A single spiral artefact in arthropod cuticle.
Spirals are often seen in sections transverse to the axes of bumped structures in arthropod cuticle. (Sections through arthropod cornea or exocones yield excellent examples.) As arthropod cuticle has a helicoidal architecture (Bouligand, 1965), it might be expected that the spirals are a simple consequence of that structure. According to a symmetry argument, the spirals thus predicted must be double spirals. In contrast, the observed spirals are usually single. We propose that the single spirals result from an interaction between the microtome knife and the cuticle architecture. The direction of knife travel defines an orientation within the cuticle, subverting the symmetry arguments that require double spirals. Bouligand (1972) presented a model for the interaction of the knife with the cuticle. However, we offer arguments and observations show that Bouligand's model is incorrect. We argue from detailed observations of the single spiral that it is indeed a knifing artifact and that its explanation probably lies within a certain class of models. Two related models based on relative movements of cuticle components are examined via computer techniques.


Long limb Roux en Y gastric bypass revisited.
Roux-en-Y gastric bypass (RYGB) that is performed with at least a 150-cm Roux limb results in significantly greater weight loss than shorter (<100-cm) Roux limb procedures in superobese patients(BMI >50 kg/m2). Conversely, longer Roux limb procedures do not provide greater weight loss in less obese (BMI <50 kg/m2)patients. Modest elongation of the Roux limb-in the range of 150 cm to 200 cm-does not result in more frequent nutritional sequelae compared with shorter Roux limb procedures. This article discusses the current status of long limb Roux-en-Y gastric bypass in the context of weight loss, metabolic sequelae and CPT coding.


Antibiotic prophylaxis in recurrent erysipelas.
Recurrences of erysipelas are especially prevalent in patients suffering from local impairment of circulation and intervention might thus be of benefit. Therefore a prospective, randomized, open study was undertaken to evaluate whether daily antibiotic prophylaxis would reduce the risk of recurrence. Patients with venous insufficiency or lymphatic congestion who had suffered two or more episodes of erysipelas during the previous 3 years and were admitted to the Infectious Disease Department at Roslagstull Hospital, Stockholm, Sweden, between November 1988 and November 1991 were included. Fourty patients, 20 on prophylaxis and 20 controls were followed according to a life table analysis during a median time of 15 months. Phenoxymethylpenicillin was prescribed as daily prophylaxis (while erythromycin was given to patients allergic to penicillin). Recurrences of erysipelas appeared to be reduced by daily antibiotic prophylaxis but the effect was not dramatic (p = 0.06). Only in patients with a high recurrence rate continuous antibiotic prophylaxis against erysipelas is indicated.


The role of the cytoskeleton and molecular motors in endosomal dynamics.
The endocytic pathway is essential for processes that define how cells interact with their environment, including receptor signalling, cell adhesion and migration, pathogen entry, membrane protein turnover and nutrient uptake. The spatial organisation of endocytic trafficking requires motor proteins that tether membranes or transport them along the actin and microtubule cytoskeletons. Microtubules, actin filaments and motor proteins also provide force to deform and assist in the scission of membranes, thereby facilitating endosomal sorting and the generation of transport intermediates.


Risk of Mortality Associated With QT and JT Intervals at Different Levels of QRS Duration (from the Third National Health and Nutrition Examination Survey).
QT prolongation in the setting of QRS >120 ms is believed to be triggered by prolonged depolarization rather than repolarization. Hence, JT interval is suggested as an alternative to QT interval when QRS duration is prolonged. It is unclear, however, if JT and QT intervals portend similar risk of mortality for different durations of QRS. We examined the association between QT and JT, separately, with all-cause mortality across different levels of QRS duration in 8,025 participants (60 ± 13 years, 41% white and 54% women) from the Third National Health and Nutrition Examination Survey. At baseline (1986 to 1994), 486 participants (6%) had QRS duration ≥120 ms. During a follow-up of up to 18 years, 3,045 deaths (38%) occurred. There were significant nonlinear relations of QT and JT intervals with mortality (p <0.001). Hence, QT and JT were categorized as prolonged (>95th percentile), shortened (<5th percentile), and normal (reference group). In multivariate-adjusted Cox regression models, prolonged JT (hazard ratio [HR] 4.75, 95% confidence interval [CI] 1.86 to 12.11) was associated with increased risk of mortality more than prolonged QT (HR 1.50, 95% CI 1.03 to 2.17) in participants with QRS ≥120 ms (interaction p = 0.02). In participants with QRS duration <120 ms, prolonged QT and JT were equally predictive of all-cause mortality (HR 1.27, 95% CI 1.06 to 1.54, and HR 1.31, 95% CI 1.10 to 1.55, respectively). Similar patterns were observed with shortened QT and JT intervals. In conclusion, although both QT and JT intervals are predictive of mortality, JT is more predictive in the setting of QRS duration >120 ms supporting the use of JT interval in patients with prolonged QRS.


Ent-pimarane and ent-trachylobane diterpenoids from Mitrephora alba and their cytotoxicity against three human cancer cell lines.
Bioassay-guided fractionation of the hexane extract of the branches of Mitrephora alba led to the isolation of five diterpenoids: ent-8β-hydroxypimar-15-en-18-oic acid, ent-15,16-dihydroxypimar-8(14)-en-18-oic acid, ent-3β-hydroxytrachyloban-18-oic acid, ent-3β-hydroxytrachyloban-18-al and methyl ent-3β-hydroxytrachyloban-18-oate, together with five related known diterpenoids. The structures were elucidated by spectroscopic analysis and comparison with literature data. All isolated compounds were evaluated for their cytotoxic activities against three human cancer cell lines. The results showed that three ent-trachylobane diterpenes had moderate cytotoxicity against NCI-H187 cancer cells.


How Much Do Patients Value Total Hip and Knee Arthroplasty? A Prospective, Multicenter Study.
With increasing health care expenditures, reform has largely focused on cost containment, particularly in elective procedures such as total hip and knee arthroplasty (THA and TKA, respectively). The primary objective of this study is to determine what financial value patients place on these highly successful procedures. An anonymous survey was administered to 670 patients at 4 different institutions (2 private practice and 2 academic centers) in the outpatient setting over a 15-month period. Patients were asked what reimbursement a surgeon should receive for a primary total joint arthroplasty (TJA), their perception of how much Medicare actually reimburses for TJA, how much they would pay out of pocket for the procedure, and their opinion of current Medicare reimbursement rates. Of the 557 patients who participated in the survey (83% response rate), patients on average felt that orthopedic surgeons should be reimbursed $27,430 for a THA and $19,830 for a TKA. Patients would be willing to pay a significant amount of out-of-pocket costs for their procedure, mean of $14,397 for THA (50.3% of total costs) and $12,797 for TKA (46.3% of total costs). Although patients in private practice groups had higher education and household income (P < .001), patients in academic centers would be willing to pay more out-of-pocket costs ($15,922 vs $5782, P = .034 for THA, $14,419 vs $4556, P = .052 for TKA). Patients in both private practice and academic centers feel that surgeons are underpaid for primary THA and TKA. As controversy continues to surround orthopedic surgeons' participation in Medicare, many patients are still willing to pay a significant amount of out-of-pocket expenses for TJA.


Biochemical and molecular analysis of LePS2;1: a phosphate starvation induced protein phosphatase gene from tomato.
Adaptation of plants to phosphate (Pi) deficiency is a complex process involving host of biochemical changes. These changes are integrated at transcriptional level by Pi starvation mediated signal transduction pathway. Many of the signaling processes are regulated by reversible protein phosphorylation directed by protein kinases and protein phosphatases. In this study, we report the characterization of a protein phosphatase gene (LePS2;1) from tomato induced during phosphate starvation. The bacterially expressed recombinant LePS2;1 protein readily dephosphorylated a synthetic phospho-Ser/Thr peptide. Okadaic acid, an inhibitor of Ser/Thr protein phosphatases, suppressed the enzyme activity. Western blot analysis revealed the Pi starvation dependent accumulation of LePS2;1 protein. Over-expression of LePS2;1 in tomato plants resulted in increased anthocyanin accumulation and acid phosphatase activity under Pi sufficient condition. Transgenic plants exhibited distinct changes in morphology and delayed flower initiation. These results provide evidence that the protein phosphatase LePS2;1, plays an important role in phosphate starvation induced processes in tomato. To our knowledge this is the first comprehensive analysis of a protein phosphatase induced during phosphate starvation.


Effect of soft tissue tension on measurements of coronal laxity in mobile-bearing total knee arthroplasty.
The purpose of this study was to determine the effect of intraoperative coronal laxity in total knee arthroplasty on the postoperative condition. We conducted stress arthrometric studies using a Telos arthrometer on 40 knees in 36 patients. Both posterior cruciate ligament-retaining (PCLR) prostheses and posterior cruciate-sacrificing (PCLS) prostheses were placed in 20 knees respectively. All of the TKA procedures were judged clinically successful (Hospital for Special Surgery scores: PCLR 92 +/- 3 points, PCLS 91 +/- 4 points). Laxities were measured under spinal anesthesia (immediately postoperatively) and 6 months postoperatively. PCLR prostheses had an average of 2.9 degrees +/- 1.8 degrees and 3.0 degrees +/- 1.2 degrees in abduction and 4.4 degrees +/- 2.8 degrees and 3.6 degrees +/- 1.5 degrees in adduction under anesthesia and the postoperative condition. PCLS prostheses had average laxities of 3.8 degrees +/- 1.4 degrees and 3.5 degrees +/- 0.9 degrees in abduction and 4.6 degrees +/- 3.8 degrees and 4.0 degrees +/- 1.7 degrees in adduction. There were no significant differences between them. The findings suggest that surgeons should emphasize the achievement of suitable laxity under anesthesia to ensure the success of total knee arthroplasty.


1,1'-bipyrroles: synthesis and stereochemistry.
1,1'-Bipyrrole is synthesized in four steps from hydrazine. A colorless solid, mp 52 degrees C, it sublimes readily at room temperature and forms X-ray quality crystals in which the rings are not coplanar but are nearly orthogonal.


