigate the evolution of the human major histocompatibility complex (MHC) itself, and second, to reveal the relationships among Siberian populations. We determined allelic frequencies at five HLA class II loci (DRB1, DQA1, DQB1, DPA1, and DPB1) in seven Siberian populations (Ket, Evenk, Koryak, Chukchi, Nivkh, Udege, and Siberian Eskimo) by the combination of single-stranded conformational polymorphism and DNA sequencing analysis. We then used the gene frequency data to deduce the HLA class II haplotypes and their frequencies. Despite high polymorphism at four of the five loci, no new alleles could be detected. This finding is consistent with a conserved evolution of human class II MHC genes. We found a high number of HLA class II haplotypes in Siberian populations. More haplotypes have been found in Siberia than in any other population. Some of the haplotypes are shared with non-Siberian populations, but most of them are new, and some represent "forbidden" combinations of DQA1 and DQB1 alleles. We suggest that a set of "public" haplotypes was brought to Siberia with the colonizers but that most of the new haplotypes were generated in Siberia by recombination and are part of a haplotype pool that is turning over rapidly. The allelic frequencies at the DRB1 locus divide the Siberian populations into eastern and central Siberian branches; only the former shows a clear genealogical relationship to Amerinds.


Indicators of material hardship and depressive symptoms among homebound older adults living in North Carolina.
This study used the concept of material hardship to understand how unmet needs related to food, housing, and health influence depressive symptoms among homebound older adults (N = 345) in North Carolina. Using data from the Nutrition and Function Study, 37% reported high levels of depressive symptoms and 17.4% indicated not receiving needed health care. Approximately 10% of respondents were food insecure; 30.7% were at risk for food insecurity; and 39.7% reported having to choose between either food and medication or food and paying bills. Adjusted logistic regression model revealed that food insecurity status (OR = 4.9) and age 60-74 y (OR = 2.4) were significantly associated with a greater number of depressive symptoms. Other indicators of material hardship, such as having a major financial difficulty, unmet health need, and inadequate housing, were not significant. By far, food insecurity was the most salient influence on depressive symptoms. These findings have important implications for service providers, researchers, and policymakers.


[Spatio-temporal dynamics of fishing effort in a multi-species artisanal diving fishery and its effects on catch variability: insights for sustainable management].
Artisanal diving fisheries are a source of income, employment and food security of coastal areas in many countries. Understanding the dynamics of these fisheries, including the spatial and temporal dynamics of fishing effort, gears and species can help to address the challenges involved in fisheries management. We aimed to analyze the differences in fishing strategies undertaken by fishers that use two different diving methods (hookah and free diving), the conditions and their potential impacts on catches when adjustments to those strategies are applied over time. For this, detailed information of fishing operations from artisanal boats in the North Pacific coast of Costa Rica was analyzed in two fishing seasons (2007-2008 and 2011-2012). Data were collected by onboard observers (fishing site, fishing time, species composition, depth and visibility). Additionally, interviews with divers were applied to obtain information of price per species, species volume and fishing operations. From the total number of trips during both seasons, hookah diving was represented by a sample size of 69.3%, while free diving, with a sample of 41.9%. More than 15 species were identified in each fishing season. Nevertheless, three categories had substantial contributions in both seasons with differences in the proportions for each case: green lobster (Panulirus gracilis), octopus (Octopus sp.) and parrotfish (Scarus perrico and S. ghobban). It is worth noting that an important proportion of catch was retained by fishers for personal consumption purposes, including species of high commercial value. Additional night diving activity, increased the number of dives from one season to another. Besides, cooperation processes in free diving fishing operations, and changes in fishing effort between seasons, defined important changes in fishing strategies. Potential causes of changes in fishing strategies and the implications for management to ensure the sustainability of these fisheries in the long term are discussed.


Isotretinoin in lacrimal gland fluid and tears.
Isotretinoin (13-cis-retinoic acid) is used in the treatment of severe cystic acne. Adverse ocular reactions, including blepharoconjunctivitis and dry eye symptoms, are frequent side effects of this drug. Our previous observation that retinol is present in tears and lacrimal gland fluid suggests that isotretinoin may also be secreted by the lacrimal gland. Rabbits were treated with isotretinoin, and lacrimal gland fluid was collected from the cannulated lacrimal gland duct. Tears were collected from patients who were being treated with isotretinoin. Lacrimal gland fluid and tears were analyzed by reverse-phase high-pressure liquid chromatography and a peak eluted from each sample, which was identified as isotretinoin. We conclude that the lacrimal gland is able to secrete isotretinoin in addition to retinol and that, in animals and patients treated systemically with isotretinoin, the ocular surface is exposed to the drug via the tear film.


