Inconsistent evidence: analysis of six national guidelines for vaginal birth after cesarean section.
Guidelines are increasingly used to direct clinical practice, with the expectation that they improve clinical outcomes and minimize health care expenditure. Several national guidelines for vaginal birth after cesarean section (VBAC) have been released or updated recently, and their range has created dilemmas for clinicians and women. The purpose of this study was to summarize the recommendations of existing guidelines and assess their quality using a standardized and validated instrument to determine which guidelines, if any, are best able to guide clinical practice. English language guidelines on VBAC were purposively selected from national and professional organizations in the United Kingdom, United States, Canada, New Zealand, and Australia. The Appraisal of Guidelines for Research and Evaluation (AGREE) instrument was applied to each guideline, and each was analyzed to determine the range and level of evidence on which it was based and the recommendations made. Six guidelines published or updated between 2004 and 2007 were examined. Only two of the six guidelines scored well overall using the AGREE instrument, and the evidence used demonstrated great variety. Most guidelines cited expert opinion and consensus as evidence for some recommendations. Reported success rates for VBAC ranged from 30 to 85 percent, and reported rates of uterine rupture ranged from 0 to 2.8 percent. VBAC guidelines are characterized by quasi-experimental evidence and consensus-based recommendations, which lead to wide variability in recommendations and undermine their usefulness in clinical practice.


Primary Squamous Cell Carcinoma of the Thyroid.
Background: Primary squamous cell carcinoma of the thyroid (PSCCT) is a rare malignancy of the head and neck, with fewer than 60 cases reported in the literature. We report a case of PSCCT and provide a brief review of the literature. Case Report: A 66-year-old female with a history of a hemithyroidectomy for a benign thyroid lesion presented with 3 months of progressively worsening compressive symptoms and shortness of breath. Physical examination revealed right-sided thyromegaly and right-sided true vocal fold immobility. Preoperative imaging with ultrasound and computed tomography scan confirmed an enlarged right thyroid, as well as right anterior cervical lymphadenopathy, subglottic stenosis, and bilateral pulmonary nodules. Fine needle aspiration of the thyroid was suggestive of carcinoma. Intraoperative findings of gross tracheal invasion during a planned completion thyroidectomy prompted limited resection and impromptu tracheotomy. Histopathologic and immunohistochemical evaluation confirmed a squamous cell carcinoma of thyroid origin. Further oncologic workup with core lung biopsy and positron emission tomography scan demonstrated metastasis to the lung and cervical spine. Palliative chemotherapy was begun, but the patient died 1 week into therapy. Conclusion: PSCCT is a rare but aggressive malignancy of the head and neck. Histopathologic and immunohistochemical evaluations are essential for diagnosis. While locoregional surgery and radiation therapy may improve the length of survival, the prognosis of patients with PSCCT is poor. Physicians should be mindful of this unique but deadly disease process, as early diagnosis and rapid treatment initiation are essential to optimize treatment outcomes.


[Regeneration of the function of the hypophyseal-gonadal system after its prolonged suppression with luliberin agonists].
The paper is concerned with the results of investigation into the nature of regeneration of function of the hypophyseo-gonadal system in 15 mature male Papio hamadryas, subjected to infusion of LH-RH agonists (buserelin, Hoechst A. G. Germany) and surfagon (All-Union Cardiology Research Center, USSR) using osmotic mini-pumps (Alzo Corp., Palo Alto, USA) for 5-16 weeks. Regeneration of this system was characterized by 3 main phases: latent; gonadal hyperfunction and return to the basal level of functioning. The time of phases was determined by a period of administration of the drug and individual features of functioning of the hypothalamo-hypophyseo-gonadal system. Unlike the sex glands, regeneration of hypophyseal gonadotropic function did not undergo the stage of hyperfunction but included the development of 2 phases of refractivity of gonadotropocytes to exogenous LH-RH, differing in the level of functional activity. Regeneration of function of the hypophyseo-gonadal system under basal conditions was followed by regeneration of a reaction of this system under the conditions of its activation.


[Effect of alcohol on the phospholipid composition of human myocardial mitochondria].
Phospholipid composition of myocardial mitochondria in persons, consuming alcohol, was characterized by a distinct increase in content of lysophospholipids (lysophosphatidyl serine, lysophosphatidyl choline, lysophosphatidyl ethanolamine) simultaneously with a decrease in content of phosphatidyl choline and phosphatidyl ethanolamine as well as by unaltered total concentration of phospholipids.


Enhancement of nonlinear effects at the degenerate band edge of two-dimensional photonic crystals.
The ability of two-dimensional (2D) photonic crystals (PC) for high enhancements of nonlinear processes is analyzed in the case of a degenerate band edge when two symmetrical diffracted beams are generated by Bragg diffraction in the 2D-PC. Calculations are performed using the very simple Bragg-coupled wave theory which only involves three coupled waves (the incident wave and the two diffracted waves) for the linear interaction. The validity of the approximation is proved for wavelengths lying at the neighborhood of the band edges of 2D-PC. Very large local-field intensities are predicted around the band-edge wavelengths, in particular for the upper band edge. Nonlinear propagation is studied through the analysis of degenerate four-wave mixing. For counterpropagating pump beams orthogonally sent onto the 2D-PC huge improvement of the phase conjugate reflectivity are predicted at least for small incidence angles of the signal beam. These results represent an improvement by a factor of 20 when compared to the case of a one-dimensional PC of the same thickness made of the same materials. As three intense phase conjugate beams are generated in the four-wave mixing interaction, the 2D-PC could be very interesting for the purpose of dense parallel optical signal processing. Moreover, the simple theoretical analysis developed in the paper can be used for any kind of 2D-PC.


[Symbiotic interactions of microorganisms during infection].
Symbiotic interactions of microorganisms during infection are reviewed. Infectious process is presented as a model system of associative symbiosis with 3 functional vectors of symbiont interactions. The principal attention is paid to microsymbiocenosis and estimation of its role during infection. Materials on population-communicative dialogue of microsymbionts are given, and their applied importance for medical-biological science is shown. Algorithm of microbial "self-non self" recognition under the control of opposite (increase/ suppression) effect of dominant-associant microbe pair on principal physiological (growth and persistence) functions of microsymbionts is presented.


Yersinia enterocolitica septicemia.
Yersinia enterocolitica was recovered from the blood of an infant with sepsis and fever but with few gastrointestinal symptoms. The age of this patient was unusual as septicemia owing to this organism has most frequently been seen in adults. Because of the absence of digestive symptoms, it is uncertain what the portal of entry of the organism might have been. Yersinia enterocolitica is not often recognized, either because of difficulties in identification or because it may not be recognized as a human pathogen.


Clinical-pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer.
Objective: Long-term survivors (LS) of non-small cell lung cancer (NSCLC) without driver alterations, displaying an overall survival (OS) of more than 3 years, comprise around 10% of cases in several series treated with chemotherapy. There are classical prognosis factors for these cases [stage, Eastern Cooperative Oncology Group (ECOG), etc.], but more data are required in the literature. In this multi-center study, we focused on LS of advanced NSCLC with OS above 36 months to perform a clinical-pathological and molecular characterization. Methods: In the first step, we conducted a clinical-pathological characterization of the patients. Afterwards, we carried out a genetic analysis by comparing LS to a sample of short-term survivors (SS) (with an OS less than 9 months). We initially used whole-genome RNA-seq to identify differentiating profiles of LS and SS, and later confirmed these with reverse transcription-polymerase chain reaction (RT-PCR) for the rest of the samples. Results: A total of 94 patients were included, who were mainly men, former smokers, having adenocarcinoma (AC)-type NSCLC with an ECOG of 0-1. We obtained an initial differential transcriptome expression, displaying 5 over- and 33 under-expressed genes involved in different pathways: namely, the secretin receptor, surfactant protein, trefoil factor 1 (TFF1), serpin, Ca-channels, and Toll-like receptor (TLRs) families. Finally, RT-PCR analysis of 40 (20 LS/20 SS) samples confirmed that four genes (surfactant proteins and SFTP) were significantly down-regulated in SS compared to LS by using an analysis of covariance (ANCOVA) model: SFTPA1 (P = 0.023), SFTPA2 (P = 0.027), SFTPB (P = 0.02), and SFTPC (P = 0.047). Conclusions: We present a sequential genetic analysis of a sample of NSCLC LS with no driver alterations, obtaining a differential RNA-seq/RT-PCR profile showing an abnormal expression of SF genes.


Chemically forced dormancy termination mimics natural dormancy progression in potato tuber meristems by reducing ABA content and modifying expression of genes involved in regulating ABA synthesis and metabolism.
The length of potato tuber dormancy depends on both the genotype and the environmental conditions during growth and storage. Abscisic acid (ABA) has been shown to play a critical role in tuber dormancy control but the mechanisms regulating ABA content during dormancy, as well as the sites of ABA synthesis, and catabolism are unknown. Recently, a temporal correlation between changes in ABA content and certain ABA biosynthetic and catabolic genes has been reported in stored field tubers during physiological dormancy progression. However, the protracted length of natural dormancy progression complicated interpretation of these data. To address this issue, in this study the synthetic dormancy-terminating agent bromoethane (BE) was used to induce rapid and highly synchronous sprouting of dormant tubers. The endogenous ABA content of tuber meristems increased 2-fold 24 h after BE treatment and then declined dramatically. By 7 d post-treatment, meristem ABA content had declined by >80%. Exogenous [(3)H]ABA was readily metabolized by isolated meristems to phaseic and dihydrophaseic acids. BE treatment resulted in an almost 2-fold increase in the rate of ABA metabolism. A differential expression of both the StNCED and StCYP707A gene family members in meristems of BE-treated tubers is consistent with a regulatory role for StNCED2 and the StCYP707A1 and StCYP707A2 genes. The present results show that the changes in ABA content observed during tuber dormancy progression are the result of a dynamic equilibrium of ABA biosynthesis and degradation that increasingly favours catabolism as dormancy progresses.