Luteal expression of factors involved in the metabolism and sensitivity to oestrogens in the dog during pregnancy and in non-pregnant cycle.
The canine corpus luteum (CL) is the main source of reproductive steroids during dioestrus in the dog and remains active even in the absence of pregnancy (non-pregnant dioestrus, physiological pseudopregnancy). Whereas the biological effects of 17β-oestradiol (E2) in the canine CL remain unclear, the transcriptional availability of oestrogen receptors, ESR1 and ESR2, as well as other modulators of local availability of E2, for example, HSD17B7 (converts oestrone into oestradiol), SULT1E1 (inactivates E2 binding capacity to its own receptors through sulphonation) and STS (reverts E2 sulphonation), were previously detected in the CL of non-pregnant bitches. The aim of the present work was to evaluate the mRNA amounts of these factors involved in luteal sensitivity and metabolism of E2 in the canine CL during the course of non-pregnant dioestrus (days 10, 20, 30, 40, 50 and 60 post-ovulation, n = 5/group) and at different stages of pregnancy (n = 4-6/group): pre-implantation (days 8-12), post-implantation (days 18-25), mid-gestation (days 35-40) and prepartum luteolysis. During pregnancy, the availability of ESR1, HSD17B7, SULT1E1 and STS decreased from mid-pregnancy to prepartum luteolysis. The main findings during non-pregnant dioestrus were as follows: increased ESR2:ESR1 ratio on days 40 and 50 after ovulation, decreasing during luteal regression (day 60); increased STS at day 30 when SULT1E1 levels decreased; increased availability of SULT1E1 transcripts during luteal regression; and decreased amounts of HSD17B7 mRNA in early dioestrus, increasing towards later stages. These results suggest that E2 signalling and biologically active local concentrations could diverge in response to time and pregnancy status of the bitch.


Massive emissions of toxic gas in the Atlantic.
Recurrent eruptions of toxic hydrogen sulphide gas in the waters along the Namibian coast off southwestern Africa have been considered to be local features with only limited ecosystem-scale consequences. But satellite remote sensing has revealed that these naturally occurring events are much more extensive and longer-lasting than previously suspected, and that the resultant hypoxia may last for much longer. The effects on the marine ecology and valuable coastal fisheries of this region are likely to be important.


Using low carbon footprint high-pressure carbon dioxide in bioconversion of aspen branch waste for sustainable bioethanol production.
An innovative approach was developed by incorporating high-pressure CO2 into the separate hydrolysis-fermentation of aspen leftover branches, aiming to enhance the bioethanol production efficiency. The high-pressure CO2 significantly increased the 72-h enzymatic hydrolysis yield of converting aspen into glucose from 53.8% to 82.9%. The hydrolysis process was performed with low enzyme loading (10 FPU g-1 glucan) with the aim of reducing the cost of fuel bioethanol production. The ethanol yield from fermentation of the hydrolyzed glucose using yeast (Saccharomyces cerevisiae) was 8.7 g L-1, showing increment of 10% compared with the glucose control. Techno-economic analysis indicated that the energy consumption of fuel bioethanol production from aspen branch chips was reduced by 35% and the production cost was cut 44% to 0.615 USD L-1, when 68 atm CO2 was introduced into the process. These results furtherly emphasized the low carbon footprint of this sustainable energy production approach.


Monitoring of Target-Site Mutations Conferring Insecticide Resistance in Spodoptera frugiperda.
Fall armyworm (FAW), Spodoptera frugiperda, a major pest of corn and native to the Americas, recently invaded (sub)tropical regions worldwide. The intensive use of insecticides and the high adoption of crops expressing Bacillus thuringiensis (Bt) proteins has led to many cases of resistance. Target-site mutations are among the main mechanisms of resistance and monitoring their frequency is of great value for insecticide resistance management. Pyrosequencing and PCR-based allelic discrimination assays were developed and used to genotype target-site resistance alleles in 34 FAW populations from different continents. The diagnostic methods revealed a high frequency of mutations in acetylcholinesterase, conferring resistance to organophosphates and carbamates. In voltage-gated sodium channels targeted by pyrethroids, only one population from Indonesia showed a mutation. No mutations were detected in the ryanodine receptor, suggesting susceptibility to diamides. Indels in the ATP-binding cassette transporter C2 associated with Bt-resistance were observed in samples collected in Puerto Rico and Brazil. Additionally, we analyzed all samples for the presence of markers associated with two sympatric FAW host plant strains. The molecular methods established show robust results in FAW samples collected across a broad geographical range and can be used to support decisions for sustainable FAW control and applied resistance management.


FBP1 loss contributes to BET inhibitors resistance by undermining c-Myc expression in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide. BET inhibitors display anti-tumor activity in pancreatic cancer, however the cells often develop resistance after a long-term treatment and the underlying molecular basis is not fully understood. Drug screening assay in Fructose-1, 6-biphosphatase (FBP1) knockdown or overexpressing pancreatic cancer cells was performed. Tumor cell motility, FBP1 protein and mRNA changes were investigated after BET inhibitors treatment. The interaction between TRIM28 and FBP1 after BET inhibitors treatment was examined by Co-immunoprecipitation (IP) and GST pull-down. The relationship between FBP1 and c-Myc was examined by western blot, RT-qPCR and immunohistochemistry (IHC). The expression of FBP1 protein increased the sensitivity of pancreatic cancer cells to JQ1. Furthermore, we showed that JQ1 stabilized FBP1 protein level by disrupting the interaction between FBP1 and TRIM28 in pancreatic cancer cells. Moreover, we demonstrated that FBP1 promoted c-Myc degradation through disrupting the ERK-c-Myc axis. FBP1 modulates the sensitivity of pancreatic cancer cells to BET inhibitors by decreasing the expression of c-Myc. These findings highlight FBP1 could be used as a therapeutic niche for patient-tailored therapies.


Chronic pediatric diseases into adulthood and the challenge of adolescence.
One of the priorities of public health is to improve the equity of access to a continuous interdisciplinary medical and social survey of patients with chronic complex conditions, and, notably, the switch from pediatric to adult-oriented healthcare, including the specific issues of adolescence. In spite of the many barriers related to the patients, their family, pediatricians, and even adult health providers, the concept of a planned, dynamic, multidisciplinary transition program has to be designed around the adolescent with the aim of reinforcing his autonomy, coordinating medical care, and addressing his educational/professional and psychosocial needs. The primary care physician is the pivot of adult heathcare, and should have a close relationship with the private or hospital referent specialist and paramedical structures. A key worker may make an important contribution to the coordination, the registration, and the follow-up of some cohorts.


Association between socio-economic status and estimated atherosclerotic cardiovascular disease risk: results from a middle-aged population-based study.
The association between cardiovascular disease (CVD) risk and socio-economic status (SES) remains poorly studied. The purpose of this study was to investigate the relationship between SES and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk among the general UK Biobank population. This was a population-based study. Among 311,928 volunteers (47.7% men) of the UK Biobank population, SES was assessed by a questionnaire, and ASCVD risk was calculated using pooled cohort equation models. Associations between SES and ASCVD risk were estimated using multiple gender-specific regressions. The findings from this study showed that men had higher estimated 10-year ASCVD risk than women (8.6% vs 2.7%; P < 0.001), higher education level (38.3% vs 36.2%; P < 0.001), higher income level (31.0% vs 25.1%; P < 0.001), higher levels of employment (65.4% vs 60.5%; P < 0.001) and higher scores of Townsend deprivation (P < 0.001). Using the multiple logistic regression model, a decreased 10-year ASCVD risk in men was associated with high income level (odds ratio [OR] = 0.64 [95% confidence interval {CI} 0.61-0.68]; P < 0.001), high educational level (OR = 0.71 [95% CI 0.68-0.74]; P < 0.001), higher Townsend deprivation quintile (OR = 0.81 [95% CI 0.78-0.85]; P < 0.001) and employed status (OR = 0.74 [95% CI 0.69-0.80]; P < 0.001). The same results were observed in women, with high income level (OR = 0.68 [95% CI 0.55-0.68]; P < 0.001), high educational level (OR = 0.87 [95% CI 0.82-0.93]; P < 0.001), higher Townsend deprivation quintile (OR = 0.74 [95% CI 0.69-0.80]; P < 0.001) and employed status (OR = 0.53 [95% CI 0.45-0.63]; P < 0.001) being associated with a lower 10-year ASCVD risk. When considering the false discovery rate logworth analysis, SES factors presented a similar contribution to CVD risk as lifestyle factors. Health policies should consider the SES factors identified in this study, in addition to traditional risk factors, when designing prevention campaigns for CVD. Further research is required to improve the ASCVD risk prediction models among different SES variables.


End cap versus no end cap in intramedullary nailing for displaced midshaft clavicle fractures: influence on implant-related irritation.
Implant-related irritation at the entry site is a known disadvantage of intramedullary nailing for clavicle fractures. The purpose of this study was to compare implant-related irritation rates of intramedullary nailing with or without an end cap for displaced midshaft clavicle fractures. Two cohorts of patients treated with intramedullary nailing with or without an end cap were matched and compared. Primary outcome was patient-reported implant-related irritation. Secondary outcome parameters were complications. A total of 34 patients with an end cap were matched with 68 patients without an end cap. There was no difference in implant-related irritation (41 versus 53%, P = 0.26). Significantly more minor revisions were observed in the group without an end cap (15 versus 0%, P = 0.03). For complications requiring major revision surgery, significantly more implant failures were observed in the end cap group (12 versus 2%, P = 0.04). Regardless of their treatment, patients with complex fractures (AO/OTA B2-B3) reported significantly more medial irritation compared to patients with simple fractures (AO/OTA B1)(P = 0.02). The use of an end cap after intramedullary nailing for displaced midshaft clavicle fractures did not result in lower patient-reported irritation rates. Although less minor revisions were observed, more major revisions were reported in the end cap group. Based on the results of this study, no end caps should be used after intramedullary nailing for displaced midshaft clavicle fractures. However, careful selection of simple fractures might be effective in reducing implant-related problems after intramedullary nailing.


Removal of tropomyosin overlap modifies cooperative binding of myosin S-1 to reconstituted thin filaments of rabbit striated muscle.
Cooperative binding of myosin S-1.ADP to regulated F-actin was previously reported and has been interpreted by a two-state model in which an important source of cooperativity is nearest neighbor interactions between the 7-actin.tropomyosin (TM).troponin units (functional units) (Hill, T.L., Eisenberg, E., and Greene, L. (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 3186-3190). It has been postulated that the head-to-tail overlap between adjacent TM molecules is the structural basis of the nearest neighbor interactions. We tested the hypothesis by examining S-1.ADP binding to reconstituted regulated F-actin containing either intact TM or nonpolymerizable TM from which the COOH-terminal 11 residues were removed. In the absence of Ca2+, substitution of nonpolymerizable TM for TM reduced significantly the slope of the steeply rising phase of the sigmoidal S-1.ADP binding curve. Nevertheless, considerable residual cooperativity remained. Analysis of the data using the two-state model of Hill et al. suggests that removal of TM overlap abolishes nearest neighbor interactions, while the concerted change of the state of 7 actins in a functional unit can account for the residual cooperativity.


Sex differentiation in postnatal growth rate: a test in a wild boar population.
In wild boar individual growth rate is linear between 0.5 and 6 months after birth, based on successive body weight measurements. Contrary to expectation for a dimorphic and polygynous mammal like wild boar, no sexual dimorphism in growth rate could be detected between 0.5 and 6 months. We argue that high total maternal invesment in offspring due to large litter size and/or strong selection for early reproduction in this population with a short generation time could explain this absence of early differentiation in postnatal growth rate according to offspring sex.