Biology and data-intensive scientific discovery in the beginning of the 21st century.
The life sciences are poised at the beginning of a paradigm-changing evolution in the way scientific questions are answered. Data-Intensive Science (DIS) promise to provide new ways of approaching scientific challenges and answering questions. This article is a summary of the life sciences issues and challenges as discussed in the DIS workshop in Seattle, September 19-20, 2010.


Establishment of a total liquid ventilation system using saline-based oxygen micro/nano-bubble dispersions in rats.
Micro/nano-bubbles are practical nanomaterials designed to increase the gas content in liquids. We attempted to use oxygen micro/nano-bubble dispersions as an oxygen-rich liquid as a means for total liquid ventilation. To determine the oxygen content in the bubble dispersion, a new method based on a spectrophotometric change between oxy- and deoxy-hemoglobin was established. The oxygen micro/nano-bubble dispersion was supplied to an experimental total ventilation liquid in anesthetic rats. Though the amount of dissolving oxygen was as low as 6 mg/L in physiological saline, the oxygen content in the oxygen micro/nano-bubble dispersion was increased to 45 mg/L. The positive correlation between the oxygen content and the life-saving time under liquid ventilation clearly indicates that the life-saving time is prolonged by increasing the oxygen content in the oxygen micro/nano-bubble dispersion. This is the first report indicating that the oxygen micro/nano-bubbles containing a sufficient amount of oxygen are useful in producing oxygen-rich liquid for the process of liquid ventilation.


Assessment of serum chromogranin-A as prognostic factor in high-risk prostate cancer.
The presence of neuroendocrine differentiation may play a key role in androgen-independent tumor progression. The prognostic significance of plasma chromogranin-A (CgA) was assessed in a series of consecutive patients with high-risk prostate cancer (PCa). Twenty-three patients presenting high-risk PCa and 8 healthy individuals, as control group, had their blood samples collected to evaluate CgA, free and total prostate specific antigen, and free and total testosterone in a pilot study. The correlations of serum CgA levels with PSA, testosterone, Gleason score, number of foci of hypercaptation in bone scan, age, and outcomes were evaluated at baseline and after 12 months. Patients with PCa had significantly higher levels of plasma CgA (mean, 8.7; range, 1.9-73) than healthy patients (mean, 3.45; range, 0.6-5.6), P = 0.02. Analyzing only the patients group through correlation of the ranks, it was observed that CgA has low, insignificant correlations with PSA (P = 0.07) and with metastatic extension (P = 0.09). No association was found between the plasma CgA levels and the Gleason score (P = 0.20), age (P = 0.15), or disease progression (P = 0.27). The serum levels of CgA were significantly increased in the group with PCa compared with the healthy group. However, there were low correlations between serum CgA and known prognostic factors (such as total and free PSA, age, Gleason score, and bone metastases) or clinical deterioration. Although future studies are needed with larger samples and longer follow-up, the presented data envisage a limited role to serum CgA as high-risk PCa prognostic factor.


Elevated serum gamma-glutamyltransferase activity is associated with increased risk of mortality, incident type 2 diabetes, cardiovascular events, chronic kidney disease and cancer - a narrative review.
Abstract In clinical practice, increased serum gamma-glutamyltransferase (GGT) activity is usually interpreted as a marker of alcohol abuse and liver dysfunction. The knowledge of the GGT's physiological functions has expanded and several important epidemiological associations have been reported. This review examines evidence for an association of high normal serum GGT enzyme activity, mostly within the reference range, with the risk of mortality and major vascular (i.e., cardiovascular morbidity and mortality) and non-vascular outcomes (i.e., incident type 2 diabetes, chronic kidney disease and cancer), independent of alcohol consumption and other prognostic factors.