Evidence that relaxin's effects on growth and softening of the cervix are not mediated through prostaglandins in the rat.
Relaxin plays a major role in promoting the growth and softening of the cervix that occurs during the second half of pregnancy in the rat. There is limited evidence that prostaglandins play a role in cervical softening in mammalian species. Accordingly, this study was conducted to determine if prostaglandins mediate relaxin's effects on the rat cervix. To attain that objective, indomethacin was used to inhibit cyclooxygenase, the key enzyme in the conversion of arachidonic acid to prostaglandins. Twenty-six nonpregnant female rats were ovariectomized when they were 78 days old (day 1 of treatment). At ovariectomy (O), each rat was fitted with silicon tubing implants containing progesterone (P) and estrogen (E) in doses that provided blood levels similar to those during late pregnancy in rats. Rats were randomly assigned to three treatment groups. Group OPE controls (n = 8 rats) received 2 ml indomethacin vehicle (0.5% methyl cellulose, 0.025 Tween 80 in water) via gavage at 0900 h on days 8 and 9 and 0.5 ml relaxin vehicle (0.9% NaCl) s.c. at 6-h intervals from 1200 h on day 8 through 0600 h on day 10. Group OPER (n = 9 rats) was treated as group OPE except that 20 microg highly purified porcine relaxin was administered. Group OPERI (n = 9 rats) was treated as group OPER except that indomethacin was administered at a dose (20 mg/kg BW) that reduced cervical PGE2 levels by more than 90%. Between 0800 h and 1000 h on day 10, the cervices were removed, trimmed of fat, weighed, and placed in ice-cold Krebs-Ringer bicarbonate buffer, pH 7.5. Cervical extensibility (degree of softening) was determined within 4 h of tissue collection. Both the mean cervical wet weight and the mean cervical extensibility in the relaxin-treated group OPER rats were markedly greater (P < 0.01) than in the group OPE controls. Treatment with indomethacin did not diminish relaxin's effects on either cervical wet weight or cervical extensibility. In conclusion, this study provides evidence that relaxin's effects on cervical growth and softening in the rat are not mediated through prostaglandins.


Vancomycin dosage requirements among pediatric intensive care unit patients with normal renal function.
The purpose of this study was to determine a vancomycin dosage regimen among pediatric intensive care unit (PICU) patients with normal renal function resulting in desired peak and trough serum concentration and to determine the predictability of vancomycin peak concentrations based on reported trough concentrations. The medical records of all PICU patients who received vancomycin over a 12-month period were identified through a hospital computer search and were obtained from the hospital's Department of Medical Records. Demographic and laboratory data as well as the patient's vancomycin dosing history were recorded. Patients who lacked appropriately timed vancomycin peak and trough concentrations or who exhibited renal dysfunction were excluded from the study population. The optimal vancomycin dose and the predictability of peak concentrations based on trough concentrations were assessed. A total of 135 patients were identified as having received vancomycin therapy during their PICU hospitalization between June 1997 and June 1998. Fifty-nine patients were excluded due to renal dysfunction or inappropriate vancomycin concentrations resulting in 76 patients representing our study population. The initial mean dose of vancomycin was 47 mg/kg/day resulting in a mean peak and trough serum concentration of 19 and 6 microg/mL, respectively. A mean of 2.2 (range, 1 to 5) and 2.1 (range, 1 to 5) peak and trough serum concentrations were reported for each patient, respectively. A mean of 1.1 (range, 0 to 4) dosing changes per patient was noted resulting in a final mean dose of 60 mg/kg/day corresponding to a mean peak and trough serum concentration of 26 and 8 microg/mL, respectively. A vancomycin trough concentration >5 microg/mL was highly predictive for a corresponding peak concentration >20 microg/mL (P > .0001). Eighty percent of the trough concentrations <5 microg/mL were associated with peak concentrations <20 microg/mL, whereas 81% of trough concentrations >5 microg/mL were associated with corresponding peak concentrations >20 microg/mL. PICU patients required higher doses of vancomycin than are typically prescribed to achieve conventionally accepted peak and trough vancomycin serum concentrations. In the absence of renal impairment, we recommend an initial dosage regimen of 60 mg/kg/day divided every 8 hours. Vancomycin trough concentrations are highly predictive of corresponding peak concentrations and therefore may negate the need to obtain routine peak concentrations.


Pharmacokinetic drug-drug interactions in the intensive care unit - single-centre experience and literature review.
Drug-drug interactions constitute a serious health hazard in everyday clinical practice in critically ill patients. Drug-drug interactions may be pharmacokinetic or pharmacodynamic in their nature. We aimed to investigate the quantity and quality of possible drug-drug interactions, and their possible side effects in intensive care unit patients in a 12-month period. This retrospective study covered data on pharmacological treatment of 43 consecutive patients (11 females, 32 males) aged 62 ± 15 years, hospitalized between January 2015 and February 2016. Pharmacokinetic DDIs were identified and graded. Only severe and clinically important drug-drug interactions were subjected for further analysis. Median baseline SAPS III was 53 (IQR 38-67) points. Median intensive care unit stay was 12 (6-25) days. Subjects were treated with a median number of 22 (12-27) drugs. We identified 27 (16-41) possible drug-drug interactions per patient, including 3 (1-7) drug-drug interactions of a severe grade. The total number of severe and clinically important drug-drug interactions was 253 of which 227 were analyzed in detail. No possible side-effects of drug-drug interactions were identified. DDIs as well as their side-effects are challenging regarding their precise evaluation, especially due to the need for multidrug treatment in critically ill patients. Concentration-controlled therapy should be recommended, especially for treatment with vancomycin, digoxin and valproate. Pantoprazole should be a proton pump-inhibitor of choice. Drug dose modification is necessary in combined treatment with fluconazole and amiodarone or rifampicin. From a clinical point of view, the most important impact of drug-drug interactions is on antibiotic treatment effectiveness, especially with meropenem when valproate is also prescribed.


Understanding the Role of the Antioxidant System and the Tetrapyrrole Cycle in Iron Deficiency Chlorosis.
Iron deficiency chlorosis (IDC) is an abiotic stress often experienced by soybean, owing to the low solubility of iron in alkaline soils. Here, soybean lines with contrasting Fe efficiencies were analyzed to test the hypothesis that the Fe efficiency trait is linked to antioxidative stress signaling via proper management of tissue Fe accumulation and transport, which in turn influences the regulation of heme and non heme containing enzymes involved in Fe uptake and ROS scavenging. Inefficient plants displayed higher oxidative stress and lower ferric reductase activity, whereas root and leaf catalase activity were nine-fold and three-fold higher, respectively. Efficient plants do not activate their antioxidant system because there is no formation of ROS under iron deficiency; while inefficient plants are not able to deal with ROS produced under iron deficiency because ascorbate peroxidase and superoxide dismutase are not activated because of the lack of iron as a cofactor, and of heme as a constituent of those enzymes. Superoxide dismutase and peroxidase isoenzymatic regulation may play a determinant role: 10 superoxide dismutase isoenzymes were observed in both cultivars, but iron superoxide dismutase activity was only detected in efficient plants; 15 peroxidase isoenzymes were observed in the roots and trifoliate leaves of efficient and inefficient cultivars and peroxidase activity levels were only increased in roots of efficient plants.


[Reparative giant cell granuloma with orbital involvement].
A 54-year-old woman was evaluated for a left orbital mass that had been present for one year. Examination showed mild superolateral displacement of the normal left eye and a firm medical orbital mass. A complete resection of the lesion was accomplished via a combined neurosurgical, otolaryngologic and ophthalmologic superior orbital approach. Histologic features of the mass were consistent with giant-cell (reparative) granuloma. However, it has to be pointed out that fibroosseous lesions with giant-cells display similar histologic features and require clinicopathologic correlation including radiographic studies for final diagnosis.


Cross-sectional study of the health of southern African truck drivers.
Lifestyle and working conditions of truck drivers predisposes them to risk-factors associated with communicable and non-communicable diseases, but little is known about the health status of African truck driver. This study aims to assess a cross-section of truckers in South Africa to describe their health information. The study took place across three truck-stop rest areas in the South African provinces of Free State and Gauteng. Eligibility criteria included being males aged 18 years and older, full-time employment as a long-distance truck driver. A total of 614 male truck drivers participated; 384 (63%) were Zimbabwean and 325 (55%) completed high-school. The trucker survey explored demographics; working conditions; sexual, eating and sleeping behaviours; mental health status, medical history and cardiac risk-factors. Medical assessments included physical measurements, glucose and lipid measurements, ECG, carotid intima-media thickness (CIMT) and cardiac ultrasound. In the previous month, 554 (91%) participants were sexually active; 522 (86%) had sex with a regular partner; 174 (27%) with a casual partner; 87 (14%) with a sex worker. Average time driving was 10 hours/day, 20 days/month, 302 (50%) never worked night shifts and 74 (12%) worked nights approximately four times per week. 112 (18%) experienced daytime sleepiness and 59 (10%) were ever hospitalised from an accident. Forty-seven (8%, 95% CI 5.3 to 9.5) were HIV-positive, with half taking antiretrovirals. Forty-eight (8%) truckers had some moderate depression, while 21 (4%) suffered from post-traumatic stress disorder. Reported tuberculosis, myocardial infarction, and diabetes were <3%. Prominent cardiac risk-factors included smoking (n=63, 11%), consuming alcohol (>15 drinks/week) (n=54, 9%), overweight/obesity (n=417, 69%), and hypertension (n=220, 36%,95% CI 32.1 to 39.7). ECG results showed 23 (4.9%) and 29 (5.3%) drivers had left ventricular hypertrophy using the Cornell criterion and product, respectively. CIMT measurements indicated nine (4.2%) drivers had a carotid atherosclerotic plaque. This first holistic assessment of health among southern African male truck drivers demonstrates substantial addressable cardiovascular risk factors, mental health issues and sexual risk behaviours.


The effects of marathon swimming on serum leptin and plasma neuropeptide Y levels.
It seems likely that the neuropeptide Y (NPY)-leptin axis is involved in the regulation of energy expenditure in man. The purpose of this study was to observe the effect of a model of intense prolonged exercise-mediated energy expenditure (25 km swim race in 6.9-10.5 hours) on leptin and NPY concentrations in male long-distance swimmers. Sixteen long-distance swimmers (mean age 25, range 18-45 years) who took part in a 25 km sea swimming competition (Toroneos golf, Chalkidiki, Greece) participated in the study. Mean competition time was 8.5 hours (range 6.5-10.5). The participants were allowed food and beverage intake ad libitum before and throughout the 25 km race. Venous blood samples were taken prior and immediately after the race for the measurement of serum leptin and plasma NPY. Non-esterified free fatty acids (NEFFA) and glycerol levels were determined as indicators of adipose tissue lipids mobilization. Results showed that leptin levels after marathon swimming were significantly reduced (p<0.001) in all athletes. There was a statistically significant negative correlation (r=-0.812, p<0.01) between the values of leptin and glycerol just after the termination of swimming. Blood serum glycerol and free fatty acid levels were significantly increased (p<0.001) in all swimmers. Plasma NPY levels were also increased (p<0.01) in 81.2% of the swimmers. Linear regression analysis revealed a significant negative correlation between the values of leptin and NPY (r=-0.789, p<0.01). In conclusion, these data support our initial hypothesis that appropriate changes in leptin and NPY take place during marathon swimming to compensate for the negative energy balance produced due to this prolonged effort. This indicates the NPY-leptin axis involvement in the regulation of energy expenditure in man.