Colorectal cancer management: strategies in drug delivery.
Colorectal cancer (CRC) is the third most common cancer leading to death worldwide following breast and lung cancer with the incidence rate of 10%. The treatment comprises surgery, radiation, and ablation therapy depending upon the stage of cancer. The review focuses on various drug delivery strategies explored to circumvent the major constraints associated with the conventional drug delivery systems-poor bioavailability, intra- and inter individual variability, exposure of normal cells to antineoplastic agents, and presence of efflux pump. All these attributes impact the effective delivery of chemotherapeutic agents at the tumor site. The various target specific drug delivery systems developed for colorectal cancer include pH-dependent, microbiologically triggered, time-dependent, magnetically driven, pressure-dependent, prodrug/polysaccharide-based, osmotic and ligand-mediated systems. This review enumerates novel target specific approaches developed and investigated for potential utility in CRC therapeutics. The limitations of conventional delivery systems can be overcome by the development of colon-specific targeted drug delivery systems that overcome the obstacles of nonspecific biodistribution, drug resistance, and unwanted adverse effects of conventional drug delivery systems. In addition, nanotechnology approaches help to increase drug solubility, bioavailability, reduce side effects, and provide superior drug response in CRC.


Protein interactions of Merocyanine 540: spectroscopic and crystallographic studies with lysozyme as a model protein.
Spectroscopic and crystallographic studies reveal that Merocyanine 540 (MC 540), a well-known therapeutically important anionic cyanine dye, interacts with hen egg white lysozyme in ground state. The formation of the complex is validated by two isosbestic points in absorption spectra of lysozyme with varied concentration of MC 540 and appearance of an isodichroic point in induced CD spectra of MC 540 with lysozyme. The blue shift of fluorescence maximum of lysozyme in presence of MC 540 shows hydrophobic effect on Trp due to complex formation probably through cooperative binding. Above 1:3M stoichiometric ratio (lysozyme:MC 540) an additional fluorescence hump arises because of structural changes in protein, where MC 540 acts as self-denaturant, inducing non-linearity in Stern-Volmer plot. The van't Hoff isotherms with negative changes in enthalpy at lower concentration and positive changes in entropy for entire concentration range of MC 540 depict the binding forces as hydrogen bonding/van der Waal's and ionic/hydrophobic respectively. Finally X-ray crystallographic structure of the complex shows that MC 540 adopts two conformations, cis and trans, while it binds to lysozyme. Benzoxole moiety of MC 540 interacts with Trp123 through π-stacking and SO3(2-) group is stabilized by ionic interaction/H-bonding with Arg125 of lysozyme.


Catalyst-Free Synthesis of O-Heteroacenes by Ladderization of Fluorinated Oligophenylenes.
A novel catalyst-free approach to benzoannulated oxygen-containing heterocycles from fluorinated oligophenylenes is reported. Unlike existing methods, the presented reaction does not require an oxygen-containing precursor and relies on an external oxygen source, potassium tert-butoxide, which serves as an O2- synthon. The radical nature of the reaction facilitates nucleophilic substitution even in the presence of strong electron-donating groups and enables de-tert-butylation required for the complete annulation. Also demonstrated is the applicability of the method to introduce five-, six-, and seven-membered rings containing oxygen, whereas multiple annulations also open up a short synthetic path to ladder-type O-heteroacenes and oligodibenzofurans.


Does Masking Matter? Shipping Noise and Fish Vocalizations.
Shipping creates large near-field background noises at levels similar to or higher than fish vocalizations and in the same critical bandwidths. This noise has the potential to "mask" biologically important signals and prevent fish from hearing them; any interference with the detection and recognition of sounds may impact fish survival. The Lombard effect, whereby vocalizations are altered to reduce or exclude masking effects, is an adaptation that has been observed in mammals and birds. Research is needed to establish whether the Lombard effect occurs in fish to gain a better understanding of the implications of noise pollution on fish populations.


Simultaneous stimulation of sedoheptulose 1,7-bisphosphatase, fructose 1,6-bisphophate aldolase and the photorespiratory glycine decarboxylase-H protein increases CO2 assimilation, vegetative biomass and seed yield in Arabidopsis.
In this article, we have altered the levels of three different enzymes involved in the Calvin-Benson cycle and photorespiratory pathway. We have generated transgenic Arabidopsis plants with altered combinations of sedoheptulose 1,7-bisphosphatase (SBPase), fructose 1,6-bisphophate aldolase (FBPA) and the glycine decarboxylase-H protein (GDC-H) gene identified as targets to improve photosynthesis based on previous studies. Here, we show that increasing the levels of the three corresponding proteins, either independently or in combination, significantly increases the quantum efficiency of PSII. Furthermore, photosynthetic measurements demonstrated an increase in the maximum efficiency of CO2 fixation in lines over-expressing SBPase and FBPA. Moreover, the co-expression of GDC-H with SBPase and FBPA resulted in a cumulative positive impact on leaf area and biomass. Finally, further analysis of transgenic lines revealed a cumulative increase of seed yield in SFH lines grown in high light. These results demonstrate the potential of multigene stacking for improving the productivity of food and energy crops.


"Knowing That I'm Not Necessarily Alone in My Struggles": UK Autistic Performing Arts Professionals' Experiences of a Mentoring Programme.
This research examined whether professional mentoring could have a positive effect on the occupational self-efficacy of autistic performing arts professionals. We compared the outcomes of one group who received mentoring to a waitlist control group. 26 participants took part in this study: 15 autistic mentees and 11 mentors, three of whom were also autistic. The mentoring programme was well received and felt to be beneficial by the participating mentees and mentors, particularly regarding gains in mentees' occupational self-efficacy. Professional mentoring also addressed several work-oriented challenges identified by autistic performing arts professionals such as feelings of isolation in the industry and need for consultation and advice on both a professional level, and for mentees with autistic mentors, also a neurodivergent one.


ERRATUM: "Evolution of speech therapists supply in SUS: a study about the correlation with social indicatiors in Brazil in the last decade".
[This corrects the article doi: 10.1590/2317-1782/20202019243] [This corrects the article doi: 10.1590/2317-1782/20202019243].


BRAF inhibitor resistance of melanoma cells triggers increased susceptibility to natural killer cell-mediated lysis.
Targeted therapies and immunotherapies are first-line treatments for patients with advanced melanoma. Serine-threonine protein kinase B-RAF (BRAF) and mitogen-activated protein kinase (MEK) inhibition leads to a 70% response rate in patients with advanced melanoma with a BRAFV600E/K mutation. However, acquired resistance occurs in the majority of patients, leading to relapse. Immunotherapies that activate immune cytotoxic effectors induce long-lasting responses in 30% of patients. In that context, combination of targeted therapies with immunotherapy (IT) is a promising approach. We considered boosting natural killer (NK) cell tumor immunosurveillance, as melanoma cells express stress-induced molecules and activate NK cell lysis. Here we have generated vemurafenib (a BRAF inihibitor)-resistant (R) cells from BRAFV600E SK28 and M14-sensitive (S) melanoma cell lines and investigated how resistance interferes with immunogenicity to NK cells. We determined the levels of several soluble molecules including NK ligands in 61 melanoma patients at baseline and 6 months M post-treatment with targeted therapies or immunotherapies. Vemurafenib resistance involved activation of p-AKT in SK28R and of p-MEK/p-ERK in M14R cells and was accompanied by modulation of NK ligands. Compared with S cells, SK28R displayed an increased expression of natural killer group 2 D (NKG2D) receptor ligands (major histocompatibility complex class (MHC) I chain-related protein A (MICA) and UL16-binding protein 2 (ULBP2)) whereas M14R exhibited decreased ULBP2 . SK28R and M14R cells induced higher NK degranulation and interferon gamma secretion and were more efficiently lysed by donor and patient NK cells. SK28R showed increased tumor necrosis factor-related apoptosis-inducing ligand receptor II (TRAIL-RII) expression and TRAIL-induced apoptosis, and TRAIL-induced apoptosis of M14R was decreased. Combined BRAF/MEK inhibitors abrogated the growth of SK28S, M14S, and M14R cells, while growth of SK28R was maintained. BRAF/MEK inhibition attenuated NK activity but R cell lines activated polyfunctional NK cells and were lysed with high efficiency. We investigated the relationship of soluble NK ligands and response to treatment in a series of melanoma patients. Soluble NKG2D ligands known to regulate the receptor function have been associated to cancer progression. Serum analysis of patients treated with target therapies or IT indicates that soluble forms of NK ligands (MICA, B7H6, programmed cell death ligand 1, and carcinoembryonic antigen cell adhesion molecule 1) may correlate with clinical response. These results support strategies combining targeted therapies and NK-based immunotherapies.


Oxidative stress and cholinesterase inhibition in saliva and plasma of rats following subchronic exposure to malathion.
The aim of this study was to examine whether malathion, a commonly used organophosphate (OP), might induce oxidative stress and cholinesterase (ChE) depression in saliva and plasma in rats following subchronic exposure mimicking human exposure. Malathion was administered orally at doses of 100, 500 and 1500 ppm for 4 weeks. Oxidative stress was determined by measuring the malondialdehyde concentration, the end product of lipid peroxidation, and assessing total antioxidant power. Four weeks oral administration of malathion at doses of 100 ppm, 500 ppm and 1500 ppm depressed plasma ChE activity to 45% (P<0.01), 48% (P<0.01) and 41% (P<0.01) of control, respectively. Malathion at doses of 100 ppm, 500 ppm and 1500 ppm depressed saliva ChE activity to 73% (P<0.01), 75% (P<0.01) and 78% (P<0.01) of control, respectively. Malathion at doses of 100 ppm, 500 ppm and 1500 ppm increased plasma antioxidant power by 33% (P<0.01), 59% (P<0.01) and 118% (P<0.01) of control, respectively. Malathion did not change saliva antioxidant power. Malathion at doses of 100 ppm, 500 ppm and 1500 ppm increased plasma thiobarbituric acid reactive substances (TBARS) by 61% (P<0.01), 69% (P<0.01) and 63% (P<0.01) of control, respectively. Malathion at doses of 500 ppm and 1500 ppm increased saliva TBARS by 19% (P<0.01) and 22% (P<0.01) of control, respectively. Malathion (100 ppm) did not change saliva TBARS level. We concluded that in OP subchronic exposure, depression of ChE is accompanied by induction of oxidative stress that might be beneficial in monitoring OP toxicity.