Chemosensors for pyrophosphate.
The selective detection of the anion pyrophosphate (PPi) is a major research focus. PPi is a biologically important target because it is the product of ATP hydrolysis under cellular conditions, and because it is involved in DNA replication catalyzed by DNA polymerase, its detection is being investigated as a real-time DNA sequencing method. In addition, within the past decade, the ability to detect PPi has become important in cancer research. In general, the sensing of anions in aqueous solution requires a strong affinity for anions in water as well as the ability to convert anion recognition into a fluorescent or colorimetric signal. Among the variety of methods for detecting PPi, fluorescent chemosensors and colorimetric sensors for PPi have attracted considerable attention during the past 10 years. Compared with the recognition of metal ions, it is much more challenging to selectively recognize anions in an aqueous system due to the strong hydration effects of anions. Consequently, the design of PPi sensors requires the following: an understanding of the molecular recognition between PPi and the binding sites, the desired solubility in aqueous solutions, the communicating and signaling mechanism, and most importantly, selectivity for PPi over other anions such as AMP and ADP, and particularly phosphate and ATP. This Account classifies chemosensors for PPi according to topological and structural characteristics. Types of chemosensors investigated and reported in this study include those that contain metal ion complexes, metal complexes combined with excimers, those that function with a displacement approach, and those based on hydrogen-bonding interaction. Thus far, the utilization of a metal ion complex as a binding site for PPi has been the most successful strategy. The strong binding affinity between metal ions and PPi allows the detection of PPi in a 100% aqueous solution. We have demonstrated that carefully designed receptors can distinguish between PPi and ATP based on their different total anionic charge densities. We have also demonstrated that a PPi metal ion complex sensor has a bioanalytical application. This sensor can be used in a simple and quick, one-step, homogeneous phase detection method in order to confirm DNA amplification after polymerase chain reaction (PCR).


Stromal transforming growth factor-beta signaling mediates prostatic response to androgen ablation by paracrine Wnt activity.
Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-beta (TGF-beta) occurs after androgen ablation. To determine the role of TGF-beta on prostate response to androgen ablation, conditional TGF-beta type II receptor knockout mouse models of the epithelia (Tgfbr2(NKX3.1KO)) and stromal fibroblasts (Tgfbr2(fspKO)) were used. After castration, the prostates of Tgfbr2(NKX3.1KO) mice had apoptosis levels similar to those expected for control Tgfbr2(floxE2/floxE2) mice. Prostates of Tgfbr2(fspKO) mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2(floxE2/floxE2) prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2(floxE2/floxE2) and Tgfbr2(fspKO) stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2(fspKO) prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2(fspKO)-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-beta, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival.