Exclusion and diagnosis of deep vein thrombosis in outpatients by sequential noninvasive tools.
Phlebography is the reference gold standard for the diagnosis of deep vein thrombosis (DVT), but due to its invasive nature and associated side effects it has been replaced by compression ultrasonography (CUS). Patients suspected of DVT are subjected to leg vein CUS that actually confirms DVT in only 16 to 28% of outpatients in large prospective management studies. CUS has a high positive predictive value of more than 98% for proximal DVT but usually misses calf vein thrombosis. Its negative predictive value for proximal DVT is about 97-98%, on the basis of which repeated scanning at day 7 after a negative first CUS (serial CUS) in outpatients with a first suspicion of DVT is advocated. Serial ultrasonography is costly and can be simplified and improved by the addition of clinical score and D-dimer testing. The safe exclusion of DVT by a rapid sensitive D-dimer test in combination with clinical score and/or CUS requires a negative predictive value of >99%. The negative predictive value for DVT is determined by the sensitivity of the rapid ELISA D-dimer test and the prevalence of DVT in subgroups of outpatients suspected of the condition. The prevalence of DVT in outpatients with a low, moderate and high clinical score varies widely from 3-10%, 15-30% and >70%, respectively. The combination of a low clinical score (prevalence DVT 3-5%) and a negative rapid ELISA D-dimer alone test will have a very high negative predictive value of >99.9% to exclude DVT without the need of CUS testing. The combination of a negative CUS and a negative rapid ELISA D-dimer test safely excludes DVT in patients with suspected DVT irrespective of the clinical score. The combination of a negative CUS, a low clinical score and a positive ELISA D-dimer but <1000 ng/ml excludes DVT with a negative predictive value of >99% without the need to repeat CUS. Patients with a negative CUS, scan but a positive ELISA D-dimer, and a moderate or high clinical score are still at risk with a probability of DVT of 3-5% and 20-30%, respectively and are thus candidates for repeated ultrasound scanning. The rapid ELISA D-dimer first followed by risk-based no, single or repeated CUS will be the most cost-effective strategy.


NuSAP is essential for chromatin-induced spindle formation during early embryogenesis.
Mitotic spindle assembly is mediated by two processes: a centrosomal and a chromosomal pathway. RanGTP regulates the latter process by releasing microtubule-associated proteins from inhibitory complexes. NuSAP, a microtubule- and DNA-binding protein, is a target of RanGTP and promotes the formation of microtubules near chromosomes. However, the contribution of NuSAP to cell proliferation in vivo is unknown. Here, we demonstrate that the expression of NuSAP highly correlates with cell proliferation during embryogenesis and adult life, making it a reliable marker of proliferating cells. Additionally, we show that NuSAP deficiency in mice leads to early embryonic lethality. Spindle assembly in NuSAP-deficient cells is highly inefficient and chromosomes remain dispersed in the mitotic cytoplasm. As a result of sustained spindle checkpoint activity, the cells are unable to progress through mitosis, eventually leading to caspase activation and apoptotic cell death. Together, our findings demonstrate that NuSAP is essential for proliferation of embryonic cells and, simultaneously, they underscore the importance of chromatin-induced spindle assembly.


Yellow ooze.
This is a piece from the annual Yale Internal Medicine Residency Program's Writers' Workshop, which began in 2003. Abraham Verghese and Richard Selzer, among the best known physician-writers in the United States, have served as workshop leaders, teaching the craft of writing to more than 35 residents. In designing the workshop, Anna B. Reisman, assistant professor in the Department of Internal Medicine at the Yale University School of Medicine and VA Connecticut Health Care System, and Dr. Asghar Rastegar had the goal of making participants better physicians by providing a creative outlet for reflection. The stories and essays written by the Writers' Workshop participants present a range of experiences, real and imagined, and take readers deep into the minds of young doctors trying to make sense of what they do.


Expression of interleukin-16 by human epithelial cells. Inhibition by dexamethasone.
Production of chemoattractants by bronchial epithelial cells may contribute to the local accumulation of inflammatory cells in patients with bronchial asthma and other pulmonary diseases. Recently, interleukin (IL)-16 (lymphocyte chemoattractant factor) was reported to be a potent chemotactic stimulus for CD4(+) T lymphocytes and eosinophils, the types of leukocyte found in the proximity of bronchial epithelium in asthmatic individuals. To test the possibility that bronchial epithelial cells produce IL-16, we analyzed RNA and culture supernatants from the human bronchial epithelial cell line BEAS-2B, using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. BEAS-2B constitutively expressed IL-16 messenger RNA (mRNA) and protein; IL-16 expression was significantly upregulated in a concentration-dependent manner within 24 h by stimulation with histamine, IL-1beta, or tumor necrosis factor (TNF)-alpha whereas interferon-gamma did not significantly increase IL-16. Findings in BEAS-2B cells were confirmed in primary bronchial epithelial cells. Using TA cloning, IL-16 was cloned from BEAS-2B airway epithelial cells. Sequence analysis confirmed its near identity with lymphocyte-derived IL-16. The combination of IL-1beta and TNF-alpha had an additive effect on IL-16 expression. This combination of cytokines also had a priming effect on histamine-induced IL-16 mRNA expression, which was observed within 24 h and which increased to at least 48 h after stimulation. The IL-16 expression induced by histamine and combined cytokines was significantly inhibited by pretreatment with the protein synthesis inhibitor cycloheximide (10 microg/ml). Pretreatment with dexamethasone also significantly suppressed the expression of IL-16, in a concentration-dependent manner. Sputum samples from asthmatic subjects were found to have higher levels of IL-16 than were samples from subjects with other pulmonary inflammatory diseases. These findings suggest that bronchial epithelial cells have the capacity to produce IL-16 after stimulation with histamine, IL-1beta, and TNF-alpha, and raise the possibility that epithelium-derived IL-16 may play a role in recruitment of eosinophils and CD4(+) T lymphocytes in the airways. Downregulation of IL-16 expression by dexamethasone suggests that glucocorticoids may inhibit airway inflammation partly by suppressing the synthesis of inflammatory cytokines including IL-16.


Effect of sevelamer on mineral and lipid abnormalities in hemodialysis patients.
We conducted a prospective study in hemodialysis patients to assess the safety and efficacy of sevelamer, a non-absorbable phosphate binding polymer free of calcium and aluminum, in lowering serum phosphorus, serum intact parathyroid hormone, and serum lipids. Phosphate binders were discontinued during a two-week washout period. We considered the patients with serum phosphorus levels more than 1.8 mmol/l during the washout period eligible for treatment. Sevelamer was administered to 29 hemodialysis patients for eight weeks. Sevelamer reduced the mean serum phosphorus levels to 1.8 mmol/l by the end of the eight-week treatment period (p < 0.0001). Two weeks after the completion of the sevelamer study the mean serum phosphorus levels increased to 2.09 mmol/l (p < 0.02). Mean serum calcium levels did not significantly change during sevelamer trial. Mean serum intact parathyroid hormone declined from 501 pg/ml at the start of the study to 425 pg/l at the end of the eight week treatment period (p = 0.05). In addition, sevelamer reduced the mean serum total cholesterol levels from 5.22 mmol/l to 4.26 mmol/l (p < 0.0001), and the mean serum low density lipoprotein cholesterol from 3.56 mmol/l to 2.79 mmol/l (p < 0.0001) at the end of the study. However, the mean serum levels of high density lipoprotein and triglycerides did not change during the study period. We conclude that sevelamer can control serum phosphorus and reduce the level of intact parathyroid hormone and cholesterol without inducing hypercalcemia or other side effects.


Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion.
Oranges are rich sources of flavonoids that are bioactive and may protect against age-related diseases. The absorption of orange flavanones may be affected by factors such as processing and subject anthropometric variables, and the bioactivity of the absorbed phytochemicals depends on how they are metabolised during absorption. In a randomised cross-over study, twenty subjects consumed a single portion of orange fruit (150 g) or juice (300 g) that contained the flavanones narirutin and hesperidin, and an additional 109 subjects across a broad age range (18-80 years) consumed the juice. Flavanone metabolites were measured in regularly collected samples of plasma and urine. After consumption of fruit or juice, flavanone conjugates, but not the aglycones, were detected in plasma and urine. The flavanone conjugates were shown to include the 7- and 4'-O-monoglucuronides of naringenin, the 7- and 3'-O-monoglucuronides of hesperetin, two hesperetin diglucuronides and a hesperetin sulfo-glucuronide, but no aglycones or rutinosides. Analysis of the plasma pharmacokinetic and urinary excretion data on a dose-adjusted basis indicated no difference in absorption or excretion of either flavanone between the fruit and juice matrices. In the extended urinary excretion dataset the individual variation was very large (range 0-59 % urinary yield). There was a small but significant (P < 0.05) decrease in the excretion of hesperetin (but not naringenin) with increasing age (P < 0.05), but the effects of sex, BMI and contraceptive pill use were shown not to be associated with the variation in flavanone excretion.