Fungal metabolic profile dataset was not influenced by long-term in vitro preservation of strains.
Comparative ecophysiology is highly valuable approach to reveal adaptive traits linked with specific ecological niches. Although long-term in vitro preserved fungal isolates are often used for analyses, only sparse data is available about the effect of such handling on fungal physiology. The purpose of our data is to show the effect of long-term in vitro preservation of fungal strains on their metabolic profiles. This data is related to research paper "Adaptive traits of bark and ambrosia beetle-associated fungi" (Veselská et al., 2019). Biolog MicroPlates™ for Filamentous fungi were used to compare metabolic profiles between freshly isolated and long-term in vitro preserved strains of two Geosmithia species. Additionally, carbon utilization profiles of 35 Geosmithia species were assessed, including plant pathogen G. morbida and three ambrosia species. Data also shows differences in carbon utilization profiles among diverse ecology types presented in the genus Geosmithia.


New Coll-HA/BT composite materials for hard tissue engineering.
The integration of ceramic powders in composite materials for bone scaffolds can improve the osseointegration process. This work was aimed to the synthesis and characterization of new collagen-hydroxyapatite/barium titanate (Coll-HA/BT) composite materials starting from barium titanate (BT) nanopowder, hydroxyapatite (HA) nanopowder and collagen (Coll) gel. BT nanopowder was produced by combining two wet-chemical approaches, sol-gel and hydrothermal methods. The resulting materials were characterized in terms of phase composition and microstructure by X-ray diffraction, Raman spectroscopy, scanning electron microscopy and transmission electron microscopy. Moreover, the biocompatibility and bioactivity of the composite materials were assessed by in vitro tests. The synthesized BT particles exhibit an average size of around 35 nm and a spherical morphology, with a pseudo-cubic or tetragonal symmetry. The diffraction spectra of Coll-HA and Coll-HA/BT composite materials indicate a pronounced interaction between Col and the mineral phases, meaning a good mineralization of Col fibres. As well, the in vitro tests highlight excellent osteoinductive properties for all biological samples, especially for Coll-HA/BT composite materials, fact that can be attributed to the ferromagnetic properties of BT.


Room temperature and high response ethanol sensor based on two dimensional hybrid nanostructures of WS2/GONRs.
Here in this research, room temperature ethanol and humidity sensors were prepared based on two dimensional (2D) hybrid nanostructures of tungsten di-sulfide (WS2) nanosheets and graphene oxide nanoribbons (GONRs) as GOWS. The characterization results based on scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (ESD), Raman spectroscopy and X-ray diffraction (XRD) analysis confirmed the hybrid formations. Ethanol sensing of drop-casted GOWS films on SiO2 substrate indicated increasing in gas response up to 5 and 55 times higher compared to pristine GONRs and WS2 films respectively. The sensing performance of GOWS hybrid nanostructures was investigated in different concentrations of WS2, and the highest response was about 126.5 at 1 ppm of ethanol in 40% relative humidity (R.H.) for WS2/GONRs molar ratio of 10. Flexibility of GOWS was studied on Kapton substrate with bending radius of 1 cm, and the gas response decreased less than 10% after 30th bending cycles. The high response and flexibility of the sensors inspired that GOWS are promising materials for fabrication of wearable gas sensing devices.


Functional and oncological outcome of patients with benign hindfoot tumors treated by curettage.
Only 3 % of osseous tumors occur in the foot. The metatarsals are the -most common site whereas the calcaneus and talus are less common sites. Because these tumors are rare, the aim of our study is to assess the functional and the oncological outcome of patients with benign hindfoot tumors managed by curettage. The clinical and radiological data of 41 patients diagnosed with benign hindfoot tumors were retrospectively reviewed. The study included 31 males and 10 females. The average age was 23.68 (range, 5-49) years. The average follow-up period was 92.7 (range, 12-244) months. At the last follow-up visit, the average Musculoskeletal Tumor Society scoring system (MSTS) score was 28.12 (range, 21-30). MSTS scores were higher in patients with latent tumors (P = .028) and patients managed by simple curettage (P = .018). The recurrence rate in calcaneal tumors was higher than those in the talus. The overall complication rate was 12.2 % (5 of 41 patients). Infection and subtalar arthritis were the most common complications. Curettage of benign bone tumors of talus or calcaneus proved to be an effective method in the management of these patients. Their functional outcome is also excellent. All the complications are manageable without long term morbidity. Level IV Therapeutic study.


Precise technique for simple and accurate pip arthrodesis using a blunt KW technique.
Proximal interphalangeal joint (PIP) arthrodesis is a very common procedure in the practice of foot and ankle surgeons. The standard technique recommends using a Kirschner wire (KW) with double sharp ends. Using this technique there are some complication that can be eliminated by small modification. The technique of proximal interphalangeal joint arthrodesis using a simple blunt KW on one side with an accurate placement and avoidance of metatarsophalangeal joint (MTPJ) penetration without the need for fluoroscopy is described. This technique is simple, reproducible, very economical and avoiding most of the complications attributed to the KW.


An apparatus for studying the response of cultured endothelial cells to stresses.
In order to simulate the hemodynamic environment of human arteries in vivo, we designed a laminar flow apparatus which can precisely simulate the normal stress and shear stress to which cultured endothelial cells are exposed. Under both normal and abnormal physiological conditions, this apparatus can accurately control and adjust the values of normal stress and shear stress and the frequency of pulse waves, as well as the amplitude of pulsatile flow. This in vitro apparatus provides an experimental platform for studying the response of the biological characteristics of cultured endothelial cells in a hemodynamic environment.


Spectral and time domain characteristics of single muscle fibre action potentials during continuous activity extracted from model considerations.
A model of the muscle fibre extracellular action potentials (ECAPs) calculation using experimentally recorded intracellular action potentials (ICAPs) has been applied to investigate the effect of repetitive stimulation on the electrical activity of isolated frog muscle fibres. The ECAPs were calculated both at small (0.01 mm) and at large (5 mm) radial distances to the fibre axis, and their relationship with the original ICAP parameters has been inferred. Fourier transformation of the calculated ECAPs in order to obtain the spectral characteristics and to trace out their behaviour during continuous fibre activity was performed. Stimulation frequency dependence on the ECAP time characteristics and on the shift of the maximum spectral density towards low frequencies at small and large radial distance were observed. The spectral density peak frequency is propagation velocity (PV)-dependent. The advantage of the presented method over the available experimental extracellular recording techniques from isolated muscle fibers is the possibility to show the effect of continuous muscle fibre activity on the parameters of the ECAPs and their spectral characteristics at large radial distance, which is not experimentally accessible. Our results are in agreement with those experimentally obtained. The results from the model prove the role of changes in PV of excitation along the muscle fibres (representing the last link in the complex organized motor system) in the development of fatigue.


Evaluation of Wells score and repeated D-dimer in diagnosing venous thromboembolism.
Patients presenting with symptoms suggestive of venous thromboembolism (VTE), i.e., deep vein thrombosis (DVT) and pulmonary embolism (PE), are common at the emergency departments. However, of those, only 15-25% actually have the disease. The aims of this study were to determine (1) if low pre-test probability (PTP) using the Wells score, together with a normal D-dimer, safely excludes VTE in outpatients and (2) if a follow-up D-dimer adds extra information. Patients (n=151, 68% women) with suspected VTE, a PTP below 1.5, and a D-dimer test (TinaQuant) below 0.5 mg/L were included in the study and underwent no further diagnostic investigations. Patients (n=177, 54% women) with D-dimer levels of 0.5 mg/L or higher or a PTP of 1.5 or higher were excluded. A follow-up D-dimer test was conducted 3-7 days after the initial hospital visit and further diagnostic investigations were made if test results were abnormal. Patients were studied for 3 months. A follow-up D-dimer test was conducted in 101/151 cases (67%), 13/101 of which revealed elevated D-dimer levels. None of these 13 patients had persistent symptoms or was diagnosed with VTE. All 151 patients were contacted after 3 months; none of them had clinical signs of VTE. Of the 177 patients excluded, 45 (25%) were diagnosed with VTE. Of the 176/328 (151+177) patients with normal D-dimer levels, only 1 had VTE (<0.01%). A normal PTP using the Wells score and a normal D-dimer safely excludes VTE at the emergency department. A follow-up D-dimer test adds no further information.


Pulmonary fibrosis associated with ANCA-positive vasculitides. Retrospective study of 12 cases and review of the literature.
To describe the clinical presentation of the association between pulmonary fibrosis (PF) and systemic vasculitis related to antineutrophil cytoplasmic antibodies (ANCA-V). 12 patients (three female, mean age 70.7 years) with ANCA-V associated with "idiopathic" PF were studied retrospectively. ANCA-V and PF were diagnosed simultaneously in eight cases; PF occurred earlier in three cases and during ANCA-V follow-up in one. No patient had intra-alveolar haemorrhage (IAH). ANCA were myeloperoxidase (MPO)-ANCA in all cases. Seven patients had blood eosinophilia at diagnosis. Two patients died during ANCA-V induction therapy. The respiratory status of five patients worsened and three of them died from exacerbation of end-stage respiratory failure. The five remaining patients had a stable respiratory status. The association of PF and ANCA-V does not seem to be fortuitous, even though their clinical evolutions are clearly not related. PF was the major cause of death.


The effect of the endoscopist on the wait-time for colorectal cancer surgery.
The effect of the specialty of physicians who perform endoscopy on preoperative wait-time of colorectal cancer patients was evaluated. Data from 86 patients who have been operated with a diagnosis of colorectal cancer from January 2011-February 2013 regarding age, sex, tumor location, colonoscopy date, surgery date, the expertise and institution of the endoscopist were retrospectively examined. The time between colonoscopy and surgery was accepted as the pre-operative wait time (PWT). Out of 86 patients, 24 (27.9%) colonoscopies were performed by general surgeons (GS), and 62 (72.1%) by gastroenterologists (GE). When patients who underwent colonoscopy in other centers were extracted, the PWT for our center was 20.4±10.8 days. When grouped according to specialties, the PWT of patients who had their colonoscopy performed by GS was significantly shorter than patients who underwent colonoscopy by GE at the same center (p<0.05). Patient's age, sex and location of the tumor had no effect on PWT (p>0.05). The preparation time for surgery in colorectal cancer patients is influenced by the specialty of the physician performing the procedure. In order to standardize this period, a common flow diagram after endoscopy should be established for patients with suspected malignancy.