Measuring the Value of New Drugs: Validity and Reliability of 4 Value Assessment Frameworks in the Oncology Setting.
Several organizations have developed frameworks to systematically assess the value of new drugs. To evaluate the convergent validity and interrater reliability of 4 value frameworks to understand the extent to which these tools can facilitate value-based treatment decisions in oncology. Eight panelists used the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), Institute for Clinical and Economic Review (ICER), and National Comprehensive Cancer Network (NCCN) frameworks to conduct value assessments of 15 drugs for advanced lung and breast cancers and castration-refractory prostate cancer. Panelists received instructions and published clinical data required to complete the assessments, assigning each drug a numeric or letter score. Kendall's Coefficient of Concordance for Ranks (Kendall's W) was used to measure convergent validity by cancer type among the 4 frameworks. Intraclass correlation coefficients (ICCs) were used to measure interrater reliability for each framework across cancers. Panelists were surveyed on their experiences. Kendall's W across all 4 frameworks for breast, lung, and prostate cancer drugs was 0.560 (P= 0.010), 0.562 (P = 0.010), and 0.920 (P < 0.001), respectively. Pairwise, Kendall's W for breast cancer drugs was highest for ESMO-ICER and ICER-NCCN (W = 0.950, P = 0.019 for both pairs) and lowest for ASCO-NCCN (W = 0.300, P = 0.748). For lung cancer drugs, W was highest pairwise for ESMO-ICER (W = 0.974, P = 0.007) and lowest for ASCO-NCCN (W = 0.218, P = 0.839); for prostate cancer drugs, pairwise W was highest for ICER-NCCN (W = 1.000, P < 0.001) and lowest for ESMO-ICER and ESMO-NCCN (W = 0.900, P = 0.052 for both pairs). When ranking drugs on distinct framework subdomains, Kendall's W among breast cancer drugs was highest for certainty (ICER, NCCN: W = 0.908, P = 0.046) and lowest for clinical benefit (ASCO, ESMO, NCCN: W = 0.345, P = 0.436). Among lung cancer drugs, W was highest for toxicity (ASCO, ESMO, NCCN: W = 0. 944, P < 0.001) and lowest for certainty (ICER, NCCN: W = 0.230, P = 0.827); and among prostate cancer drugs, it was highest for quality of life (ASCO, ESMO: W = 0.986, P = 0.003) and lowest for toxicity (ASCO, ESMO, NCCN: W = 0.200, P = 0.711). ICC (95% CI) for ASCO, ESMO, ICER, and NCCN were 0.800 (0.660-0.913), 0.818 (0.686-0.921), 0.652 (0.466-0.834), and 0.153 (0.045-0.371), respectively. When scores were rescaled to 0-100, NCCN provided the narrowest band of scores. When asked about their experiences using the ASCO, ESMO, ICER, and NCCN frameworks, panelists generally agreed that the frameworks were logically organized and reasonably easy to use, with NCCN rated somewhat easier. Convergent validity among the ASCO, ESMO, ICER, and NCCN frameworks was fair to excellent, increasing with clinical benefit subdomain concordance and simplicity of drug trial data. Interrater reliability, highest for ASCO and ESMO, improved with clarity of instructions and specificity of score definitions. Continued use, analyses, and refinements of these frameworks will bring us closer to the ultimate goal of using value-based treatment decisions to improve patient care and outcomes. This work was funded by Eisai Inc. Copher and Knoth are employees of Eisai Inc. Bentley, Lee, Zambrano, and Broder are employees of Partnership for Health Analytic Research, a health services research company paid by Eisai Inc. to conduct this research. For this study, Cohen, Huynh, and Neville report fees from Partnership for Health Analytic Research. Outside of this study, Cohen receives grants and direct consulting fees from various companies that manufacture and market pharmaceuticals. Mei reports a grant from Eisai Inc. during this study. The other authors have no disclosures to report. Study concept and design were contributed by Bentley and Broder, with assistance from Elkin and Cohen. Bentley took the lead in data collection, along with Elkin, Huynh, Mukherjea, Neville, Mei, Popescu, Lee, and Zambrano. Data interpretation was performed by Bentley and Broder, along with Elkin, Cohen, Copher, and Knoth. The manuscript was written primarily by Bentley, along with Elkin and Broder, and revised by Bentley, Broder, Elkin, Cohen, Copher, and Knoth. Select components of this work's methods were presented at ISPOR 19th Annual European Congress held in Vienna, Austria, October 29-November 2, 2016, and Society for Medical Decision Making 38th Annual North American Meeting held in Vancouver, Canada, October 23-26, 2016.


Is There a Role for Preoperative 5 Alpha Reductase Inhibitors in Reducing Prostate Vascularity and Blood Loss?
Benign prostatic hyperplasia (BPH) and the related medical problems are a major burden as health care costs and as a cause of patient morbidity. The introduction of medical therapy largely offered an alternative to surgical therapy, and these medications have been linked with multiple positive BPH-related outcomes. With ubiquitous use, however, a variety of adverse side effects and unsupported claims to these medications have been reported both in scientific literature and popular press. The use of 5 alpha reductase inhibitors (5ARIs) to reduce recurrent bleeding due to BPH is a reasonable option for men with recurrent trips to the physician or hospital. After a largely anecdotal report of their use in the preoperative period to reduce bleeding during BPH surgery, there was interest in the use of 5ARIs for this indication considering the effusive bleeding that can occur during BPH-related surgery, a dreaded and not uncommon complication. While the pathophysiology for the use of 5ARI to reduce BPH-related bleeding is sound, the actual clinical outcomes still require scrutiny to determine if the efficacy is both scientifically valid and clinically significant. This report will review the current literature on this topic and make attempts to determine if the use of a 5ARI before BPH-related surgery should be encouraged.