Discriminative and convergent validity of strain elastography for detecting tendinopathy within the supraspinatus tendon: a cross-sectional study.
We aimed to explore the discriminative validity of ultrasound strain elastography (SEL) between patients with painful supraspinatus tendinopathy and healthy control shoulders, as well as the associations between SEL and magnetic resonance imaging (MRI), conventional ultrasound (tendon thickness), and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). Thirty patients with shoulder pain and MRI-verified supraspinatus tendinopathy and 30 healthy control shoulders (no pain) were examined using SEL, MRI, and conventional ultrasound of the supraspinatus tendon. SEL variables included raw data, ratios between the deltoid muscle and supraspinatus tendon (deltoid ratio), color rating, and presence of red/yellow lesions (middle, worst part, and total tendon). Statistically significant increases in odds ratios for being symptomatic (increased softening) were seen for all raw data variables, corresponding to 3.978 (95% confidence interval [CI], 1.414-11.197) for middle, 4.602 (95% CI, 1.536-13.788) for worst, and 4.865 (95% CI, 1.406-16.836) for total tendon, and 1.260 (95% CI, 1.027-1.545) for the deltoid ratio (worst), adjusted for sex and body mass index (BMI). Tendon thickness was not associated with SEL; however, significantly positive associations were found between raw data variables and MRI (β ≥ 0.58, P < .01), and positive associations were found between raw data variables and the DASH score (β = 0.01, P ≤ .04), adjusted for sex and BMI. Raw data variables and the deltoid ratio (worst) discriminated between patients with painful supraspinatus tendinopathy and healthy control shoulders when adjusted for sex and BMI. Associations were statistically significant for raw data variables and MRI or DASH score when adjusted for sex and BMI. Further studies are needed to understand SEL and the role of sex and BMI, including the responsiveness of SEL.


Systemic effects of acute cigarette smoke exposure in mice.
Cigarette smoke (CS) causes both pulmonary and extrapulmonary disorders. To determine the pulmonary and extrapulmonary effects of acute CS exposure in regard to inflammation, oxidative stress and DNA damage. Mice were exposed to CS for 10 days and then their lungs, heart, liver, pancreas, kidneys, gastrocnemius muscle and subcutaneous (inguinal and flank) and visceral (retroperitoneum and periuterus) adipose tissues were excised. Bronchoalveolar lavage fluid samples were obtained for differential cell analysis. Inflammatory cell infiltration of the tissues was assessed by immunohistochemistry for Mac-3(+) cells, F4/80(+) cells and CD45(+) cells. Oxidative stress was determined by immunohistochemistry for thymidine glycol (a marker of DNA peroxidation) and 4-hydroxy hexenal (a marker of lipid peroxidation), by enzyme-linked immunosorbent assay for protein carbonyls (a marker of protein peroxidation) and by measurements of enzyme activities of glutathione peroxidase, superoxide dismutase and catalase. DNA double-strand breaks were assessed by immunohistochemistry for γH2AX. CS exposure-induced inflammatory cell infiltration, oxidative stress and DNA damage in the lung. Neither inflammatory cell infiltration nor DNA damage was observed in any extrapulmonary organs. However, oxidative stress was increased in the heart and inguinal adipose tissue. Induction of inflammatory cell infiltration and DNA damage by acute CS exposure was confined to the lung. However, an increased oxidative burden occurred in the heart and some adipose tissue, as well as in the lung. Although extrapulmonary effects of CS are relatively modest compared with the pulmonary effects, some extrapulmonary organs are vulnerable to CS-induced oxidative stress.


Use of whole blood in the measurement of neutrophil migration.
A whole-blood method was used for measuring neutrophil migration in micropore membrane. The method is reproducible (coefficient of variation (CV) 10.3% and 9.8% in two normal individuals tested repeatedly) and can be performed on an 0.25 ml lithium heparin blood sample. Migration is independent of leucocyte and erythrocyte counts and is comparable with that obtained for separated cells. As in separated cell techniques, cytochalasin and casein respectively inhibit and stimulate neutrophil migration. The technique is of value when testing large numbers of samples and when only small volumes of blood can be obtained, for example, in neonates.


Automated global structure extraction for effective local building block processing in XCS.
Learning Classifier Systems (LCSs), such as the accuracy-based XCS, evolve distributed problem solutions represented by a population of rules. During evolution, features are specialized, propagated, and recombined to provide increasingly accurate subsolutions. Recently, it was shown that, as in conventional genetic algorithms (GAs), some problems require efficient processing of subsets of features to find problem solutions efficiently. In such problems, standard variation operators of genetic and evolutionary algorithms used in LCSs suffer from potential disruption of groups of interacting features, resulting in poor performance. This paper introduces efficient crossover operators to XCS by incorporating techniques derived from competent GAs: the extended compact GA (ECGA) and the Bayesian optimization algorithm (BOA). Instead of simple crossover operators such as uniform crossover or one-point crossover, ECGA or BOA-derived mechanisms are used to build a probabilistic model of the global population and to generate offspring classifiers locally using the model. Several offspring generation variations are introduced and evaluated. The results show that it is possible to achieve performance similar to runs with an informed crossover operator that is specifically designed to yield ideal problem-dependent exploration, exploiting provided problem structure information. Thus, we create the first competent LCSs, XCS/ECGA and XCS/BOA, that detect dependency structures online and propagate corresponding lower-level dependency structures effectively without any information about these structures given in advance.


Terahertz phase jumps for ultra-sensitive graphene plasmon sensing.
Phase behavior of the reflected terahertz radiation (THz) under surface plasmon resonance (SPR) supported by doped graphene has been comprehensively investigated via theoretical analysis with simulation verifications. For a TM-polarized wave, the dependence of the phase on the angle of incidence has a region with an abrupt jump-like change. We found in particular that the resonance phase dependence would change from step-like contour to Fano lineshape when the system passed through the optimum SPR conditions (i.e., R = 0) in terahertz regime. Monitoring the transformation could provide ultrahigh-sensitive label-free detection of biomolecules. Importantly, the characteristic of phase jumps as a readout response to achieve refractive index sensing that outperforms traditional terahertz-amplitude-based attenuated total reflection (ATR) spectroscopy is valuable. The results demonstrated a high figure of merit (FOM) of up to 171, based on the terahertz phase information. Moreover, the sensing range could be tuned by changing the surface conductivity of graphene via high doping levels or with few-layer graphene. These terahertz phase response characteristics of graphene plasmon are promising for tunable ultra-sensitivity (bio)chemical sensing applications.


Unenhanced helical CT of ureterolithiasis: incidence of secondary urinary tract findings.
To determine the incidence of secondary signs of obstruction in patients with ureteral stones on unenhanced helical CT scans. Three hundred consecutive patients with suspected renal colic referred by the emergency department for an unenhanced helical CT scan were evaluated. One hundred and thirty two patients with ureteric calculi were viewed prospectively for the secondary signs of obstruction, which include hydronephrosis, hydroureter, perinephric stranding, nephromegaly, periureteral edema and difference in attenuation between acutely obstructed kidney and unobstructed kidney. In the evaluated 132 patients, calculi were present in the proximal, mid and distal ureter in 12, 18 and 112 patients respectively. Four patients had a contralateral ureteric calculus while none had more than one ureteric calculus on the same site. Concurrent renal parenchymal calculi were seen in 40 patients with ureteric stones, hydronephrosis in 69, hydroureter in 93 and perinephric strandings in 66 patients. Nephromegaly was seen in 15 and periureteral edema in 42 patients. In 87% patients with acute renal obstruction, the affected kidney was less dense than the unobstructed kidney. Only 5 of 132 patients had no associated findings. Unenhanced helical CT has rapidly become the imaging technique of choice in evaluating patients with acute ureteric colic. The secondary signs of obstruction provide supportive evidence of acute obstructive process.


Clinical Outcomes and Multidisciplinary Patterns of Failure for Olfactory Neuroblastoma: The Ohio State Experience.
Purpose Olfactory neuroblastoma (ONB) is a rare head and neck cancer believed to be originated from neural crest cells of the olfactory membrane located in the roof of the nasal fossa. This study evaluates clinical outcomes and failure patterns in ONB patients of those patients treated with surgical resection at a high-volume tertiary cancer center. Methods and Materials Thirty-nine ONB patients who underwent surgical resection at our institution from 1996 to 2017 were retrospectively identified. Univariate, multivariate, and survival analysis were calculated using Cox regression analysis and Kaplan-Meier log-rank. Results Median follow-up time was 59 months (range: 5.2-236 months). The median overall survival (OS) and disease-free survival (DFS) for the entire cohort were 15 and 7.6 years, respectively. The 5-year cumulative OS and DFS were 83 and 72%, respectively. The 5-year OS for low Hyams grade (LHG) versus high Hyams grade (HHG) was 95 versus 61% ( p = 0.041). LHG was found in 66% of the early Kadish stage patients compared with 28% in the advanced Kadish stage patients ( p = 0.057). On multivariate analysis, HHG and positive node status predicted for worse OS and only HHG predicted for worse DFS. Of note, five patients (all Kadish stage A) who received surgical resection alone had no observed deaths or recurrences with a median follow-up of 44 months (range: 5-235 months). Conclusion In this retrospective cohort, patients with positive nodes or HHG have significantly worse clinical outcomes. Future studies should explore treatment intensification for HHG or positive nodes.


Inflammatory responses to hepatitis B virus vaccine in healthy term infants.
Hepatitis B virus (HBV) infection continues to be a serious global health problem. During the course of HBV vaccination, we observed C-reactive protein (CRP) elevation in term infants without sepsis. Therefore, we prospectively studied interleukin-6 (IL-6) and CRP responses to HBV immunization. In 70 healthy term infants without signs and symptoms of sepsis and sepsis risk factors, IL-6, CRP, and white blood cell count levels were determined before and 24 h after immunization. Significant increases in CRP levels were seen 24 h after vaccination (p < 0.001). Although CRP levels of 22 infants at second evaluation were above the cutoff level for sepsis (4.82 mg/L), they had no clinical signs and symptoms of sepsis. After 48-72 h, CRP levels of these infants returned to normal levels with no blood culture positivity. our study showed that HBV vaccine is responsible for CRP elevation in term infants after vaccination at birth. To the best of our knowledge, this is the first study evaluating CRP response to HBV vaccine at birth in term infants. We suggest that this response should be considered in differentiation of early neonatal sepsis to avoid unnecessary antibiotic use.