Fracture load and failure mode of semi-direct resin composite occlusal veneers: Influence of design and mechanical cycling.
To evaluate the influence of the type of preparation and mechanical cycling on the fracture load and failure mode of semi-direct posterior resin composite restorations. In total, 70 healthy third molars were used; 10 belonging to the control group (C - unprepared teeth) and 60 teeth prepared and restored with nanoparticle resin composite, divided into 3 groups (n = 20): O - exclusively occlusal preparation (Table Top); OV - occlusal preparation with buccal extension (Veneerlay); OVP - Occlusal preparation with chamfer on the proximal and buccal-lingual/palatal surfaces (Overlay). The preparations were performed with diamond burs with a thickness of 1 mm. The restorations were made with nanoparticulate resin composite (Filtek Z350 XT) and subsequently received additional polymerization (thermoprocessing). Cementation was performed with the use of universal adhesive system (Single Bond Universal) on dental substrate and dual resin cement (RelyX ARC). Half of the teeth in each group (n = 10) were submitted to mechanical cycling, simulating 6 months of clinical service (5 × 105 fatigue cycles), under dynamic loading of 130 N, at a frequency of 2Hz. Fracture load tests were performed in a universal testing machine with a 200 kgf load cell. Failure mode was classified using scores. Generalized linear models and Fisher Exact tests were applied to the data (significance level of 5%). There were no significant differences between the types of preparation (p = 0.9435), or relative to cycling (p = 0.3764). The Fisher Exact Test showed a significant association between the groups and the type of failure (p = 0.0006), with preparations O (with cycling) and OVP (with and without cycling) exhibiting most failures with restoration fractures without involvement of the dental remnant. Semi-direct restorations showed resistance to fracture load similar to that of healthy teeth and were capable of withstanding functional masticatory loads. The type of preparation influenced the failure mode of teeth. The Table Top and Overlay types of preparations were those had fewer catastrophic failures, suggesting that since they are more conservative preparations, they made it possible for the tooth to receive a new restorative procedure in the future in cases of failures.


Ganglioneuromatous tumor of the skin: a combined heterotopia of ganglion cells and hamartomatous neuroma: report of a case.
We report the histologic and ultrastructural findings of a solitary, unusual cutaneous tumor in a 69-year-old woman. The tumor is characterized by many mature ganglion cells in the papillary dermis and fascicles of unmyelinated axons in the lower dermis. The lesion is ganglioneuromatous but differs from the other ganglioneuromas histologically in that the ganglion cells do not intermingle with the neuromatous elements. It may represent a combined heterotopia of ganglion cells and hamartomatous neuroma. The histologic differential diagnosis and the possible pathogenesis are discussed.


Optimal debulking surgery followed by paclitaxel/platinum chemotherapy is very effective in treating ovarian carcinosarcomas: a single center experience.
There have been only a few reports on the survival and management of patients with ovarian carcinosarcomas. We evaluated the clinical characteristics, outcomes and prognostic factors of ovarian carcinosarcomas. Retrospective analysis of data obtained from medical records of 40 patients treated at the Asan Medical Center, Seoul, Korea, between January 1989 and January 2008. Median survival was significantly longer in patients <60 years of age than in those ≥60 (p = 0.001), patients with early-stage compared to advanced tumors (p = 0.035), those with optimally debulked tumors compared to suboptimally (p < 0.001) in the advanced stage, and patients treated with paclitaxel/platinum compared to patients treated with other chemotherapies (p < 0.001). The progression-free interval was longer in patients with early-stage (p = 0.003) and optimally debulked tumors (p = 0.001), as well as in those treated with paclitaxel/platinum (p = 0.049). Multivariate analysis showed that advanced-stage, non-optimal debulking and non-paclitaxel/platinum chemotherapy were significant independent predictors of a shorter progression-free interval, and that non-optimal debulking and non-paclitaxel/platinum chemotherapy were significant independent predictors of shorter overall survival. Early-stage optimal debulking and adequate chemotherapy can influence time to progression and survival, indicating that the most effective treatment for patients with ovarian carcinosarcomas consists of optimal debulking surgery followed by paclitaxel/platinum chemotherapy.


The relationship between obstructive sleep apnea with hearing and balance: A scoping review.
Obstructive sleep apnea (OSA) has been linked to multiple co-morbidities, and some research points to a potential relationship between OSA and hearing and balance dysfunction, and the benefits of continuous positive airway pressure (CPAP) treatment. The present study was undertaken as a scoping review of research on OSA and its impact on hearing and balance function in adults and children and whether the treatment of CPAP would affect hearing and balance function. Online databases were used to identify 45 papers published that used hearing and balance assessments concerning OSA and CPAP therapy as a primary outcome. The secondary outcome was the subjective perception through validated questionnaires. Whilst the data on the effect of OSA on middle ear function remains inconclusive, most papers demonstrate an increase in hearing thresholds, an absence of otoacoustic emissions (OAE) and delayed auditory brainstem response (ABR) in adults with OSA. Nystagmus and abnormal vestibular evoked myogenic potentials (VEMPs) were observed in the small number of papers. The positive pressure from CPAP significantly and transiently increases middle ear pressure, however, its effects on other auditory regions and the vestibular system remains inconclusive. Research on hearing and balance function in children with OSA is limited. Narrow assessments of hearing and balance are not sufficient to understand the nature of hearing and balance function in OSA patients and the effect of CPAP therapy. More comprehensive assessments are necessary to observe peripheral and central changes in the auditory and vestibular pathways.


[Limits of pharmacodynamic differentiation of pupillary-disturbances (author's transl)].
Pharmacodynamic tests to differentiate pupillary disturbances are of considerable importance in neuroophthalmological examinations. However, they do not always enable anisocoria to be diagnosed beyond doubt. The possibility of misinterpretation and causes of occasional failure of the tests are mentioned.


99mTc-doxorubicin-loaded gallic acid-gold nanoparticles (99mTc-DOX-loaded GA-Au NPs) as a multifunctional theranostic agent.
The development of cancer theranostic nanomedicines is recommended to concurrently achieve and evaluate the therapeutic benefit and progress. The current work aims to develop gallic acid-gold nanoparticles (GA-Au NPs) as a theranostic probe for 99mTc-Doxorubicin (99mTc-DOX) based on the spatiotemporal release pattern induced intra-tumoral (IT) delivery. DOX-loaded GA-Au NPs were developed and identified via UV-Vis spectroscopy. The system was characterized for drug loading efficiency%, particle size, zeta potential, topography, in vitro DOX release and anti-proliferative activity against the MCF-7 cell-line. The factors influencing radiolabeling efficiency of DOX with 99mTc (DOX concentration, stannous chloride concentration, reaction time and pH) were optimized. The in vitro stability in mice serum and in vivo distribution studies in mice of 99mTc-DOX-loaded GA-Au NPs were investigated following IV and IT administration. Dox-loaded GA-Au NPs had a loading efficiency of 91%, a small particle size (≈50 nm), a promising zeta potential (-20 mV) and a sustained drug release profile at pH 5.3. GA-Au NPs exhibited increased anti-proliferative activity, with approximately a four-fold lower IC50 value (0.15 μg/ml) than free DOX. The optimized radiolabeling efficiency of 99mTc-DOX was ≈93%. It showed good physiological stability in mice serum for at least 8 h. The IT delivery of 99mTc-DOX-loaded GA-Au NPs in tumor-induced mice showed dramatic tumor accumulation. A maximum magnitude of 86.73%ID/g was achieved, at 15 min post-injection, with a target/non-target ratio of ≈56. 99mTc-DOX-loaded GA-Au NPs could be used for the selective IT delivery of a chemotherapeutic agent and an imaging agent to a target organ.


Radioactive secular equilibrium in ²³⁸U and ²³²Th series in granitoids from Greece.
Granitoid rocks belonging to plutons of Greece, covering a wide range of compositions and rock-types, have been studied for their specific activity (Bq/kg) of (238)U and (226)Ra from (238)U radioactive series and (228)Ra and (228)Th from (232)Th radioactive series by using gamma-ray spectroscopy. Results on the radioactive secular equilibrium of both (238)U and (232)Th radioactive series are presented by studying the (226)Ra/(238)U and (228)Ra/(228)Th ratios. The majority of the samples are in radioactive secular equilibrium for (226)Ra/(238)U ± 1σ. However, several samples exhibit (226)Ra/(238)U ratios significantly different from 1. The distortion of the secular equilibrium in the (226)Ra-(238)U isotopic system of those samples has occurred over the last 1 Ma, and can be associated with post-magmatic processes, mainly rock-water interactions. All studied samples have (228)Ra/(228)Th ratios equal to unity ±1σ. Consequently, they can be considered to be in secular equilibrium for the last 40 a.


Tailored quinones support high-turnover Pd catalysts for oxidative C-H arylation with O2.
Palladium(II)-catalyzed carbon-hydrogen (C-H) oxidation reactions could streamline the synthesis of pharmaceuticals, agrochemicals, and other complex organic molecules. Existing methods, however, commonly exhibit poor catalyst performance with high palladium (Pd) loading (e.g., 10 mole %) and a need for (super)stoichiometric quantities of undesirable oxidants, such as benzoquinone and silver(I) salts. The present study probes the mechanism of a representative Pd-catalyzed oxidative C-H arylation reaction and elucidates mechanistic features that undermine catalyst performance, including substrate-consuming side reactions and sequestration of the catalyst as an inactive species. Systematic tuning of the quinone cocatalyst overcomes these deleterious features. Use of 2,5-di-tert-butyl-p-benzoquinone enables efficient use of molecular oxygen as the oxidant, high reaction yields, and >1900 turnovers by the Pd catalyst.


Adenovirus-mediated siRNA targeting Bcl-xL inhibits proliferation, reduces invasion and enhances radiosensitivity of human colorectal cancer cells.
Bcl-xL, an important member of anti-apoptotic Bcl-2 family, plays critical roles in tumor progression and development. Previously, we have reported that overexpression of Bcl-xL was correlated with prognosis of colorectal cancer (CRC) patients. The aim of this study was to investigate the association of Bcl-xL expression with invasion and radiosensitivity of human CRC cells. RT-PCR and Western blot assays were performed to determine the expression of Bcl-xL mRNA and protein in CRC cells and normal human intestinal epithelial cell line. Then, adenovirus-mediated RNA interference technique was employed to inhibit the expression of Bcl-xL gene in CRC cells. The proliferation of CRC cells was analyzed by MTT and colony formation assay. The migration and invasion of CRC cells was determined by wound-healing and tranwell invasion assays. Additionally, the in vitro and in vivo radiosensitivity of CRC cells was determined by clonogenic cell survival assay and murine xnograft model, respectively. The levels of Bcl-xL mRNA and protein expression were significantly higher in human CRC cells than in normal human intestinal epithelial cell line. Ad/shBcl-xL could significantly reduce the expression of Bcl-xL protein in CRC cells. Also, we showed that adenovirus-mediated siRNA targeting Bcl-xL could significantly inhibit proliferation and colony formation of CRC cells. Ad/shBcl-xL could significantly suppress migration and invasion of CRC cells. Moreover, Ad/shBcl-xL could enhance in vitro and in vivo radiosensitivity of CRC cells by increasing caspase-dependent apoptosis. Targeting Bcl-xL will be a promising strategy to inhibit the metastatic potential and reverse the radioresistance of human CRC.