Post-infectious bronchiolitis obliterans in children.
To review publications about the main features of post-infectious bronchiolitis obliterans and its history, etiology, epidemiology, risk factors, pathogenesis, histological findings, clinical presentation, complementary tests, diagnostic criteria, differential diagnosis, treatment and prognosis. Non-systematic review of MEDLINE and LILACS databases and selection of 66 most relevant studies. In the post-infectious bronchiolitis obliterans there is an insult to respiratory epithelial cells, and its clinical severity is associated with the degree of lesion and inflammation. Diagnosis is made according to clinical signs and symptoms, by exclusion of main differential diagnoses and with the aid of complementary tests. High resolution CT, particularly images obtained during inspiration and expiration, provide information for the evaluation of the small airways. Pulmonary function tests show fixed airway obstructions and marked decrease of FEF25-75%. Treatment has not been definitely established, and corticoids have been administered as pulse therapy or by inhalation of high doses of steroids. However, data about its efficacy are scarce in the literature. Long-term prognosis is variable, and there might be either clinical improvement or deterioration into respiratory insufficiency and death. Post-infectious bronchiolitis obliterans is a disease with a high morbidity rate; it should be treated by a multidisciplinary team, and patients should be followed up for a long period of time.


[Petrous bone tumors: primary non-Hodgkin lymphoma of the inner ear canal and cerebellopontile angle].
We report about a primary Non-Hodgkin Lymphoma (NHL) of the internal auditory canal. The only previously known manifestations of a NHL in the temporal bone have been infiltrations or hemorrhagic complications due to a late manifestation or advanced systemic disease. Involvement of both temporal bones is typical. The 60-year-old female patient complained of an acute one-sided deafness, accompanied by a high-pitched tinnitus, rotating vertigo, and paralysis of the left half of the face. We found a deafness in the left ear, spontaneous nystaxis, which was interpreted as a deficiency in excitement of the vestibular organ, and a complete peripheral facial paralysis. Diagnostic imaging studies revealed a large, intrameatal solid mass in the temporal bone, measuring 1.2 x 0.8 cm. Histologic examination after translabyrinthine tumor removal demonstrated a centroblastic Non-Hodgkin Lymphoma. The following extensive interdisciplinary staging examination showed no other tumor manifestations; the CSF analysis was negative. The uniqueness of this case lies in the detection of a primary nongeneralized centroblastic lymphoma of the internal auditory canal. In contrast to infiltrations of systemic NHL in the same location, in which the advanced disease is responsible for the bad prognosis, this isolated lymphoma of the internal auditory canal seems analogous to extranodal MALT Lymphomas with a better prognosis. The primary extranodal NHL of the temporal bone, not reported in previous studies, is discussed with regard to clinical symptoms, differential diagnoses, and therapeutic strategies.


Medical Debt and Related Financial Consequences Among Older African American and White Adults.
To evaluate African American-White differences in medical debt among older adults and the extent to which economic and health factors explained these. We used nationally representative data from the 2007 and 2010 US Health Tracking Household Survey (n = 5838) and computed population-based estimates of medical debt attributable to economic and health factors with adjustment for age, gender, marital status, and education. African Americans had 2.6 times higher odds of medical debt (odds ratio = 2.62; 95% confidence interval = 1.85, 3.72) than did Whites. Health status explained 22.8% of the observed disparity, and income and insurance explained 19.4%. These factors combined explained 42.4% of the observed disparity. In addition, African Americans were more likely to be contacted by a collection agency and to borrow money because of medical debt, whereas Whites were more likely to use savings. African Americans incur substantial medical debt compared with Whites, and more than 40% of this is mediated by health status, income, and insurance disparities. Public health implications. In Medicare, low-income beneficiaries, especially low-income African Americans with poor health status, should be protected from the unintended financial consequences of cost-reduction strategies.


Dynamic perfusion computerized tomography in cerebral vasospasm following aneurysmal subarachnoid hemorrhage: a comparison with technetium-99m-labeled ethyl cysteinate dimer-single-photon emission computerized tomography.
The aim of this study was to correlate cerebral blood flow (CBF) and mean transient time (MTT) measured on dynamic perfusion computerized tomography (CT) with CBF using (99m)Tc ethyl cysteinate dimer-single-photon emission computerized tomography (SPECT) in patients with cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). Thirty-five patients with vasospasm following aneurysmal SAH (12 men and 23 women with a mean age of 49.3 +/- 10.1 years) underwent imaging studies; thus, 35 perfusion CT scans and 35 SPECT images were available for comparison. The CBF and MTT values in 12 different brain regions were defined relative to the interhemispheric occipital cortex values using perfusion CT scans and were compared with qualitative relative (rel)CBF estimated on SPECT images. In brain regions with normal, mild (relCBF 71-85%), moderate (relCBF 50-70%), and severe (relCBF < 50%) hypoperfusion on SPECT, the mean relCBF values measured on perfusion CT were 1.01 +/- 0.08, 0.82 +/- 0.22, 0.6 +/- 0.15, and 0.32 +/- 0.08, respectively (p < 0.0001); the mean relMTT values were 1.04 +/- 0.14, 1.4 +/- 0.31, 2.16 +/- 0.46, and 3.3 +/- 0.54, respectively (p < 0.0001). All but one brain region (30 regions) with severe hypoperfusion on SPECT images demonstrated relCBF values less than 0.6 and relMTT values greater than 2.5 on perfusion CT scans. Relative CBF and MTT values on perfusion CT showed a high concordance rate with estimated relCBF on SPECT in patients with vasospasm following aneurysmal SAH. Given its logistical advantages, perfusion CT may be a valuable method of assessing perfusion abnormality in the acute setting of vasospasm and in patients with an unstable condition following aneurysmal SAH.


Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion.
In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen® Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.


[Optically controlled bone marrow removal in osteomyelitis treatment].
The present paper reports on the various methods of treating osteomyelitis and the development of an aid to visual monitoring of surgical findings in long bones. With this instrument a true-color assessment of bone cavities is possible without major cortical fenestrations causing impairment of biomechanics. On the basis of examples of treatment of various cases of hematogenous and chronic osteomyelitis, as well as infected total replacements, the potential of this instrument and the necessity of painstaking and visually monitored removal of marrow from the cavities is demonstrated. Results so far, after 6 years of use, admit the conclusion that the chances of success in the treatment of osteomyelitis are increased with this instrument.


An Entamoeba histolytica LINE/SINE pair inserts at common target sites cleaved by the restriction enzyme-like LINE-encoded endonuclease.
The non-long-terminal-repeat (non-LTR) retrotransposons (also called long interspersed repetitive elements [LINEs]) are among the oldest retroelements. Here we describe the properties of such an element from a primitive protozoan parasite, Entamoeba histolytica, that infects the human gut. This 4.8-kb element, called EhLINE1, is present in about 140 copies dispersed throughout the genome. The element belongs to the R4 clade of non-LTR elements. It has a centrally located reverse transcriptase domain and a restriction enzyme-like endonuclease (EN) domain at the carboxy terminus. We have cloned and expressed a 794-bp fragment containing the EN domain in Escherichia coli. The purified protein could nick supercoiled pBluescript DNA to yield open circular and linear DNAs. The conserved PDX(12-14)D motif was required for activity. Genomic sequences flanking the sites of insertion of EhLINE1 and the putative partner short interspersed repetitive element (SINE), EhSINE1, were analyzed. Both elements resulted in short target site duplications (TSD) upon insertion. A common feature was the presence of a short T-rich stretch just upstream of the TSD in most insertion sites. By sequence analysis an empty target site in the E. histolytica genome, known to be occupied by EhSINE1, was identified. When a 176-bp fragment containing the empty site was used as a substrate for EN, it was prominently nicked on the bottom strand at the precise point of insertion of EhSINE1, showing that this SINE could use the LINE-encoded endonuclease for its insertion. The nick on the bottom strand was toward the right of the TSD, which is uncommon. The lack of strict target site-specificity of the restriction enzyme-like EN encoded by EhLINE1 is also exceptional. A model for retrotransposition of EhLINE1/SINE1 is presented.


Translocated c-myc oncogene of Burkitt lymphoma is transcribed in plasma cells and repressed in lymphoblastoid cells.
We examined somatic cell hybrids between Burkitt lymphoma cells and either human lymphoblastoid cells or mouse plasmacytoma cells for the expression of the translocated c-myc oncogene. The results of this study indicate that the translocated c-myc oncogene is transcribed in plasma cells but is repressed in lymphoblastoid cells. Thus, the factors necessary for translocated c-myc transcription are present in plasma cells and Burkitt lymphoma cells but are absent or inactive in lymphoblastoid cells. Since the distance between the rearranged immunoglobulin loci and the c-myc oncogene can even exceed 30-50 kilobases, we speculate that the translocated c-myc oncogene is under the transcriptional control of enhancer-like elements capable of acting over long distances. The activity of this long-range enhancer may depend on the interaction with transacting factors that are active in plasma cells and in Burkitt lymphoma cells but are not active in lymphoblastoid cells. We also examined the transcription of the first exon of the c-myc oncogene, which becomes separated from the second and third exon because of the chromosomal break involving the first intron. This exon is transcribed at high levels in ST486 Burkitt lymphoma cells with the t(8;14) chromosome translocation. Hybrids between lymphoblastoid and ST486 cells expressed high levels of transcripts of the first exon, whereas hybrids between plasma cells and ST486 cells did not. Thus, transcription of the separated first exon can be enhanced in lymphoblastoid and Burkitt lymphoma cells because of its close proximity to the heavy chain enhancer that is normally located between the joining and the switch region of the C mu gene. Such enhancement, however, does not occur in plasma cells, possibly because these cells are able to suppress completely the c-myc oncogene, unless it has been placed in the proximity of a rearranged immunoglobulin constant region gene.