HELLP Syndrome, Thrombotic Thrombocytopenic Purpura or Both: Appraising the Complex Association and Proposing a Stepwise Practical Plan for Differential Diagnosis.
Both thrombocytopenia and microangiopathic hemolytic anemia (TMA) are seen in thrombotic thrombocytopenic purpura (TTP) and HELLP syndrome among other disorders during pregnancy. Although both share backgrounds of endothelial injury and microvascular thrombi and some clinical features, yet, they have different etiologies and courses. In late pregnancy, differentiating between these two pathologies can be extremely difficult due to the immense overlap in clinical and laboratory manifestations and this becomes only possible with the use of specific markers as ADAMTS-13, when available. Hereby, we describe three cases that may exemplify the complex association between PE/HELLP syndrome and TTP. The first case presented with PE/HELLP syndrome and deteriorated postpartum to improve on plasmapheresis. The second case was a known TTP patient who developed superimposed PE/HELLP at 27 weeks gestation which necessitated emergent delivery. The third was a case of preeclampsia that progressed to HELLP syndrome on day 2 postpartum but 3 days later was complicated by TTP. HELLP syndrome and TTP can co-exist, but can also complicate one another. In the absence of instantaneous results of ADAMTS-13 and when diagnosis with clinical judgement alone cannot be done with certainty, a short trial-plasmapheresis could be attempted with close observation of the immediate response. This stepwise approach might prove to be a valuable tool when integrated in the usual workup of clinical and laboratory evaluation both before and after delivery.


Persistent dysphagia after laser uvulopalatoplasty: a videoradiographic study of pharyngeal function.
In a follow-up study of 79 patients two years after laser uvulopalatoplasty 21 (27%) reported persistent postoperative dysphagia, with aspiration symptoms in 22%. None of the patients had suffered from recurrent pneumonia. A total of 4% of the patients regretted the treatment because of their dysphagia problems. The objective of this study was to examine oral and pharyngeal function videoradiographically during swallowing in the patients with persistent dysphagia, to determine whether the subjective symptoms of dysphagia correlated with objective signs of pharyngeal dysfunction. Pharyngeal function during swallowing was deviant in 76% of the dysphagic patients. In 52% of the dysphagic patients premature leakage of bolus down to different levels of the pharynx, from the tongue base to sinus piriformis, was observed before the swallowing reflex was elicited. In the dysphagic patients substantial bolus retention was observed on the epiglottis or in the valleculae alter the propagation wave had passed (43%) as well as epiglottal dysmotility (24%). Of the dysphagic patients, 10% could not avoid aspiration during the examination. These findings could explain the symptoms reported by the patients.


Anti-inflammatory drugs in the vascular response to burn injury.
Within 24 hours after a full-thickness burn injury, predictable alterations occur in the dermal vasculature. At the immediate site of injury, vessels lose patency. In the periphery, vasodilation and increased permeability become widespread. A variety of interventions were employed to prevent these vascular sequelae. While systemic treatment, immediately after burn trauma, with hydrocortisone or the non-steroidal anti-inflammatory compound indomethacin, was ineffective in preventing vascular alteration, treatments with other NSAI agents such as ibuprofen and imidazole were effective in preventing microvascular occlusion. In addition, utilizing standard radioimmunoassay techniques, the concentrations of the metabolites of two potent eicosanoids, thromboxane and prostacyclin, were measured from fluid collected in the implanted wound chambers. Following full-thickness burns, the synthesis and release of thromboxane were inhibited by indomethacin, imidazole, and ibuprofen. Furthermore, indomethacin and ibuprofen, but not imidazole, blocked the synthesis and release of prostacyclin into wound fluid. Significantly, ibuprofen was effective in preserving the dermal vasculature, even when administration was delayed as long as 6 hours after burn trauma. Pharmacologic actions not associated with the production of thromboxane or prostacyclin appear responsible for the protective effects of ibuprofen during burn injury. Such findings do not support an important role for either thromboxane or prostacyclin in the development of vascular alterations following burn injury.


A conjugative 'plasmid' lacking autonomous replication.
Attempts were made to isolate open and covalently closed circular DNA from strains containing the IncJ plasmids. All of the methods tried were unsuccessful. It was shown that the IncJ plasmid R391 can integrate into the Escherichia coli K12 chromosome and can mobilize chromosomal markers from a single origin in an orientated manner. It is proposed that the IncJ plasmids are integrated in the chromosome for most, if not all, of their existence and this explains the inability to isolate plasmid DNA from strains containing them.


In vivo inosine protects alveolar epithelial type 2 cells against hyperoxia-induced DNA damage through MAP kinase signaling.
Inosine, a naturally occurring purine with anti-inflammatory properties, was assessed as a possible modulator of hyperoxic damage to the pulmonary alveolar epithelium. Rats were treated with inosine, 200 mg/kg ip, twice daily during 48-h exposure to >90% oxygen. The alveolar epithelial type 2 cells (AEC2) were then isolated and cultured. AEC2 isolated from inosine-treated hyperoxic rats had less DNA damage and had increased antioxidant status compared with AEC2 from hyperoxic rats. Inosine treatment during hyperoxia also reduced the proportion of AEC2 in S and G2/M phases of the cell cycle and increased levels of the DNA repair enzyme 8-oxoguanine DNA glycosylase. Bronchoalveolar lavage (BAL) recovered from hyperoxic, inosine-treated rats contained threefold higher levels of active transforming growth factor-beta than BAL from rats exposed to hyperoxia alone, and Smad2 was activated in AEC2 isolated from these animals. ERK1/2 was activated both in freshly isolated and 24-h-cultured AEC2 by in vivo inosine treatment, whereas blockade of the MAPK pathway in vitro reduced the protective effect of in the vivo inosine treatment. Together, the data suggest that inosine treatment during hyperoxic exposure results in protective signaling mediated through pathways downstream of MEK. Thus inosine may deserve further evaluation for its potential to reduce hyperoxic damage to the pulmonary alveolar epithelium.


Treatment of Valgus-Impacted and Nondisplaced Femoral Neck Fragility Fractures in the Elderly.
As the life expectancy of the worldwide population increases, the number of hip fractures in the elderly cohort is expected to grow. It is important for surgeons to critically analyze available treatment options for these injuries, with the goal of optimizing outcomes and minimizing complications. Femoral neck fractures make up approximately half of all hip fractures. Nonoperative treatment of valgus-impacted and nondisplaced (Garden I and II) femoral neck fractures has high rates of secondary displacement, osteonecrosis, and nonunion; only patients with notable risk for perioperative complications are treated nonoperatively. Surgical intervention is the standard of care, with options including internal fixation (IF) with multiple cancellous screws or a sliding hip screw, hemiarthroplasty, or total hip arthroplasty. Patients with a posterior tilt of greater than 20° have a high rate of revision surgery when treated with IF and may benefit from primary arthroplasty. Furthermore, primary arthroplasty has demonstrated lower revision surgery rates and equivalent postoperative mortality when compared with IF. Surgeons should be aware of the functional outcomes, complications, revision surgery rates, and mortality rates associated with each treatment modality to make a patient-specific decision regarding their care.


Syntheses of 4'-thioribonucleosides and thermodynamic stability and crystal structure of RNA oligomers with incorporated 4'-thiocytosine.
A facile synthetic route for the 4'-thioribonucleoside building block (4'S)N (N = U, C, A and G) with the ribose O4' replaced by sulfur is presented. Conversion of l-lyxose to 1,5-di-O-acetyl-2,3-di-O-benzoyl-4-thio-d-ribofuranose was achieved via an efficient four-step synthesis with high yield. Conversion of the thiosugar into the four ribonucleoside phosphoramidite building blocks was accomplished with additional four steps in each case. Incorporation of 4'-thiocytidines into oligoribonucleotides improved the thermal stability of the corresponding duplexes by approximately 1 degrees C per modification, irrespective of whether the strand contained a single modification or a consecutive stretch of (4'S)C residues. The gain in thermodynamic stability is comparable to that observed with oligoribonucleotides containing 2'-O-methylated residues. To establish potential conformational changes in RNA as a result of the 4'-thio modification and to better understand the origins of the observed stability changes, the crystal structure of the oligonucleotide 5'-r(CC(4'S)CCGGGG) was determined and analyzed using the previously solved structure of the native RNA octamer as a reference. The two 4'-thioriboses adopt conformations that are very similar to the C3'-endo pucker observed for the corresponding sugars in the native duplex. Subtle changes in the local geometry of the modified duplex are mostly due to the larger radius of sulfur compared to oxygen or appear to be lattice-induced. The significantly increased RNA affinity of 4'-thio-modified RNA relative to RNA, and the relatively minor conformational changes caused by the modification render this nucleic acid analog an interesting candidate for in vitro and in vivo applications, including use in RNA interference (RNAi), antisense, ribozyme, decoy and aptamer technologies.


From Calvin Klein to Paris Hilton and MySpace: adolescents, sex, and the media.
In the absence of effective sex education at home or school, the media have become important sources of sexual information for adolescents in the United States. Mainstream media inundate teenagers with sexual images and innuendoes. In the most recent content analysis of American primetime TV, more than three-fourths of the shows had sexual content; yet less than 15% contained any references to responsible sexuality, abstinence, the risk of pregnancy, or the risk of sexually transmitted infections. Dozens of studies attest to the power of the media to influence teenagers' beliefs and attitudes about sex. Three longitudinal studies have all found that adolescents exposed to more sexual content are more likely to begin having sexual intercourse earlier than their peers who see or hear less about sex in the media. The media could become part of the solution as well as part of the problem - if there were more responsible portrayals of human sex and more widespread advertising of birth control products.


Integrating subsistence practice and species distribution modeling: assessing invasive elodea's potential impact on Native Alaskan subsistence of Chinook salmon and whitefish.
Alaska has one of the most rapidly changing climates on earth and is experiencing an accelerated rate of human disturbance, including resource extraction and transportation infrastructure development. Combined, these factors increase the state's vulnerability to biological invasion, which can have acute negative impacts on ecological integrity and subsistence practices. Of growing concern is the spread of Alaska's first documented freshwater aquatic invasive plant Elodea spp. (elodea). In this study, we modeled the suitable habitat of elodea using global and state-specific species occurrence records and environmental variables, in concert with an ensemble of model algorithms. Furthermore, we sought to incorporate local subsistence concerns by using Native Alaskan knowledge and available statewide subsistence harvest data to assess the potential threat posed by elodea to Chinook salmon (Oncorhynchus tshawytscha) and whitefish (Coregonus nelsonii) subsistence. State models were applied to future climate (2040-2059) using five general circulation models best suited for Alaska. Model evaluations indicated that our results had moderate to strong predictability, with area under the receiver-operating characteristic curve values above 0.80 and classification accuracies ranging from 66 to 89 %. State models provided a more robust assessment of elodea habitat suitability. These ensembles revealed different levels of management concern statewide, based on the interaction of fish subsistence patterns, known spawning and rearing sites, and elodea habitat suitability, thus highlighting regions with additional need for targeted monitoring. Our results suggest that this approach can hold great utility for invasion risk assessments and better facilitate the inclusion of local stakeholder concerns in conservation planning and management.