Orthopedic trauma surgery in the morbidly obese patient.
The treatment of morbidly obese patients in orthopedic trauma differs in many ways compared to injured patients with normal body mass indices. This paper highlights key differences and ways to overcome obstacles. We present specific tips, as well as considerations for initial planning, positioning for surgery, intra-operative strategies, and a discussion on both anesthesia and imaging. Several treatment strategies have been shown to have better results in morbidly obese patients. Pre-operative planning is necessary for minimizing risk to the patient. The prevalence of morbid obesity has increased in the USA in the past quarter century. Treatment for orthopedic injuries in morbidly obese patients requires a multidisciplinary approach that addresses not only their orthopedic injuries, but also medical co-morbidities. A team of medicine doctors, anesthesiologists, X-ray technicians, physical and occupational therapists, respiratory therapists, and social workers is needed in addition to the orthopedic surgeon. Modifications in both pre-operative planning and intra-operative strategies may be necessary in order to accommodate the patient. This paper presents numerous technical tips that can aid in providing stable fixation for fractures, as well as addressing peri-operative issues specific to the morbidly obese.


Putative cerebral cortical involvement in the ventilatory response to inhaled CO2 in conscious man.
1. The response of the diaphragm to both transcranial magnetic stimulation and electrical phrenic nerve stimulation was studied in thirteen normal subjects under conditions of either a 'reflex' drive to ventilation with inhaled CO2 or during volitional ventilation of similar magnitude. 2. The induced compound action potential in the diaphragm was recorded using an oesophageal electrode, and in some cases transdiaphragmatic pressure was recorded using oesophageal and gastric balloon catheters. 3. The response of the diaphragm to transcranial magnetic stimulation was invariably facilitated with volitional inspiration; there was either minimal or no response at functional residual capacity. 4. Facilitation with inspiration was also seen during a 'reflex' drive to ventilation with inhaled CO2 in the presumed absence of any volitional contribution to ventilation. A similar degree of facilitation was seen with voluntary ventilation of similar magnitude and pattern. 5. If the facilitation is predominantly a cortical phenomenon, then these results imply that there is a behavioural component in the previously supposed purely 'reflex' drive to ventilation with inhaled CO2. We also discuss the interpretation of these results if some of the facilitation occurs at the phrenic motoneurone.


sesC as a genetic marker for easy identification of Staphylococcus epidermidis from other isolates.
Staphylococcus epidermidis is one of the major concerns with respect to hospital-acquired infections. Therefore, a rapid and easy method to identify at species level S. epidermidis isolates out of a broad range of bacteria is necessary. Based on earlier studies, the sesC gene encoding a S. epidermidis surface protein revealed to be a highly conserved gene in this species. By means of an easy and inexpensive PCR assay, the presence of sesC was checked in 438 clinical staphylococcal isolates. Results showed that sesC is specifically present in all S. epidermidis. In conclusion, the sesC gene can be exploited as a genetic marker in order to distinguish S. epidermidis from other isolates.


Effect of fore-aft seat position on shoulder demands during wheelchair propulsion: part 1. A kinetic analysis.
The highly repetitive and weight-bearing nature of wheelchair (WC) propulsion has been associated with shoulder pain among persons with spinal cord injury (SCI). Manipulation of WC seat position is believed to reduce the overall demand of WC propulsion. The objective of this investigation was to document the effect of fore-aft seat position on shoulder joint kinetics. Thirteen men with complete motor paraplegia propelled a test WC in 2 fore-aft seat positions during free, fast, and graded conditions. The seat-anterior position aligned the glenohumeral joint with the wheel axle and the seat-posterior position moved the glenohumeral joint 8 cm posteriorly. The right wheel of the test chair was instrumented to measure forces applied to the pushrim. An inverse dynamics algorithm was applied to calculate shoulder joint forces, external moments, and powers. For all test conditions, the superior component of the shoulder joint resultant force was significantly lower in the seat-posterior position. During graded propulsion, the posterior component of the shoulder joint force was significantly higher with the seat posterior. Peak shoulder joint moments and power were similar during free and fast propulsion. During graded propulsion, the seat-posterior position displayed increased internal rotation moment, decreased sagittal plane power absorption, and increased transverse plane power generation. This investigation provides objective support that a posterior seat position reduces the superior component of the shoulder joint resultant force. Consequently, this intervention potentially diminishes the risk for impingement of subacromial structures.


Effective dietary intervention in hypertensives: sodium restriction and weight reduction.
A Dietary Intervention Study of Hypertension (DISH) was undertaken to determine whether patients whose high blood pressure had been controlled pharmacologically for a period of more than 5 years could maintain that control with sodium restriction or weight reduction instead of drugs. Four hundred ninety-six patients, classified by degree of overweight, were randomly assigned into one of seven groups. Included were those who would be withdrawn from antihypertensive medication and receive intervention for either sodium restriction or weight reduction. After 8 weeks of intervention, an average reduction of 24-hour urinary sodium output from a baseline of 158 mEq to 106 mEq (p less than .001) and from 130 mEq to 96 mEq (p less than .01) was achieved for the overweight and nonoverweight groups, respectively. That decline was still maintained at 56 weeks. Dietary estimates, obtained by analysis of 3-day food records, underestimated urinary output by an average of 12%, with blacks more likely to underestimate than whites, and the overweight more likely to underestimate than the nonoverweight. An average 10-lb weight loss was achieved, with no difference between men and women. Weight declined for 32 weeks, then leveled off and was maintained up to 56 weeks, indicating that sodium intake modification can be accomplished faster than weight reduction. Modest sodium restriction and weight reduction are feasible and achievable in a free-living population and have a positive effect on control of hypertension.


Gastric and esophageal pH in patients with Barrett's esophagus treated with three esomeprazole dosages: a randomized, double-blind, crossover trial.
It has been suggested that patients with Barrett's esophagus (BE) are unusually resistant to the antisecretory effects of proton pump inhibitors (PPIs). To compare intragastric and intraesophageal acidity in patients with BE receiving esomeprazole 40 mg three times daily (t.i.d.), esomeprazole 40 mg twice daily (b.i.d.), and esomeprazole 20 mg t.i.d. In this randomized, double-blind, three-way crossover study, patients with long-segment BE received each of the three esomeprazole dosages for 5 days separated by 10-14-day washout periods. Intragastric and intraesophageal pHs were measured for 24 h on day 5. Among 31 patients with evaluable pH data, intragastric pH was >4.0 for 88.4%, 81.4%, and 80.4% of day 5 after treatment with esomeprazole 40 mg t.i.d., 40 mg b.i.d., and 20 mg t.i.d., respectively. Esomeprazole 40 mg t.i.d. was significantly more effective than the other dosages (p < 0.01). Intraesophageal pH was <4.0 for mean values of <5% of the monitoring period with all the three dosing regimens, but esophageal pH remained <4.0 for >5% of the time in 16%, 23%, and 19% of patients receiving esomeprazole 40 mg t.i.d., 40 mg b.i.d., and 20 mg t.i.d., respectively. All dosages were well tolerated. All the three esomeprazole dosages significantly decreased intragastric acidity and reduced esophageal acid exposure to mean normal values in the total group of patients with BE. However, abnormal esophageal acid exposure continued in 16-23% of patients despite the significant decrease in gastric acidity. These results suggest that the apparent "PPI resistance" described in patients with BE may be caused by their profound reflux diathesis rather than by gastric resistance to the antisecretory effects of PPIs.


Evaluating precursor-directed biosynthesis towards novel erythromycins through in vitro studies on a bimodular polyketide synthase.
Modular polyketide synthases (PKSs) catalyse the biosynthesis of complex polyketides using a different set of enzymes for each successive cycle of chain extension. Directed biosynthesis starting from synthetic diketides is a potentially valuable route to novel polyketides. We have used a purified bimodular derivative of the erythromycin-producing polyketide synthase (DEBS 1-TE) to study chain extension starting from a variety of diketide analogues and, in some cases, from the alternative acyl-CoA thioester substrates. Chain initiation in vitro by DEBS 1-TE module 2 using a synthetic diketide analogue as a substrate was tolerant of significant structural variation in the starter unit of the synthetic diketide, but other changes completely abolished activity. Interestingly, a racemic beta-keto diketide was found to be reduced in situ on the PKS and utilised in place of its more complex hydroxy analogue as a substrate for chain extension. The presence of a diketide analogue strongly inhibited chain initiation via the loading module. Significantly higher concentrations of diketide N-acetylcysteamine analogues than their corresponding acyl-CoA thioesters are required to achieve comparable yields of triketide lactones. Although a broad range of variation in the starter residue is acceptable, the substrate specificity of module 2 of a typical modular PKS in vitro is relatively intolerant of changes at C-2 and C-3. This will restrict the usefulness of approaches to synthesise novel erythromycins using synthetic diketides in vivo. The use of synthetic beta-keto diketides in vivo deserves to be explored.


Systemic delivery of siRNA to the colon using peptide modified PEG-PCL polymer micelles for the treatment of ulcerative colitis.
Ulcerative colitis (UC) is a refractory inflammatory bowel disease that causes inflammation and ulcers in the digestive tract, and significantly reduces the patient's quality of life. While existing UC treatments have many challenges, nanotechnology, and small interfering RNA (siRNA) based formulations are novel and promising for UC treatment. We previously reported that intravenous administration of MPEG-PCL-CH2R4H2C nanomicelles had high inflammatory site accumulation and remarkable therapeutic effects on rheumatoid arthritis by a phenomenon similar to enhanced permeability and retention effect. In this study, we investigated the effects of siRNA delivered using MPEG-PCL-CH2R4H2C nanomicelles through intravenous administration to the inflammation site of dextran sulfate sodium-induced colitis mice. The MPEG-PCL-CH2R4H2C micelles had optimum physical properties and high siRNA compaction ability. Moreover, model-siRNA delivered through MPEG-PCL-CH2R4H2C showed higher accumulation in the inflammatory site than that of the naked siRNA. Furthermore, intravenous administration of MPEG-PCL-CH2R4H2C/siRelA micelles, targeting siRelA, a subunit of NF-κB, significantly decreased the shortening of large intestine, clinical score, and production of inflammatory cytokines compared the 5-ASA and naked siRelA. These results suggest that MPEG-PCL-CH2R4H2C is a useful carrier for the systemic delivery and accumulation of siRNA, thus improving its therapeutic effect.


[Subcutaneous rupture of the Achilles tendon (a review of 42 cases treated by tenoplasty with fascia lata)].
The authors relate their experience in the treatment of subcutaneous disruption of the Achilles tendon with tenorraphy and neutering tenoplasty by quadriceps muscular aponeurosis. The results obtained in 33 patients confirm the effectiveness of this method.