Theoretical investigation of the coupling between hydrogen-atom transfer and stacking interaction in adenine-thymine dimers.
Three different dimers of the adenine-thymine (A-T) base pair are studied to point out the changes of important properties (structure, atomic charge, energy and so on) induced by coupling between the movement of the atoms in the hydrogen bonds and the stacking interaction. The comparison of these results with those for the A-T monomer system explains the role of the stacking interaction in the hydrogen-atom transfer in this biologically important base pair. The results support the idea that this coupling depends on the exact dimer considered and is different for the N-N and N-O hydrogen bonds. In particular, the correlation between the hydrogen transfer and the stacking interaction is more relevant for the N-N bridge than for the N-O one. Also, the two different mechanisms of two-hydrogen transfer (step by step and concerted) can be modified by the stacking interaction between the base pairs.


Staphylococcus aureus nasal colonization in preoperative orthopaedic outpatients.
Nasal colonization with Staphylococcus aureus (SA) increases the risk of surgical site infection (SSI). We first (1) determined the prevalence of asymptomatic nasal colonization with SA, (2) assessed trends in methicillin resistance with time, (3) ascertained risk factors for nasal colonization; and (4) correlated SSI to nasal colonization status and procedure. We performed a cross-sectional analysis of SA nasal colonization among healthy preoperative orthopaedic outpatients between 2003-2005 who were within 2 weeks of surgery. Of 284 patients, 86 (30%) carried SA; of these, 81 (94%) were colonized with methicillin-sensitive and five (6%) with methicillin-resistant SA (MRSA). Total SA colonization increased from 25/78 (32%) in 2003 to 37/97 (38%) in 2005, and colonization with MRSA increased from 0/78 (0%) to four of 97 (4%), respectively. We found no associations between nasal carriage and demographics or procedures. Surgical site infection occurred in nine of 282 (3%), four of which were attributable to SA; these included 0/43 (0%) carriers who received decolonization with 2% mupirocin, two of 43 (4.7%) who declined decolonization, and two of 196 (1.0%) who were noncarriers. Nasal colonization with SA, including MRSA, among preoperative orthopaedic outpatients is increasing and their rates reflect community rates. Knowledge of colonization status may be important in decolonization, choosing perioperative or any subsequent empiric antibiotics.


Role of colonoscopy in patients with persistent acute diverticulitis.
To identify patients with persistent acute diverticulitis who might benefit from an early colonoscopy during their first hospitalization. All patients hospitalized between July 2000 and December 2006 for acute diverticulitis who underwent colonoscopy were included in the study. Patients were followed during hospitalization and after discharge. Patients were considered to have a persistent course of acute diverticulitis if symptoms continued after 1 wk of conventional treatment with IV antibiotics, or if symptoms recurred within 2 mo after discharge. Patients were considered to benefit from an early colonoscopy if the colonoscopy was therapeutic or if it changed a patient's outcome. Three hundred and six patients were hospitalized between July 2000 and December 2006 with the diagnosis of acute diverticulitis. Two hundred and twenty four of these were included in the study group. Twenty three patients (10.3%) fulfilled the criteria for a persistent course of acute diverticulitis. Of them, four patients (17.4%) clearly benefited from an early colonoscopy; these patients' clinical course is described. None of the patients with a regular non-persistent course demonstrated any benefit from colonoscopy. Early colonoscopy detected other significant pathology, which accounted for the clinical presentation in 17% of patients with persistent acute diverticulitis. Therefore, we believe an early colonoscopy should be considered in all patients with a persistent clinical course.