Virtual reality simulation training improve diagnostic knee arthroscopy and meniscectomy skills: a prospective transfer validity study.
Limited data exist on the actual transfer of skills learned using a virtual reality (VR) simulator for arthroscopy training because studies mainly focused on VR performance improvement and not on transfer to real word (transfer validity). The purpose of this single-blinded, controlled trial was to objectively investigate transfer validity in the context of initial knee arthroscopy training. For this study, 36 junior resident orthopaedic surgeons (postgraduate year one and year two) without prior experience in arthroscopic surgery were enrolled to receive standard knee arthroscopy surgery training (NON-VR group) or standard training plus training on a hybrid virtual reality knee arthroscopy simulator (1 h/month) (VR group). At inclusion, all participants completed a questionnaire on their current arthroscopic technical skills. After 6 months of training, both groups performed three exercises that were evaluated independently by two blinded trainers: i) arthroscopic partial meniscectomy on a bench-top knee simulator; ii) supervised diagnostic knee arthroscopy on a cadaveric knee; and iii) supervised knee partial meniscectomy on a cadaveric knee. Training level was determined with the Arthroscopic Surgical Skill Evaluation Tool (ASSET) score. Overall, performance (ASSET scores) was better in the VR group than NON-VR group (difference in the global scores: p < 0.001, in bench-top meniscectomy scores: p = 0.03, in diagnostic knee arthroscopy on a cadaveric knee scores: p = 0.04, and in partial meniscectomy on a cadaveric knee scores: p = 0.02). Subgroup analysis by postgraduate year showed that the year-one NON-VR subgroup performed worse than the other subgroups, regardless of the exercise. This study showed the transferability of the technical skills acquired by novice residents on a hybrid virtual reality simulator to the bench-top and cadaveric models. Surgical skill acquired with a VR arthroscopy surgical simulator might safely improve arthroscopy competences in the operating room, also helping to standardise resident training and follow their progress.


Alternative protein encapsulation with MOFs: overcoming the elusive mineralization of HKUST-1 in water.
Protein encapsulation by in situ formation of MOFs is a valuable strategy to immobilise and protect these bioentities. However the required biocompatible conditions limits the scope of MOFs under investigation, particularly in the case of hydrolytically unstable MOFs such as HKUST-1. We report alternative synthetic procedures to obtain protein@HKUST-1 biocomposites from related Cu-BTC dense biocomposites. pH dependent dense phase precursors are first obtained and their transformations into HKUST-1 are characterized. Encapsulation efficiency is affected by the protein's nature, and can be modulated by the sequential or simultaneous addition of MOF precursors.


Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts.
The repolarization phase of cardiac action potential is prone to aberrant excitation that is common in cardiac patients. Here, we demonstrate that this phase is markedly sensitive to Ca2+ because of the surprising existence of a Ca2+-activated K+ currents in cardiac cells. The current was revealed using recording conditions that preserved endogenous Ca2+ buffers. The Ca2+-activated K+ current is expressed differentially in atria compared with ventricles. Because of the significant contribution of the current toward membrane repolarization in cardiac myocytes, alterations of the current magnitude precipitate abnormal action potential profiles. We confirmed the presence of a small conductance Ca2+-activated K+ channel subtype (SK2) in human and mouse cardiac myocytes using Western blot analysis and reverse transcription-polymerase chain reaction and have cloned SK2 channels from human atria, mouse atria, and ventricles. Because of the marked differential expression of SK2 channels in the heart, specific ligands for Ca2+-activated K+ currents may offer a unique therapeutic opportunity to modify atrial cells without interfering with ventricular myocytes.


B cells and plasma cells in coronaries of chronically rejected cardiac transplants.
BACKGROUND.: Previously, we reported that transcripts of immunoglobulins were increased in coronary arteries dissected from cardiac transplants with arteriopathy, but the prevelance and patterns of B cell and plasma cell infiltration in cardiac allografts has not been documented. METHODS.: In this study, we documented the frequency and distribution of B cells and plasma cells in 16 cardiac transplants with advanced chronic rejection that were explanted during a second transplant procedure. Coronary arteries with pathologically confirmed allograft vasculopathy and controls with native atherosclerosis were immunohistologically stained for markers of T cells, B cells, plasma cells, IgG subclasses, C4d, CD21, and CXCL13. RESULTS.: We found that B cells and plasma cells were prevalent in most of the samples analyzed (14 of 16) and were distributed in three patterns: adventitial nodules, diffuse adventitial infiltrates, and neointimal infiltrates. These cells were found most frequently in nodules, some of which had distinct compartmentalization and granular C4d deposits on follicular dendritic cells (FDCs) that typify tertiary lymphoid nodules. FDCs also stained for CD21 and CXCL13. Diffuse infiltrates of B cells and plasma cells were found in fibrotic areas of the neointima and adventitia. Only a minority of control coronaries with atherosclerosis contained B cells. CONCLUSIONS.: B cells and plasma cell infiltrates are consistent findings in and around coronary arteries with allograft vasculopathy and are significantly more frequent than in coronaries with native atherosclerosis. The presence of C4d on FDCs in tertiary lymphoid nodules suggests active antigen presentation.


Induced motion: isolation and dissociation of egocentric and vection-entrained components.
Induced motion (IM) is illusory motion of a stationary test target opposite to the direction of the real motion of the inducing stimulus. We define egocentric IM as an apparent motion of the test target relative to the observer, and vection-entrained IM as an apparent motion of a stationary object along with an apparent motion of the self (vection) induced by the same stimulus. These two forms of IM are often confounded, and tests for distinguishing between them have not been devised. We have devised such tests. Our test for egocentric IM relies on evidence that this form of IM is due mainly to a misregistration of eye movements when optokinetic nystagmus (OKN) is inhibited, and on evidence that OKN is evoked only by stimuli in the plane of convergence. Our test for vection-entrained IM relies on evidence that vection is evoked only by the more distant of two superimposed inducing stimuli. Thus we found egocentric IM to be induced without vection or vection-entrained IM when subjects converged on a foreground moving display with a stationary display in the background, and vection-entrained IM to be induced without egocentric IM when subjects converged on a stationary-foreground display with a moving display in the background. The two types of IM were evoked in opposite directions at the same time when subjects converged on a foreground moving display while a background display moved in the opposite direction. The two forms of IM showed no signs of interaction, and we conclude that they rely on independent motion mechanisms that operate within distinct frames of reference. A control experiment suggested that the depth adjacency effect in IM is determined by the depth adjacency of the inducing stimulus to convergence, not just to the test target.


SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation.
The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhanced sensitivity to IR-induced cell death. Knock out of SERPINB3 sensitizes cells to a greater extent than cisplatin, the current standard of care. IR in SERPINB3 deficient cervical carcinoma cells induces predominantly necrotic cell death, with biochemical and cellular features of lysoptosis. Rescue with wild-type SERPINB3 or a reactive site loop mutant indicates that protease inhibitory activity is required to protect cervical tumor cells from radiation-induced death. Transcriptomics analysis of primary cervix tumor samples and genetic knock out demonstrates a role for the lysosomal protease cathepsin L in radiation-induced cell death in SERPINB3 knock-out cells. These data support targeting of SERPINB3 and lysoptosis to treat radioresistant cervical cancers.


Delineation of key XRCC4/Ligase IV interfaces for targeted disruption of non-homologous end joining DNA repair.
Efficient DNA repair mechanisms frequently limit the effectiveness of chemotherapeutic agents that act through DNA damaging mechanisms. Consequently, proteins involved in DNA repair have increasingly become attractive targets of high-throughput screening initiatives to identify modulators of these pathways. Disruption of the XRCC4-Ligase IV interaction provides a novel means to efficiently halt repair of mammalian DNA double strand break repair; however; the extreme affinity of these proteins presents a major obstacle for drug discovery. A better understanding of the interaction surfaces is needed to provide a more specific target for inhibitor studies. To clearly define key interface(s) of Ligase IV necessary for interaction with XRCC4, we developed a competitive displacement assay using ESI-MS/MS and determined the minimal inhibitory fragment of the XRCC4-interacting region (XIR) capable of disrupting a complex of XRCC4/XIR. Disruption of a single helix (helix 2) within the helix-loop-helix clamp of Ligase IV was sufficient to displace XIR from a preformed complex. Dose-dependent response curves for the disruption of the complex by either helix 2 or helix-loop-helix fragments revealed that potency of inhibition was greater for the larger helix-loop-helix peptide. Our results suggest a susceptibility to inhibition at the interface of helix 2 and future studies would benefit from targeting this surface of Ligase IV to identify modulators that disrupt its interaction with XRCC4. Furthermore, helix 1 and loop regions of the helix-loop-helix clamp provide secondary target surfaces to identify adjuvant compounds that could be used in combination to more efficiently inhibit XRCC4/Ligase IV complex formation and DNA repair.


Bi-aryl Analogues of Salicylic Acids: Design, Synthesis and SAR Study to Ameliorate Endoplasmic Reticulum Stress.
Endoplasmic reticulum (ER) stress condition is characterized as the accumulation of misfolded or unfolded proteins in lumen of ER. This condition has been implicated in various diseases and pathologies including β-cell apoptosis, Alzheimer's disease and atherosclerosis. We have reported that hydroxynaphthoic acids (HNA), naphthalene analogues of salicylic acid (SA), reduced ER stress. In this study, we explored structural modification to bi-aryl analogues of SA. Palladium-catalyzed cross-coupling was applied to synthesize bi-aryl analogues of SA. Anti-ER stress activity was monitored by using our cell-based assay system where ER stress is induced by tunicamycin. To monitor ER stress markers, ER stress was induced physiologically relevant palmitate system. Many analogues decreased ER stress signal induced by tunicamycin. Compounds creating dihedral angle between Ar group and SA moiety generally increased the activity but gave some cytotoxicity to indicate the crucial role of flat conformation of aromatic region. The best compound (16e) showed up to almost 6-fold and 90-fold better activity than 3-HNA and tauro-ursodeoxycholic acid, positive controls, respectively. ER stress markers such as p-PERK and p-JNK were accordingly decreased in Western blotting upon treatment of 16e under palmitate-induced condition. Anti-ER stress activity and toxicity profile of bi-aryl analogues of SA could provide a novel platform for potential therapy for protein misfolding diseases.


Most patients with abdominal aortic aneurysm are not suitable for endovascular repair using currently approved bifurcated stent-grafts.
Strict morphologic criteria must be used for patient selection to achieve durable success with endovascular aortic aneurysm repair (EVAR). The goal of this study was to assess morphologic suitability (MS) of abdominal aortic aneurysms (AAAs) for 2 currently approved bifurcated stent grafts and identify reasons for exclusion from EVAR. The authors reviewed the electronic charts of 1,795 consecutive patients who were diagnosed as having AAA between January 1999 and July 2001 at their institution. Three hundred and twenty patients had an AAA with a diameter of > or = 5.0 cm, measured on computed tomography (CT). The records of 301 patients, 254 men, 47 women, with a mean age of 74 years were available for review, and these patients constituted the study cohort. Criteria used for MS included a proximal neck length > or = 15 mm; neck diameter between 18 and 26 mm; neck angulation < or = 60 degrees ; common or external iliac artery (CIA or EIA) diameters of 7-16 mm and 8-13 mm, respectively, for AneuRx (Medtronic Ave, Santa Rosa, CA) and Ancure (Guidant Cardiac and Vascular Division, Menlo Park, CA) bifurcated grafts. AAAs were suitable for AneuRx device in 14% of patients (43 of 301; 95% CI = 11-19%) and for Ancure in 5% (16 of 301; 95% CI = 3.1-9%). The main reason for exclusion was an inadequate proximal aortic neck (73%). The neck was too short in 49.5%, too wide in 64% and badly angulated in 12% of the patients. Iliac artery morphology precluded EVAR with AneuRx and Ancure devices in 52% and 80%. Both CIAs were too wide for EVAR in 43% and 77%, respectively. When iliac artery diameter < or = 20 mm was accepted, iliac suitability for AneuRx increased from 49% to 70% and overall suitability increased from 14% to 20%. When more permissive criteria were used for MS (neck length > or = 10 mm, neck diameter < or = 30 mm, CIA < or = 20), 39% of patients became candidates for EVAR. More than three fourths of the patients with an AAA > or = 5.0 cm in size, seen in a tertiary referral center, are morphologically not suitable for EVAR using 2 currently approved bifurcated endografts. The main reasons for exclusion are a short or wide proximal aortic neck. Considerable changes in size of the devices and in proximal attachment techniques have to occur before most AAAs will be suitable for EVAR.


Chemical magnetoreception: bird cryptochrome 1a is excited by blue light and forms long-lived radical-pairs.
Cryptochromes (Cry) have been suggested to form the basis of light-dependent magnetic compass orientation in birds. However, to function as magnetic compass sensors, the cryptochromes of migratory birds must possess a number of key biophysical characteristics. Most importantly, absorption of blue light must produce radical pairs with lifetimes longer than about a microsecond. Cryptochrome 1a (gwCry1a) and the photolyase-homology-region of Cry1 (gwCry1-PHR) from the migratory garden warbler were recombinantly expressed and purified from a baculovirus/Sf9 cell expression system. Transient absorption measurements show that these flavoproteins are indeed excited by light in the blue spectral range leading to the formation of radicals with millisecond lifetimes. These biophysical characteristics suggest that gwCry1a is ideally suited as a primary light-mediated, radical-pair-based magnetic compass receptor.


Educational action in the rehabilitation of severe acquired brain injuries: the role of self-awareness.
Severe acquired brain injuries (ABI) cause a range of short-or long-term limitations in physical and neuropsychological abilities. The aim of rehabilitation is to promote the harmonious development of the individual through collaboration between medical and educational sciences, involved in the educability of the whole person, in which the aim is not only functional recovery but also social-reintegration. This "functional synergy" permits the development of the person, and establishes an indissoluble link between functions and attitudes, thus allowing the achievement of the greater possible autonomy. In this way classical and pedagogical rehabilitation may be combined in a single concept of educational action. To realize this integrated educational process it is important to evaluate and promote awareness development, based on the possibilities of brain plasticity and on the presence of multiple intelligences skillfully intertwined each other. Therefore, self-awareness plays a prime role in educational actions for the rehabilitation of persons with severe ABI.


Prognostic value of serum albumin level in patients with diffuse large B cell lymphoma.
To investigate the prognostic value of serum albumin (SA) levels before chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) after receiving chemotherapy. This is a retrospective study, and 127 patients with DLBCL including 71 males (55.9%) and 56 females (44.1%) were included. Patients' gender, age, Ann Arbor staging, eastern cooperative oncology group (ECOG) score, treatment options, international prognostic index, response rate, overall survival (OS), and progression-free survival (PFS) were obtained for statistical analysis. Univariate analysis showed that SA≤34 g/L, Ann Arbor III-IV, B symptoms, ECOG≥2, and bone marrow involvement suggest a poor prognosis in patients with DLBCL. Patients with persistent SA>34 g/L had significantly longer OS than patients with persistent SA≤34 g/L (P=0.020). Multivariate analysis showed that SA≤34 g/L (HR=0.48, 95% CI=0.26-0.90, P=0.022) and R-CHOP-like treatment regimen (HR=0.43, 95% CI=0.24-0.76, P=0.004) are independent factors that could affect the prognosis of patients with DLBCL. SA can be used as an indicator of prognosis in patients with DLBCL before the first chemotherapy. DLBCL patients with SA≤34 g/L are associated with short OS and poor prognosis, which may potentially provide guidance for the clinician to pay more attention to this population before the first chemotherapy.


Block Copolymer-Templated, Single-Step Synthesis of Transition Metal Oxide Nanostructures for Sensing Applications.
The synthesis of transition metal oxide nanostructures, thanks to their high surface-to-volume ratio and the resulting large fraction of surface atoms with high catalytic activity, is of prime importance for the development of new sensors and catalytic materials. Here, we report an economical, time-efficient, and easily scalable method of fabricating nanowires composed of vanadium, chromium, manganese, iron, and cobalt oxides by employing simultaneous block copolymer (BCP) self-assembly and selective sequestration of metal-organic acetylacetonate complexes within one of the BCP blocks. We discuss the mechanism and the primary factors that are responsible for the sequestration and conformal replication of the BCP template by the inorganic material that is obtained after the polymer template is removed. X-ray photoelectron spectroscopy (XPS) and powder X-ray diffraction (PXRD) studies indicate that the metal oxidation state in the nanowires produced by plasma ashing the BCP template closely matches that of the precursor complex and that their structure is amorphous, thus requiring high-temperature annealing in order to sinter them into a crystalline form. Finally, we demonstrate how the developed nanowire array fabrication scheme can be used to rapidly pattern a multilayered iron oxide nanomesh, which we then used to construct a prototype volatile organic compound sensor.


A preliminary study of utilization of the 1320-nm Nd:YAG laser for the treatment of acne scarring.
Multiple treatment modalities have been used for the revision of acne scarring with varying degrees of success. Nonablative laser resurfacing has recently been shown to improve the appearance of atrophic acne scars. The objective was to determine the efficacy of a 1320-nm Nd:YAG laser for the treatment of acne scars. Eight patients with facial acne scars received six monthly treatments with a 1320-nm Nd:YAG laser with built-in cryogen cooling. Results were evaluated by objective and patient assessment using a 6-point improvement scale: 1=no improvement, 6=80% to 100% improvement. Acne scar improvement was statistically significant at both the 5-month and 1-year marks. Mean improvement by objective assessment was 3.9 points (p=0.002) at 5 months and 4.3 points (p=0.011) at 1 years. The mean acne scar improvement by patient assessment was 3.6 points (p=0.002) at 5 months. The 1320-nm Nd:YAG laser with cryogen cooling significantly improves the appearance of acne scarring.


Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study.
Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021). We analyzed type/timing/duration of supplement use related to traditional cleft categories as well as to their timing (early/late embryonic periods) and underlying embryological processes (fusion/differentiation defects). Consistent supplement use during the aetiologically relevant period (weeks 0-12 postconception) was associated with an increased risk of clefts (adjusted odds ratio 1.72, 95% confidence interval 1.19-2.49), especially of cleft lip/alveolus (3.16, 1.69-5.91). Further analysis systematically showed twofold to threefold increased risks for late differentiation defects-mainly clefts of the lip/alveolus-with no significant associations for early/late fusion defects. Effects were attributable to folic acid and not to other multivitamin components, and inclusion of partial use (not covering the complete aetiologically relevant period) generally weakened associations. In conclusion, this study presents several lines of evidence indicating that periconceptional folic acid in the Northern Netherlands is associated with an increased risk of clefts, in particular of cleft lip/alveolus. This association is strengthened by the specificity, consistency, systematic pattern, and duration of exposure-response relationship of our findings, underlining the need to evaluate public health strategies regarding folic acid and to further investigate potential adverse effects.


Tipping points in tropical tree cover: linking theory to data.
It has recently been found that the frequency distribution of remotely sensed tree cover in the tropics has three distinct modes, which seem to correspond to forest, savanna, and treeless states. This pattern has been suggested to imply that these states represent alternative attractors, and that the response of these systems to climate change would be characterized by critical transitions and hysteresis. Here, we show how this inference is contingent upon mechanisms at play. We present a simple dynamical model that can generate three alternative tree cover states (forest, savanna, and a treeless state), based on known mechanisms, and use this model to simulate patterns of tree cover under different scenarios. We use these synthetic data to show that the hysteresis inferred from remotely sensed tree cover patterns will be inflated by spatial heterogeneity of environmental conditions. On the other hand, we show that the hysteresis inferred from satellite data may actually underestimate real hysteresis in response to climate change if there exists a positive feedback between regional tree cover and precipitation. Our results also indicate that such positive feedback between vegetation and climate should cause direct shifts between forest and a treeless state (rather than through an intermediate savanna state) to become more likely. Finally, we show how directionality of historical change in conditions may bias the observed relationship between tree cover and environmental conditions.


Identification of groundwater contamination zone around a reclaimed landfill using carbon isotopes.
Chemical and isotopic analyses of groundwater from piezometers localized around a reclaimed landfill were performed in order to identify the boundaries of groundwater contamination zone. Spatial distribution of dissolved inorganic carbon (DIC) concentration and stable carbon isotopes in the groundwater was used to distinguish the piezometers localized within the contaminated aquifer. Background groundwater was characterized by low DIC concentration (from 1.8 to 5.0 mmol/L) and negative values of δ13CDIC (from -20.6‰ to -12.4‰). Higher DIC concentrations (from 6.0 to 12.5 mmol/L) and higher values of δ13CDIC (from -10.9 to +3.6‰) were determined in groundwater contaminated by landfill leachate. The study confirmed that δ13CDIC value in the groundwater was a useful tracer in determining the extent of the contamination zone around the landfill. In general, upgradient from the landfill, carbon isotopic composition of groundwater depended on natural sources of carbon and δ13CDIC values were negative. Downgradient from the landfill, where groundwater was contaminated by the landfill leachate, δ13CDIC values were higher, sometimes even positive.


Murine monoclonal antibodies directed against human recombinant Macrophage Migration Inhibitory Factor.
Macrophage Migration Inhibitory Factor (MIF) is a crucial component of the immune system acting together with glucocorticosteroids to regulate immunity and inflammation. Understanding of its many putative functions and action mechanisms is still ambiguous. Due to the newest findings that a local MIF expression is up regulated in allograft rejection and in glomerulonephritis, an interest in MIF research is increasing and is focused on possibilities of anti-MIF treatment. In the present work new murine monoclonal antibodies (MAbs) directed against human recombinant MIF (hrMIF) are described. hrMIF protein used for the immunisation was tested for its biological activity and has evident macrophage migration inhibitory activity. The selected MAbs were purified and further characterised. They recognised MIF in a Western blot experiment after a native IEF. Anti-MIF MAb designated as M1 inhibited MIF activity in the test, which was performed in the 48 well Boyden chamber system. It is presumed that M1 MAb could be used as a potential therapeutic agent.


A simple computer program for calculating PSA recurrence in prostate cancer patients.
Prostate cancer is the most common tumor in men. The most commonly used diagnostic and tumor recurrence marker is Prostate Specific Antigen (PSA). After surgical removal or radiation treatment, PSA levels drop (PSA nadir) and subsequent elevated or increased PSA levels are indicative of recurrent disease (PSA recurrence). For clinical follow-up and local care PSA nadir and recurrence is often hand calculated for patients, which can result in the application of heterogeneous criteria. For large datasets of prostate cancer patients used in clinical studies PSA measurements are used as surrogate measures of disease progression. In these datasets a method to measure PSA recurrence is needed for the subsequent analysis of outcomes data and as such need to be applied in a uniform and reproducible manner. This method needs to be simple and reproducible, and based on known aspects of PSA biology. We have created a simple Perl-based algorithm for the calculation of post-treatment PSA outcomes results based on the initial PSA and multiple PSA values obtained after treatment. The algorithm tracks the post-surgical PSA nadir and if present, subsequent PSA recurrence. Times to PSA recurrence or recurrence free intervals are supplied in months. Use of the algorithm is demonstrated with a sample dataset from prostate cancer patients. The results are compared with hand-annotated PSA recurrence analysis. The strengths and limitations are discussed. The use of this simple PSA algorithm allows for the standardized analysis of PSA recurrence in large datasets of patients who have undergone treatment for prostate cancer. The script is freely available, and easily modifiable for desired user parameters and improvements.


A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization.
The public health burden of Enterotoxigenic Escherichia coli (ETEC) is high but no vaccine is specifically approved to prevent ETEC infections. We performed a Phase 1, dose escalation study (1-50 µg) evaluating the sublingual (SL) delivery of the double mutant heat-labile toxin LTR192G/L211A (dmLT) in 80 healthy adult volunteers. The primary objective was safety and the secondary was the immunogenicity of the dmLT. Subjects received 3 doses of dmLT at days 1, 15, and 29. Subjects receiving the first dose at each dosage level were observed overnight in a research facility. The second and third doses were administered on an outpatient basis. Data from cohorts 1-4 were used to select the cohort 5 dose (25 µg), comparing SL and oral routes. The vaccine appeared safe and well tolerated with only rare development of vomiting or diarrhea. The serum anti-dmLT IgA and IgG and neutralizing antibody responses were modest after any of the SL immunizations. Serum IgA and IgG titers were increased at the higher antigen doses (25 or 50 µg) but the percent with 4-fold increases was at best 38% for both IgA and IgG. The 4-fold increase among subjects receiving all 3 doses was 43% for both IgA and IgG. Antibody titers following oral administration were, in general, significantly higher than after SL. The frequency of IgA- or IgG-ASCs in circulation were somewhat vaccine dose dependent and were detected at a moderate level. However, antibodies in saliva or stool were rarely detected. Post-vaccination increases in T cells or cytokine production were also infrequent. The dmLT vaccine formulation evaluated here was safe but only moderately immunogenic at doses up to 50 µg when administered by the SL or oral route. Studies at higher doses with better formulations appear warranted.


[Degradation of a commercial surface-active agent, in the presence of a complementary source of carbon, by a selected bacterial colony in a marine environment].
Bacterial communities that can degrade surfactants have been selected from coastal seawaters contaminated by urban sewages. Only the linear fraction of commercial anionic surfactants was quickly degraded, and a residual fraction representing 10% of the initial concentration always remained. The highest concentrations of surfactant tolerated by these communities depend on the nature of the co-substrate and on the degree of adaptation of the selected bacteria.


Reduced content of homogalacturonan does not alter the ion-mediated increase in xylem hydraulic conductivity in tobacco.
Xylem hydraulic conductivity (K(s)) in stems of tobacco (Nicotiana tabacum) wild-type SR1 was compared to that of PG7 and PG16, two transgenic lines with increased levels of expression of the gene encoding the Aspergillus niger endopolygalacturonase (AnPGII). Activity of AnPGII removes in planta blocks of homogalacturonan (HG) with deesterified carboxyls, thus increasing the degree of neutrality of pectins. The effect of K+ was tested in increasing stem K(s) using model plants with more neutral polysaccharides in primary walls and, hence, in intervessel pit membranes. K(s) measured with deionized water was compared to that with KCl solutions at increasing concentrations (DeltaK(s), %). Plants transformed for HG degree of neutrality showed a dwarfed phenotype, but DeltaK(s) did not differ among the three experimental groups. The ion-mediated hydraulic effect saturated at a KCl concentration of 25 mm in SR1 plants. All the three tobacco lines showed DeltaK(s) of around +12.5% and +17.0% when perfused with 10 and 25 mm KCl, respectively. Because modification of HG content did not influence ion-mediated hydraulic enhancement, we suggest that pectin components other than HG, like rhamnogalacturonan-I and/or rhamnogalacturonan-II, might play important roles in the hydrogel behavior of pit membranes.


Characterization of the acetate binding pocket in the Methanosarcina thermophila acetate kinase.
Acetate kinase catalyzes the reversible magnesium-dependent synthesis of acetyl phosphate by transfer of the ATP gamma-phosphoryl group to acetate. Inspection of the crystal structure of the Methanosarcina thermophila enzyme containing only ADP revealed a solvent-accessible hydrophobic pocket formed by residues Val(93), Leu(122), Phe(179), and Pro(232) in the active site cleft, which identified a potential acetate binding site. The hypothesis that this was a binding site was further supported by alignment of all acetate kinase sequences available from databases, which showed strict conservation of all four residues, and the recent crystal structure of the M. thermophila enzyme with acetate bound in this pocket. Replacement of each residue in the pocket produced variants with K(m) values for acetate that were 7- to 26-fold greater than that of the wild type, and perturbations of this binding pocket also altered the specificity for longer-chain carboxylic acids and acetyl phosphate. The kinetic analyses of variants combined with structural modeling indicated that the pocket has roles in binding the methyl group of acetate, influencing substrate specificity, and orienting the carboxyl group. The kinetic analyses also indicated that binding of acetyl phosphate is more dependent on interactions of the phosphate group with an unidentified residue than on interactions between the methyl group and the hydrophobic pocket. The analyses also indicated that Phe(179) is essential for catalysis, possibly for domain closure. Alignments of acetate kinase, propionate kinase, and butyrate kinase sequences obtained from databases suggested that these enzymes have similar catalytic mechanisms and carboxylic acid substrate binding sites.


Preventing Infections by Encapsulated Bacteria Through Vaccine Prophylaxis in Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn's disease, is an immune-mediated, chronic-relapsing, disabling disorder which is associated with increased mortality and poor patients' quality of life. Patients with IBD are at increased risk of infections for many reasons. In fact, IBD often requires a lifelong immunosuppressive and/or biologic therapy, both commonly associated with respiratory and opportunistic infections, but also gastrointestinal, urinary tract infections, and sepsis. Moreover, impaired spleen function has been found in a considerable proportion of IBD patients, further increasing the risk of developing infections sustained by encapsulated bacteria, such as S. pneumoniae, H. influenzae, and N. meningitidis. Finally, comorbidities and surgery represent additional risk factors for these patients. Despite the availability of vaccinations against the most common serotypes of encapsulated bacteria, uncertainties still exist regarding a proper vaccination strategy and the actual effectiveness of vaccinations in this particular setting. Aim of this narrative review is to focus on the broad topic of vaccinations against encapsulated bacteria in IBD patients, discussing the clinical impact of infections, predisposing factors, vaccinations strategies, and unmet research and clinical needs.


In vivo transcriptome changes of human white blood cells in response to vitamin D.
In the vitamin D intervention study VitDbol (NCT02063334) blood samples were drawn directly before an oral bolus (2000 μg vitamin D3) and 24 h later. The focus of phase II of VitDbol was the transcriptome-wide analysis of the effects of vitamin D gene expression in human peripheral blood mononuclear cells (PBMCs). All five participants responded in an individual fashion to the bolus by increases in serum levels of the vitamin D metabolites 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). RNA sequencing identified 15.040 commonly expressed genes in PBMCs, 702 (4,7%) of which were significantly (p < 0,05) affected by the vitamin D3 bolus. KEGG pathway analysis suggested that these genes are involved in general protein translation, monocyte differentiation and cellular growth control. Previously published transcriptome-wide studies in comparable cell systems confirmed 234 of the 702 vitamin D target genes, leaving many genes, such as HLA-A and HLA-C, as novel discoveries. Interestingly, in vivo stimulated PBMCs of this study showed a larger number of common vitamin D target genes with the monocytic cell line THP-1 than with in vitro stimulated PBMCs. The expression pattern of vitamin D target genes differed significantly between individuals and the average expression change can serve as a marker for vitamin D responsiveness. In conclusion, this study demonstrates that under in vivo conditions changes in 25(OH)D3 and 1,25(OH)2D3 serum concentrations alter the expression of more than 700 vitamin D target genes in human leukocytes.