Excessive sinus pauses and their elimination in a patient with sleep apnea syndrome.
A 40-year-old man with severe sleep apnoea syndrome presented significant sinus pauses during a 48 h electrocardiogram Holter recording. Holter analysis showed one sinus pause of 6.4 s duration, and many pauses greater than 3 s. The 48 h Holter reevaluation, after a continuous positive air pressure device was applied, showed no pauses. The electrophysiological study was negative for sick sinus syndrome.


Regio- and stereoselective cleavage of steroidal 22-oxo-23-spiroketals catalyzed by BF3·Et2O.
The regioselective opening of the F ring of 22-oxo-23-spiroketals using BF3·OEt2 in acetic anhydride yielded novel cholestanic frameworks with pyranone E ring 20-23. The structures of the new derivatives of botogenin, diosgenin, hecogenin and tigogenin thus obtained were established using one and two dimensional (1)H, (13)C experiments (DEPT, COSY, HETCOR, HMBC). The X-ray diffraction analysis unequivocally confirmed the R configuration at C-23 in the starting 22-oxo-23-spiroketal 18 and the Z configuration of the C23-C24 double bond in the reaction product 20.


Serotype-specific outbreak of group B meningococcal disease in Iquique, Chile.
From 1979 to August 1987, there have been 178 cases of meningococcal disease in Iquique, Chile, a city of about 140,000. The attack rate for the last 5 years has been in excess of 20/100,000 per year, more than 20 times greater than for the country overall. The mortality rate was 6%. The disease occurred in patients with ages from 4 months to 60 years, but 89% of cases were in patients less than 21 years. The largest number of cases were in the age group 5-9 years (n = 54), but the highest incidence occurred in children less than 1 year of age (72.8/100,000 per year). The male/female ratio was 1.2. Cases occurred all year round with little seasonal variation. Of the 178 cases, 173 were biologically confirmed. Serogroup analysis of strains from 135 patients revealed A = 1, B = 124, C = 10. Forty-four group B strains from 1985-7 were serotyped: 15:P1.3 = 36, 15:NT = 4, 4:P1.3 = 2, NT:NT = 2. Ten of 11 of the outbreak strains tested were sulfadiazine-resistant. This is the first recognized outbreak caused by a Gp B:15 strain in South America. It shares many of the characteristics of outbreaks caused by closely related strains in Europe, such as a predilection for older children and adolescents, sulfadiazine-resistance, and sustained high attack rates. The Iquique strain (B:15:P1.3) belongs to the same genetic clone (ET-5 complex) as the Norway (B:15:P1.16) and the Cuban (B:4:P1.15) strains.


Changes in brain functional networks in remitted major depressive disorder: a six-month follow-up study.
Patients with remitted major depressive disorder (rMDD) show abnormal functional connectivity of the central executive network (CEN), salience networks (SN) and default mode network (DMN). It is unclear how these change during remission, or whether changes are related to function. Three spatial networks in 17 patients with rMDD were compared between baseline and the six-month follow-up, and to 22 healthy controls. Correlations between these changes and psychosocial functioning were also assessed. In the CEN, patients at baseline had abnormal functional connectivity in the right anterior cingulate, right dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL) compare with HCs. There were functional connection differences in the right DLPFC and left IPL at baseline during follow-up. Abnormal connectivity in the right DLPFC and medial prefrontal cortex (mPFC) were found at follow-up. In the SN, patients at baseline had abnormal functional connectivity in the insula, left anterior cingulate, left IPL, and right precuneus; compared with baseline, patients had higher connectivity in the right DLPFC at follow-up. In the DMN, patients at baseline had abnormal functional connectivity in the right mPFC. Resting-state functional connectivity of the IPL and DLPFC in the CEN correlated with psychosocial functioning. At six-month follow-up, the CEN still showed abnormal functional connectivity in those with rMDD, while anomalies in the SN and DMN has disappeared. Resting-state functional connectivity of the CEN during early rMDD is associated with psychosocial function. Pharmacotherapy and Psychotherapy for MDD after Remission on Psychology and Neuroimaging. https://www. gov/ , registration number: NCT01831440 (15/4/2013).


A Systematic Review of the State of Economic Evaluation for Health Care in India.
Economic evaluations are one of the important tools in policy making for rational allocation of resources. Given the very low public investment in the health sector in India, it is critical that resources are used wisely on interventions proven to yield best results. Hence, we undertook this study to assess the extent and quality of evidence for economic evaluation of health-care interventions and programmes in India. A comprehensive search was conducted to search for published full economic evaluations pertaining to India and addressing a health-related intervention or programme. PubMed, Scopus, Embase, ScienceDirect, and York CRD database and websites of important research agencies were identified to search for economic evaluations published from January 1980 to the middle of November 2014. Two researchers independently assessed the quality of the studies based on Drummond and modelling checklist. Out of a total of 5013 articles enlisted after literature search, a total of 104 met the inclusion criteria for this systematic review. The majority of these papers were cost-effectiveness studies (64%), led by a clinician or public-health professional (77%), using decision analysis-based methods (59%), published in an international journal (80%) and addressing communicable diseases (58%). In addition, 42% were funded by an international funding agency or UN/bilateral aid agency, and 30% focussed on pharmaceuticals. The average quality score of these full economic evaluations was 65.1%. The major limitation was the inability to address uncertainties involved in modelling as only about one-third of the studies assessed modelling structural uncertainties (33%), or ran sub-group analyses to account for heterogeneity (36.5%) or analysed methodological uncertainty (32%). The existing literature on economic evaluations in India is inadequate to feed into sound policy making. There is an urgent need to generate awareness within the government of how economic evaluation can inform and benefit policy making, and at the same time build capacity of health-care professionals in understanding the economic principles of health-care delivery system.


Neuritic growth impairment and cell death by unconjugated bilirubin is mediated by NO and glutamate, modulated by microglia, and prevented by glycoursodeoxycholic acid and interleukin-10.
Neuronal oxidative damage and cell death by unconjugated bilirubin (UCB) showed to be mediated by overstimulation of glutamate receptors and nitric oxide (NO) production, which was abrogated by the bile acid glycoursodeoxycholic acid (GUDCA). Microglia, a crucial mediator of CNS inflammation, evidenced to react to UCB by releasing glutamate and NO before becoming senescent. Our studies demonstrated that neurite outgrowth deficits are produced in neurons exposed to UCB and that conditioned media from these UCB-treated neurons further stimulate NO production by microglia. Nevertheless, microglia protective and/or harmful effects in neonatal jaundice are poorly understood, or unrecognized. Here, we investigated the role of microglia, glutamate and NO in the impairment of neurite sprouting by UCB. Therapeutic potential of the anti-inflammatory cytokine interleukin (IL)-10 and GUDCA was also evaluated. By using MK-801 (a NMDA glutamate-subtype receptor antagonist) and L-NAME (a non-specific NO synthase inhibitor) we found that glutamate and NO are determinants in the early and enduring deficits in neurite extension and ramification induced by UCB. Both GUDCA and IL-10 prevented these effects and decreased the production of glutamate and NO. Only GUDCA was able to counteract neuronal death and synaptic changes. Data from organotypic-cultured hippocampal slices, depleted or non-depleted in microglia, supported that microglia participate in glutamate homeostasis and contribute to NO production and cell demise, which were again abrogated by GUDCA. Collectively our data suggest that microglia is a key player in UCB-induced neurotoxicity and that GUDCA might be a valuable preventive therapy in neonates at risk of UCB encephalopathy.


Far Lateral/Extraforaminal Approaches for Microdiscectomy and Foraminal Decompression in the Lumbar Spine.
Far lateral approaches to the lumbar spine are uncommon procedures but are essential techniques for spine surgeons to understand and master for the treatment of extraforaminal disk herniations and foraminal stenosis. We present our preferred approaches for open and minimally invasive techniques to perform extraforaminal decompressions and/or discectomies in the lumbar spine.


The impact of surgical guide design and bone quality on heat generation during pilot implant site preparation: an in vitro study.
Surgical guides restrict the flow of cooling agent to osteotomy site, which will lead to a temperature rise that provokes tissue injury. Few studies compared differences in the temperature changes between non-limiting 'conventional' and limiting 'guided' surgical guides during implant site preparation. The objective of this study was to investigate the difference in temperature changes during bone drilling for implant placement using non-limiting and limiting surgical guides at cortical and cancellous bone levels. Forty-four bovine rib samples were used for implant bed preparation in this study with a minimum thickness of 11 mm was chosen for the ribs. The bone was stored in a freezer at 10 °C until it was used. On the day of the study, the bone was defrosted and soaked in water at 21 °C for three hours before embarking on drilling to make sure each sample was at the same temperature when tested. Forty-four bone specimens were prepared and randomly allocated to receive either a limiting or a non-limiting surgical guides (22 for each group). The osteotomy site was prepared by one operator following the manufacturer's instructions, using limiting and non-limiting surgical guides. Temperature changes were recorded during implant bed preparation using thermocouples that fit into 7 mm-horizontal channels at two different depths (Coronally) and (Apically) at 1 mm distance from the osteotomy site. The data were tested for homogeneity of variances using Levene's test, then data were analyzed using an Independent sample t-test and the significance level was set at P ≤ 0.05. The mean temperature rise for all samples was 0.55 °C. The mean temperature rises for the limiting and non-limiting surgical guides were 0.80 °C and 0.33 °C respectively. There was a statistically significant difference in temperature rise between the limiting and non-limiting surgical guides (P = 0.008). In relation to position of temperature recording (coronal vs. apical), there was no significant difference (P > 0.05). No significant difference was noted between the two groups at cancellous bone level (P = 0.68), but the difference was significant at cortical bone level (P = 0.036). Limiting surgical guides showed higher readings than non-limiting. However, for both techniques, temperature rise was not significant clinically and within a safe range.


Expression of two different isoforms of fasciclin II during postembryonic central nervous system remodeling in Manduca sexta.
Insect metamorphosis serves as a useful model to investigate postembryonic development in the central nervous system, because the transformation between larval and adult life is accompanied by a remodeling of neural circuitry. Most changes are controlled by ecdysteroids, but activity-dependent mechanisms and cell surface signals also play a role. This immunocytochemical study investigates the expression patterns of two isoforms of the neural cell adhesion molecule, fasciclin II (FasII), during postembryonic ventral nerve cord remodeling in the moth, Manduca sexta. Both the expression of the glycosyl-phosphatidylinositol (GPI)-linked isoform and the transmembrane isoform of Manduca FasII (TM-MFasII) are regulated in a stereotyped spatio-temporal pattern. TM-MFasII is expressed in a stage-specific manner in a subset of neurons. Subsets of central axons express high levels during outgrowth supporting a functional role for TM-FasII during pathfinding. Dendritic localization is not found at any stage of metamorphosis, suggesting no homophilic interactions of TM-MFasII during central synapse development. GPI-MFasII is expressed in a stage-specific manner, most likely only in glial cells. The larval and adult stages show almost no GPI-MFasII expression, whereas during pupal life, positive GPI-MFasII labeling is present around synaptotagmin-negative tracts or commissures, so that either homophilic stabilization of glial boundaries or heterophilic neuron-glial interactions possibly stabilize the axons within their tracts. GPI-MFasII expression is not co-localized with synaptotagmin-positive central terminals, rendering a role for synapse development unlikely. Neither isoform is expressed in all neurons of a specific class at any developmental stage, indicating that MFasII functions are restricted to specific subsets of neurons or to individual neurons.


DNA damage induced by reduced nitroimidazole drugs.
Five nitroimidazole drugs were reduced electrolytically and by gamma-radiolysis at fast (300 mumoles or 100% per hr) and slow (3-9 mumoles or 1-3% per hr) reduction rates in the presence of Escherichia coli DNA and single stranded or double stranded DNA from the bacteriophage phi X174. The degree of DNA damage depends upon the rate of drug reduction, where slow reduction produces more damage than fast reduction. The efficiency of damage produced is in the order metronidazole greater than ornidazole greater than azomycin greater than misonidazole greater than benznidazole which reveals a linear correlation between the one-electron reduction potential (E17) and the negative logarithm of the concentration of reduced drug at which 37% of the original DNA activity remains. Damage is not influenced by the presence of O2 at least between about 1-100 ppm. We suggest the protonated one-electron nitro radical anion as a possible candidate for the active damaging species and explain the basis of the relative cytotoxicity of these drugs under conditions of hypoxia.


Transferring intercellular signals and traits between cancer cells: extracellular vesicles as "homing pigeons".
Extracellular vesicles are cell-derived vesicles, which can transport various cargos out of cells. From their cell of origin, the content molecules (proteins, non-coding RNAs including miRNAs, DNA and others) can be delivered to neighboring or distant cells and as such extracellular vesicles can be regarded as vehicles of intercellular communication or "homing pigeons". Extracellular vesicle shuttling is able to actively modulate the tumor microenvironment and can partake in tumor dissemination. In various diseases, including cancer, levels of extracellular vesicle secretion are altered resulting in different amounts and/or profiles of detectable vesicular cargo molecules and these distinct content profiles are currently being evaluated as biomarkers. Apart from their potential as blood-derived containers of specific biomarkers, the transfer of extracellular vesicles to surrounding cells also appears to be involved in the propagation of phenotypic traits. These interesting properties have put extracellular vesicles into the focus of many recent studies.Here we review findings on the involvement of extracellular vesicles in transferring traits of cancer cells to their surroundings and briefly discuss new data on oncosomes, a larger type of vesicle. A pressing issue in cancer treatment is rapidly evolving resistance to many initially efficient drug therapies. Studies investigating the role of extracellular vesicles in this phenomenon together with a summary of the technical challenges that this field is still facing, are also presented. Finally, emerging areas of research such as the analysis of the lipid composition on extracellular vesicles and cutting-edge techniques to visualise the trafficking of extracellular vesicles are discussed.


Prevalence, incidence, and remission rates of urinary incontinence in women attended in gynecological practice.
To assess the prevalence of urinary incontinence (UI) in a cohort of women attended in primary care gynecological and estimate the incidence and remission rates of UI symptoms at 1 year. We performed a multicenter prospective cohort study of women attending eight primary care gynecological practices. Consecutive women attended for gynecological issues different from UI were invited to participate in the study by answering the International Consultation on Incontinence questionnaire-Short Form (ICIQ-UI-SF). Patients receiving treatment for UI, during pregnant, and postpartum were excluded. All women with UI symptoms (ICIQ-UI-SF > 0) wishing treatment were studied and treated following routine clinical practice. All women were invited to answer the same questionnaire by phone 1 year after inclusion. A total of 2,840 women answered the questionnaire; 1,188 (41.8%) had UI symptoms (ICIQ-UI-SF > 0). Accordingly, nearly half (44.9%) had mild UI symptoms. Treatment was requested by only 551/1,188 incontinent women (46.38%), being related to the severity of UI. At 1 year, 2,443 patients/2,840 (86.0%) were found and again responded to the ICIQ-UI-SF. At 1 year the incidence of UI was 5.3% (77 new cases of UI out of 1,652 with the initial ICIQ-UI-SF = 0) while the remission rate of UI among untreated women was 27.9% (144 with ICIQ-UI-SF = 0). Almost one half of women attended in primary care general gynecology practices have UI symptoms, with less than 50% requesting treatment. In these women, UI is a dynamic process with an incidence of 5.3% and a remission rate of 27.9% at 1 year. Neurourol. Urodynam. 36:1081-1085, 2017. © 2016 Wiley Periodicals, Inc.


Incidence patterns of childhood non-Wilms renal tumors: Comparing data of the Nationwide Registry of Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST), Greece, and the Surveillance, Epidemiology, and End Results Program (SEER), USA.
We used, for the first time, data registered in the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST)-Greece to estimate incidence/time trends of the rare childhood (0-14 years) non-Wilms tumors (non-WT), and compared the results of malignant non-WT to those from the Surveillance, Epidemiology, and End Results Program (SEER)-USA. Fifty-five cases (n = 33 malignant-only) were extracted from NARECHEM-ST (2001-2020) and 332 malignant cases from SEER (1990-2017). To allow between-country comparisons, age-standardized incidence rates (AIR) of malignant-only non-WT were calculated, and temporal trends were evaluated using Poisson and joinpoint regressions. In NARECHEM-ST, malignant and non-malignant non-WT accounted for 22.6% of all renal tumors. Among malignant tumors, the AIR was 1.0/106 children in Greece, similar to that calculated for SEER, USA (AIR=0.9/106). The proportion of infant malignant and non-malignant non-WT was 27% (20% before 6 months) in NARECHEM-ST. Most common non-WT in Greece were congenital mesoblastic nephromas (CMN) diagnosed mainly in infancy (CIR=7.2/106). The proportion of infant malignant non-WT was 20% in SEER (AIRinfancy=2.5/106), mainly attributed to rhabdoid tumors (CIR=1.6/106). The male-to-female (M:F) ratio of malignant non-WT was 0.9 in NARECHEM-ST vs. 1.2 in SEER, whereas boys outnumbered girls with clear cell sarcoma in NARECHEM-ST (M:F=4.0). Lastly, significantly increasing trends in incidence rates were noted in NARECHEM-ST [+ 6.8%, 95% confidence intervals (CI): 0.5, 13.3] and in SEER (+7.3%, 95%CI: 5.6, 9.0). Observed incidence, time trends and sociodemographic variations of non-WT may reflect differential registration practices and healthcare delivery patterns including differences regarding surveillance, coding and treatment practices.


DUB3/KLF4 combats tumor growth and chemoresistance in hepatocellular carcinoma.
This study aimed to investigate the role of deubiquitinating enzyme 3 (DUB3) in the regulation of Krüppel-like factor 4 (KLF4) expression in hepatocellular carcinoma (HCC). Gain- and loss-of-function assay, luciferase reporter assay, co-immunoprecipitation, and intracellular and extracellular deubiquitination assays were conducted in vitro. A tumor xenograft mouse model was established. The expression of DUB3 and KLF4 was examined in HCC patient specimens. The results showed that DUB3 upregulated KLF4 expression by deubiquitinating and stabilizing KLF4 protein in HCC cells through binding with KLF4. DUB3 inhibited HCC cell proliferation in vitro and tumor growth in vivo while enhancing the chemosensitivity of HCC cells in a KLF4-dependent manner. Furthermore, KLF4 promoted DUB3 transcription by binding to the DUB3 promoter. In HCC patients, DUB3 expression positively correlated with KLF4 expression in HCC tissues. Low DUB3 expression predicted worse overall survival and recurrence in HCC patients. In conclusion, this study revealed a positive DUB3/KLF4 feedback loop that inhibits tumor growth and chemoresistance in HCC. These results suggest that DUB3/KLF4 activation might be a potential therapeutic approach for HCC treatment.


WOX-ARF modules initiate different types of roots.
Seed plants have evolved a complex root system consisting of at least three root types, i.e., adventitious roots, lateral roots, and the primary root. Auxin is the key hormone that controls the initiation of different root types. Here, we show that protein complexes with different combinations of intermediate-clade WUSCHEL-RELATED HOMEOBOXs (IC-WOXs) and class-A AUXIN RESPONSE FACTORs (A-ARFs) initiate the three root types in Arabidopsis thaliana. In adventitious root founder cells from detached leaves, the WOX11-ARF6/8 complex activates RGF1 INSENSITIVEs (RGIs) and LATERAL ORGAN BOUNDARIES DOMAIN 16 (LBD16) to initiate the adventitious root primordium. In lateral root founder cells, ARF7/19 activate RGIs and LBD16 without IC-WOX to initiate the lateral root primordium. In the primary root founder cell (i.e., hypophysis of an embryo), the WOX9-ARF5 complex initiates the primary root by activation of RGIs. Overall, the WOX-ARF modules show a division of labor to initiate different type of roots.


Histamine mediates myocardial damage by an H1 mechanism independent of coronary blood flow.
Administration of histamine to rabbits may result in myocardial damage similar to that produced by catecholamines and the anthracycline antibiotics. To explore the mechanisms involved in histamine-mediated myocardial damage, conscious New Zealand white rabbits were pretreated with H1 and H2 receptor blocking agents, alone and in combination, and then administered histamine. Coronary artery blood flow was measured with radiolabeled microspheres in rabbits that received histamine alone, and in those that received an H1 blocking agent and histamine. Rabbits that received an H1 blocking agent had a significant reduction in morphological injury which was scored as follows: grade 1, minimal or no injury; grade 2, moderate; and grade 3, severe injury (mean pathology score = 1.1 +/- 0.28 for histamine alone vs. 0.06 +/- 0.06 with H1 receptor blockade, p less than 0.05). Animals pretreated with H2 receptor blockade (mean pathology score = 1.2 +/- 0.49) were not protected against morphological injury. Coronary blood flow decreased in animals that received histamine alone: control = 2.61 +/- 0.38 vs. 1.80 +/- 0.30 ml/min/g (p less than 0.05), and in animals pretreated with H1 blockade; control = 3.29 +/- 0.34 vs. 1.91 +/- 0.28 ml/min/g (p less than 0.01). We conclude that histamine-mediated myocardial damage appears to be mediated by the H1 receptor system and that this appears to be independent of initial changes in global coronary blood flow.


Tumor microenvironment metabolites directing T cell differentiation and function.
Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions.